Familial Cancer

Psychosocial barriers and facilitators for cascade genetic testing in hereditary breast and ovarian cancer: a scoping review

Despite increased awareness and availability of genetic testing for hereditary breast and ovarian cancer (HBOC) syndrome for over 20 years, there is still significant underuse of cascade genetic testing among at-risk relatives. This scoping review synthesized evidence regarding psychosocial barriers and facilitators of family communication and/or uptake of cascade genetic testing in relatives from HBOC families. Search terms included 'hereditary breast and ovarian cancer' and 'cascade genetic testing' for studies published from 2012-2022. Through searching common databases, and manual search of references, 480 studies were identified after excluding duplications. Each article was reviewed by two researchers independently and 20 studies were included in the final analysis. CASP, RoBANS 2.0, RoB 2.0, and MMAT were used to assess the quality of included studies. A convergent data synthesis method was used to integrate evidence from quantitative and narrative data into categories and subcategories. Evidence points to 3 categories and 12 subcategories of psychosocial barriers and facilitators for cascade testing: (1) facilitators (belief in health protection and prevention; family closeness; decisional empowerment; family support, sense of responsibility; self-efficacy; supportive health professionals); (2) bidirectional concepts (information; perception of genetic/cancer consequences; negative emotions and attitude); and (3) barriers (negative reactions from family and negative family dynamics). Healthcare providers need to systematically evaluate these psychosocial factors, strengthen facilitators and alleviate barriers to promote informed decision-making for communication of genetic test results and uptake of genetic testing. Bidirectional factors merit special consideration and tailored approaches, as they can potentially have a positive or negative influence on family communication and uptake of genetic testing.

Cascade genetic testing: an underutilized pathway to equitable cancer care?

The Precision Medicine Initiative was launched upon the potential of genomic information to tailor medical care. Cascade genetic testing represents a powerful application of precision medicine and involves the process of familial diffusion or the "cascade" of genomic risk information. When an individual (proband) is found to carry a cancer-associated germline pathogenic mutation, the information should be cascaded or shared with at-risk relatives. First degree relatives have a 50% likelihood of carrying the same cancer-associated mutation. This process of cascade testing offers at-risk relatives the opportunity for genetic testing and, for those who also carry the cancer-associated mutation, genetically targeted primary disease prevention through intensive cancer surveillance, chemoprevention and risk-reducing surgery, reducing morbidity and preventing mortality. Cascade testing has been designated by the Centers for Disease Control and Prevention as a Tier 1 genomic application for hereditary breast and ovarian cancer. In this manuscript we describe a cascade genetic testing and in particular focus on its potential to provide necessary care to medically underserved and vulnerable populations.

Reclassification of two germline DICER1 splicing variants leads to DICER1 syndrome diagnosis

AbstractDICER1 syndrome is an inherited condition associated with an increased risk of developing hamartomatous and neoplastic lesions in diverse organs, mainly at early ages. Germline pathogenic variants in DICER1 cause this condition. Detecting a variant of uncertain significance in DICER1 or finding uncommon phenotypes complicate the diagnosis and can negatively impact patient care. We present two unrelated patients suspected to have DICER1 syndrome. Both females (aged 13 and 15 years) presented with multinodular goiter (thyroid follicular nodular disease) and ovarian tumours. One was diagnosed with an ovarian Sertoli-Leydig cell tumour (SLCT) and the other, with an ovarian juvenile granulosa cell tumour, later reclassified as a retiform variant of SLCT. Genetic screening showed no germline pathogenic variants in DICER1. However, two potentially splicing variants were found, DICER1 c.5365-4A>G and c.5527+3A>G. Also, typical somatic DICER1 RNase IIIb hotspot mutations were detected in the thyroid and ovarian tissues. In silico splicing algorithms predicted altered splicing for both germline variants and skipping of exon 25 was confirmed by RNA assays for both variants. The reclassification of the ovarian tumour, leading to recognition of the association with DICER1 syndrome and the characterization of the germline intronic variants were all applied to recently described DICER1 variant classification rules. This ultimately resulted in confirmation of DICER1 syndrome in the two teenage girls.

Hematologic toxicities of chemotherapy in breast and ovarian cancer patients carrying BRCA1/BRCA2 germline pathogenic variants. A single center experience and review of the literature

AbstractBRCA1 and BRCA2 play a central role in DNA repair and their germline pathogenic variants (gBRCA) confer a high risk for developing breast and ovarian cancer. Standard chemotherapy regimens for these cancers include DNA-damaging agents. We hypothesized that gBRCA carriers might be at higher risk of developing chemotherapy-related hematologic toxicity and therapy-related myeloid neoplasms (t-MN). We conducted a retrospective study of women newly diagnosed with invasive breast or ovarian cancer who were screened for gBRCA1/gBRCA2 at Geneva University Hospitals. All patients were treated with (neo-)adjuvant chemotherapy. We evaluated acute hematologic toxicities by analyzing the occurrence of febrile neutropenia and severe neutropenia (grade 4) at day 7–14 of the first cycle of chemotherapy and G-CSF use during the entire chemotherapy regimen. Characteristics of t-MN were collected. We reviewed medical records from 447 patients: 58 gBRCA1 and 40 gBRCA2 carriers and 349 non-carriers. gBRCA1 carriers were at higher risk of developing severe neutropenia (32% vs. 14.5%, p = 0.007; OR = 3.3, 95% CI [1.6-7], p = 0.001) and of requiring G-CSF for secondary prophylaxis (58.3% vs. 38.2%, p = 0.011; OR = 2.5, 95% CI [1.4–4.8], p = 0.004). gBRCA2 carriers did not show increased acute hematologic toxicities. t-MN were observed in 2 patients (1 gBRCA1 and one non-carrier). Our results suggested an increased acute hematologic toxicity upon exposure to chemotherapy for breast and ovarian cancer among gBRCA1 but not gBRCA2 carriers. A deeper characterization of t-MN is warranted with the recent development of PARP inhibitors in frontline therapy in gBRCA breast and ovarian cancer.

High amount of fertility reducing tumors and procedures, but no evidence for premature ovarian failure in female Lynch syndrome patients

AbstractLynch syndrome (LS; HNPCC) patients carry heterozygous pathogenic germline variants in mismatch repair (MMR) genes, which have also been shown to play an important role in meiosis. Therefore, it was hypothesized, that LS might be associated with a higher risk for premature ovarian failure (POF) or earlier menopause. Data on medical gynaecological history, cancer diagnoses and therapy were collected from 167 female LS patients and compared to a population-based control cohort. There was no difference between the age of menopause in patients compared to controls and no evidence for a higher risk of POF in LS patients. However, around one third (35%) of the probands have already had premenopausal cancer and mostly cancer-related treatment affecting fertility before the age of 45 years. Therefore, childbearing time might still be limited in these patients, especially due to the premenopausal cancer risk. LS patients should be informed in time about the elevated premenopausal cancer risks and the possible impact on family planning. This is particularly relevant since the average childbearing age has increased during the last decades.

The germline POLD1 c.1420 C > A (p.Leu474Ile) variant segregates with endometrial cancer, colorectal cancer and colonic polyps demonstrating hypermutation and defective POLD1 mutational signatures

Germline pathogenic variants within the highly conserved exonuclease domain of the POLD1 gene predisposes to colorectal (CRC) and endometrial (EC) cancers. Tumours with POLD1-deficiency demonstrate unique genomic features including hypermutation and tumour mutational signatures (TMS) SBS10c, SBS10d and SBS20. The classification of variants within POLD1 remains challenging. The utility of incorporating tumour hypermutation status and TMS profiles into POLD1 gene-specific variant classification guidelines developed by ClinGen-InSiGHT remains to be established. We report a family with eight members heterozygous for the germline POLD1 c.1420C > A (p.Leu474Ile) variant. This variant resides within the exonuclease domain, is absent in gnomADv4.1 and is classified as a variant of uncertain clinical significance. Formalin-fixed paraffin embedded tissue and matched blood-derived DNA from person 001 (EC, 1 adenoma, 2 sessile serrated lesions), and two cousins, 009 (EC, 3 adenomas), and 010 (breast cancer, EC, CRC, 4 adenomas, 2 sessile serrated lesions and 1 traditional serrated adenoma) were tested using a custom multigene panel to determine tumour mutational burden (TMB) and TMS. All three ECs demonstrated characteristics of POLD1-deficiency namely hypermutated TMB and predominance of SBS10d. The CRC, 62.8% of the adenomas and 60% of the serrated polyps demonstrated SBS10c as the dominant TMS. EC, CRC, breast and multiple polyps from three family members heterozygous for the germline POLD1 c.1420C > A variant demonstrated hypermutation and SBS10c and SBS10d TMS, genomic features associated with defective POLD1. Somatic TMB and TMS profiling of multiple independent lesions demonstrated utility for identifying POLD1-deficiency suggesting this approach can support variant classification for POLD1.

Age at diagnosis of cancer in 185delAG BRCA1 mutation carriers of diverse ethnicities: tentative evidence for modifier factors

Germline pathogenic sequence variants (PSVs) in BRCA1 substantially increase risk for developing breast (BC) and ovarian cancer (OvC). Yet, incomplete penetrance suggests that modifier factors affect phenotypic expression of mutant BRCA1 alleles. Analysis of identical BRCA1 PSV carriers of diverse ethnicities may provide further evidence for modifier factors. Female carriers of the 185delAG BRCA1 PSV identified through high-risk clinics in Israel, and Manchester England from 1998-2018 were eligible. Data were retrieved from patients records and confirmed (in Israel) by cross referencing with the Israeli National Cancer Registry. Overall, 2503 female carriers were included: 1715 (71.4%) Ashkenazi Jews (AJ), 201 (8.3%) Iraqi Jews and 383 (15.9%) of mixed ethnicity. In 102 (4.2%) cases ethnicity could not be ascertained. Of Israeli AJ carriers 649 (37.8%), 256 (14.9%) and 62 (3.6%) were diagnosed with BC, OvC or both cancers, respectively. For the Iraqi Jews these frequencies were 76 (37.8%), 43 (21.4%), and 8 (3.98%), respectively. Age at diagnosis of BC in AJ and Iraqi Jews was 46.7 ± 12.3 years and 52.8 ± 12.2 years, respectively (p = 0.001). For OvC age at diagnosis for AJ was 53.5 ± 10.7 years and for Iraqi Jews 50.1 ± 8.8 years (p = 0.0027). No differences in these parameters were noted between English Jews (n = 110) and non-Jews (n = 32). Age at diagnosis of BC and OvC differs between AJ and Iraqi Jews who carry an identical BRCA1 PSV. This finding supports the existence of modifier factors that may be ethnic specific.

Patient reported experiences following laparoscopic prophylactic bilateral salpingo-oophorectomy or salpingectomy in an ambulatory care hospital

Women at risk of developing ovarian cancer because of a BRCA1 or BRCA2 pathogenic variant are candidates for prophylactic bilateral salpingo-oophorectomy (BSO). While BSO surgeries are routinely performed, to our knowledge there are no studies that have examined patient-reported experiences following laparoscopic BSO performed in an ambulatory care setting. The objective of this study was to examine whether women undergoing prophylactic laparoscopic BSO felt they were adequately informed about post-operative outcomes. A telephone interview was conducted among 46 women undergoing laparoscopic BSO to collect detailed information regarding surgical outcomes, complications, symptoms, and time to return to daily activities. The average age at surgery was 45.0 years (range 34-66) and 67% of women underwent BSO prior to age 50. The mean reported hospital stay was 7.2 h (range 4-12 h) and at time of discharge, 78% of the women felt well enough to go home. None of the women required a readmission to hospital. Forty-three percent (n = 20) of the women did not feel well informed about what to expect post-operatively. Most of the patient-reported outcomes (including pain, vaginal bleeding, and nausea/vomiting) were expected and patient-reported menopausal symptoms were more common among women who were premenopausal at surgery. In terms of returning to regular activities, premenopausal women (n = 36) resumed sexual activity on average at 43 days (range 2-365), which is later than postmenopausal women (n = 15) at 19 days (range 7-30). On average, women returned to full-time work in 16 days (range 1-56 days). Despite patients receiving pre-surgery counselling, our findings suggest that there is a need to provide supplemental, reinforcing patient materials in preparing patients for what to expect after surgery.

The response of pancreatic acinar cell carcinoma to platinum and olaparib therapy in a germline BRCA2 variant carrier: case report and literature review

The clinical features of polymerase proof-reading associated polyposis (PPAP) and recommendations for patient management

AbstractPathogenic germline exonuclease domain (ED) variants of POLE and POLD1 cause the Mendelian dominant condition polymerase proof-reading associated polyposis (PPAP). We aimed to describe the clinical features of all PPAP patients with probably pathogenic variants. We identified patients with a variants mapping to the EDs of POLE or POLD1 from cancer genetics clinics, a colorectal cancer (CRC) clinical trial, and systematic review of the literature. We used multiple evidence sources to separate ED variants into those with strong evidence of pathogenicity and those of uncertain importance. We performed quantitative analysis of the risk of CRC, colorectal adenomas, endometrial cancer or any cancer in the former group. 132 individuals carried a probably pathogenic ED variant (105 POLE, 27 POLD1). The earliest malignancy was colorectal cancer at 14. The most common tumour types were colorectal, followed by endometrial in POLD1 heterozygotes and duodenal in POLE heterozygotes. POLD1-mutant cases were at a significantly higher risk of endometrial cancer than POLE heterozygotes. Five individuals with a POLE pathogenic variant, but none with a POLD1 pathogenic variant, developed ovarian cancer. Nine patients with POLE pathogenic variants and one with a POLD1 pathogenic variant developed brain tumours. Our data provide important evidence for PPAP management. Colonoscopic surveillance is recommended from age 14 and upper-gastrointestinal surveillance from age 25. The management of other tumour risks remains uncertain, but surveillance should be considered. In the absence of strong genotype–phenotype associations, these recommendations should apply to all PPAP patients.

Beyond 1100delC: distinct CHEK2 variants and unique cancer phenotypes in Northeast Brazil

Monoallelic MUTYH pathogenic variants ascertained via multi-gene hereditary cancer panels are not associated with colorectal, endometrial, or breast cancer

We aimed to determine whether monoallelic MUTYH pathogenic and likely pathogenic variants (PVs) are associated with colorectal, breast, and endometrial cancer. Cases were individuals with colorectal, female breast, or endometrial cancer who reported European ancestry alone and underwent a multi-gene hereditary cancer panel at a large reference laboratory. Controls were individuals of European (non-Finnish) descent from GnomAD with cancer cohorts removed. We performed a Fisher's exact test to generate odds ratios (ORs) with 95% confidence intervals (CI). Prevalence of single MUTYH PVs in cancer cohorts versus controls, respectively, was: colorectal cancer, 2.1% vs. 1.8% (OR 1.2, 95% CI 0.99-1.5, p = 0.064); breast cancer 1.9% vs. 1.7% (OR 1.1, 95% CI 0.96-1.3, p = 0.15); and endometrial cancer, 1.7% vs. 1.7% (OR 0.98; 95% CI 0.70-1.3, p = 0.94). Using the largest colorectal and endometrial cancer cohorts and one of the largest breast cancer cohorts from a single case-control study, we did not observe a significant difference in the prevalence of monoallelic MUTYH PVs in these cohorts compared to controls. Additionally, frequencies among cancer cohorts were consistent with the published MUTYH carrier frequency of 1-2%. These findings suggest there is no association between colorectal, endometrial, or breast cancer and MUTYH heterozygosity in individuals of European ancestry.

5’UTR gene regions in germline DNA sequencing panels: lessons from the analysis of breast and ovarian cancer patients of Tatar and Bashkir ethnic origin

Tatars and Bashkirs are large and closely related ethnic communities that reside in the territory of the Russian Federation but have managed to preserve their national identity through the course of history. This study included 446 Tatars, 53 Bashkirs, and 26 women of mixed Tatar-Bashkir ethnicity. Germline DNA analysis was performed for 349 breast cancer (BC) patients with clinical features of hereditary disease (family history, or young onset ( T, was observed in 11 subjects. Among 27 women with BRCA2 PVs, six and five women were carriers of the c.-39-1_-39del and c.468dup variants, respectively. The loss-of-heterozygosity (LOH) test confirmed the pathogenic nature of the c.-39-1_-39del [rs758732038] allele, which is located in the 5'UTR of BRCA2. Analysis of other BC-associated genes revealed single instances of PVs affecting PALB2, TP53, ATM, RAD51, and RAD51D genes. Tatars and Bashkirs, which are ethnically and religiously separated from Russians, carry an unexpectedly high proportion of Slavic BRCA1/2 founder alleles. The identification of recurrent Tatar/Bashkir BRCA2 pathogenic 5'UTR variant c.-39-1_-39del calls for a systematic analysis of regulatory regions of cancer-predisposing genes in patients with missing heritability.

The patterns and spectrum of BRCA1 and BRCA2 mutations in Iranian breast and ovarian cancer patients

Women with inherited BRCA1/2 mutations are at increased risk of breast and ovarian cancer. The reports on the prevalence and spectrum of these mutations have been primarily focused on individuals with European ancestry. A previous study on Iranian breast cancer patients reported no BRCA1/2 mutation in early-onset breast cancer with no other criteria, which is contrary to other populations. The purpose of this study was to characterize the patterns of these mutations in Iranian breast and ovarian cancer patients and evaluate the predictive efficacy of the Manchester scoring system in patients and their unaffected family members. We retrospectively reviewed the genetic testing performed for breast and ovarian cancer patients and unaffected individuals with a positive family history. The study participants were selected based on the NCCN (National Comprehensive Cancer Network) criteria (version 2.2024). A total of 376 female breast cancer patients, 49 ovarian cancer patients, and 74 unaffected individuals were enrolled in this study. In breast cancer patients, 24 (6.4%) BRCA1 and 23 (6.1%) BRCA2 mutations were detected. In ovarian cancer patients, 9 (18.5%) BRCA1 and 1 (2%) BRCA2 mutations were identified. Three (4.1%) BRCA2 mutations were identified in unaffected individuals. Seven breast cancer patients with age of cancer diagnosis ≤ 40 and no other criteria (including family history) had an underlying mutation: Four BRCA2, and three BRCA1 mutations. The Manchester score performed well, with a sensitivity of 81% and a specificity of 70%. More research is needed to clarify the hereditary component of breast and ovarian cancer in Iranian patients.

Endometrial thickness among BRCA mutation carriers undergoing prophylactic oophorectomy

It has been suggested that women with a pathogenic variant (mutation) in BRCA1 or BRCA2 are at a higher risk of developing high-grade endometrial cancer. Furthermore, significantly higher follicular (but lower luteal) endometrial thickness, a surrogate marker for endometroid adenocarcinoma risk, has been reported for this high-risk population. Given that medications known to affect endometrial thickness (i.e., tamoxifen, oral contraceptives) are often indicated for BRCA mutation carriers, it is important to elucidate substantial differences exist in carriers. Thus, we conducted a retrospective chart review of endometrial thickness among women with a BRCA1 or BRCA2 who had an intact uterus and were referred to a specialized ovarian cancer clinic between 2007 and 2016. Clinical data was collected from chart review, while endometrial thickness (millimeters; mm) was abstracted from transvaginal ultrasound reports with endometrial dating and compared to published levels in the general population. In total, 114 women were identified, 73 of whom were premenopausal and 41 who were postmenopausal. Among premenopausal women, the median follicular endometrial thickness found was 7.00 mm (n = 40, range 3-13) compared to 6.8 mm (range 2.4-14) in non-carriers and the median luteal endometrial thickness was 10.85 mm (n = 30, range 5-18), compared to 9.6 mm (range 3.3-18.2) in non-carriers. Among postmenopausal women, the median menopausal endometrial thickness was 4.0 mm (n = 41, range 1-18) compared to 4.0 mm (range 1-25) in non-carrier controls. Although based on small numbers, we found no significant difference in the endometrial thickness of BRCA mutation carriers versus non-carriers.

Hereditary breast and ovarian cancer genetic testing in unselected patients: example of private supplementation of public healthcare service

In the Emilia-Romagna region (Northern Italy), the identification and management of women at familial/hereditary risk of breast and ovarian cancer is guided by a well-established regional protocol. Here we report the results of the experience of private supplementation of public healthcare service in offering the possibility to undergo BRCA1/2 testing and/or multigene panel testing (MGPT) within a well-defined pathway to women unfulfilling regional criteria. Out of 177 patients referred to our center who underwent BRCA1/2 testing, 175 tested negative while two (1.1%) resulted carriers of pathogenic variants in BRCA2; 69 patients also underwent MGPT, and in four cases (5.8%) a pathogenic variant were found (two in ATM and one in CHEK2 and RAD51C, respectively). Overall, this private supplementation of territorial public healthcare system has made it possible to confirm the validity of regional criteria for genetic testing access (concordance: 98.9%), but also to identify carriers of pathogenic variants of BRCA1/2 that would have escaped regional protocol, to support the effectiveness of MGPT for the identification of rare cases (not BRCA) at mild/high risk, and to provide reassurance to women who were found to be non-carriers of pathogenic variants, who may benefit from a more accurate assessment of their risk.

Prevalence of cardiometabolic outcomes in women who underwent salpingo-oophorectomy to prevent hereditary breast and ovarian cancer: a meta-analysis

Risk reduction salpingo-oophorectomy (RRSO) is usually performed in women with hereditary breast and ovarian cancer (HBOC) syndrome for BRCA1 and BRCA2 gene mutation carriers, resulting in surgical menopause, which is more associated with a high risk of cardiovascular and metabolic disease than in premenopausal and natural menopausal women. This study assessed the prevalence of cardiovascular and metabolic outcomes in women who underwent salpingo-oophorectomy as a preventive measure against HBOC. This meta-analysis assessed prevalence rates for four metabolic/cardiovascular conditions: myocardial infarction, hypertension, hypercholesterolemia, and type 2 diabetes mellitus. DerSimonian and Laird random-effects models were applied to all analyses, with 95% confidence interval (CI). Heterogeneity was assessed with I². We used OpenMeta Analyst software for statistical analysis. A total of five retrospective studies and one observational study involving 1,320 patients were included. The average body mass index (BMI) was 25.97 kg/m2 and the average waist circumference was 87.94 cm. The analysis across a mean 4.94-year follow-up revealed prevalence rates for acute myocardial infarction of 1.5% (95% CI 0.3-2.7; P = 0.077; I²=56.25%), hypertension of 28% (95% CI 6.9-49.1; P < 0.001; I

Identification of women at risk of hereditary breast–ovarian cancer among participants in a population-based breast cancer screening

Women attending mammography screening may benefit from family history (FH) assessment for the identification of Hereditary Breast Ovarian Cancer (HBOC). Few studies explored the efficacy of tailored educational interventions in driving the attention on FH-associated risk among these women. To compare the efficacy of two educational tools in increasing attention towards FH, 6.802 women with a negative mammography were randomized to receive a note on FH of breast/ovarian cancer (letter A, n = 3.402) or a note with details on possible implication of FH patterns (letter B, n = 3.200). Upon women's request, a brief questionnaire was administered on phone at the Screening Unit (S.U.) to select those eligible for an in-depth FH evaluation at the Genetic Unit (G.U.). Each affected relative was scored 1-3 according to type of cancer, age at diagnosis, gender, position in the family tree. In all, 401 women contacted the S.U.: 244 (6.6%) in group A and 177 (5.2%) in group B (adjOR 1.27; 95%CI 1.03-1.56). FH scored ≥ 3 for 164 women: 177 (47.5%) in group B and 224 (35.7%) in group A, (adjOR 1.59, 95%CI 1.06-2.38). The G.U. traced and interviewed 148 women, 65 (43.9%) were offered an in-person consultation: 38 attended and 30 were eligible for testing. A test was performed for 24 women: no BRCA pathogenic variant was found. Among mammographic screening attendees, educational material with a simple description of FH may improve self-referral of women deserving an in-depth evaluation for HBOC identification. Additional educational efforts are needed to enhance the efficiency of the intervention.

A recurrent pathogenic BRCA2 exon 5–11 duplication in the Christian Arab population in Israel

Germline pathogenic variants (PVs) in BRCA1/BRCA2 are well-established risk factors for breast cancer (BC) and/or ovarian cancer (OC). Founder PVs have been described in BRCA1/ BRCA2 in several genetic isolates. The Christian Arab population in the Middle East is a relatively isolated ethnic group, yet founder, or recurrent BRCA1/BRCA2 PVs have not been reported in this population. In this study we describe PVs detected in cancer susceptibility genes among a cohort of Christian Arabs from Israel. We reviewed patient records from the Oncogenetic clinic at Rambam Health Care Campus during the years 2013- mid 2020. Thirty-five unrelated Christian Arab patients, with personal or family history of BC and/or OC underwent BRCA1/BRCA2 (14/35) testing or cancer gene panel testing (21/35) as part of their diagnostic workup. Three clinically significant variants in BRCA2, CHEK2 and RAD51C were found in 7/35 patients (20%). A recurrent duplication of the BRCA2 genomic region, encompassing exons 5-10 and the 5' portion of exon 11, was found in 5/33 (15.2%) patients for whom copy number variants (CNVs) analysis was performed. We identified a recurrent pathogenic BRCA2 duplication in Christian Arab patients with a personal/ family history of BC and/or OC. Our findings emphasize the importance of inclusion of CNVs analysis in BRCA1/BRCA2 genetic testing, and specifically for Christian Arab patients suspected of hereditary BC and/or OC.

Pilot study of an online training program to increase genetic literacy and communication skills in oncology healthcare professionals discussing BRCA1/2 genetic testing with breast and ovarian cancer patients

The increasing use of genetic testing for BRCA1/2 and other pathogenic variants in the management of women with breast and ovarian cancer necessitates increased genetic literacy in oncology healthcare professionals. This pilot study aimed to evaluate an online training program to increase genetic literacy and communication skills in Australian oncology healthcare professionals tasked with discussing and coordinating mainstream genetic testing with breast and ovarian cancer patients. A training website with embedded videos was developed. This study assesses the website's acceptability and user-friendliness; suggestions for improvement were also elicited. Oncology healthcare professionals were recruited through relevant professional organisations, invited to the study by email, asked to work through the website and then complete an online questionnaire. Thirty-two oncology healthcare professionals completed the questionnaire after viewing the website. Nearly all participants were satisfied with the information contained in the program (very satisfied: n = 14/32, 44%, satisfied: n = 17/32, 53%, neither satisfied nor dissatisfied: n = 1/32, 3%) and reported that they had gained new skills (n = 29/32, 91%) and had increased confidence (n = 29/31, 94%) in communicating with breast and ovarian cancer patients about genetic testing. More than 93% (28/30) of participants endorsed the online program as clearly presented, informative, relevant and useful. This pilot study demonstrated high feasibility and acceptability of the training program to increase genetic literacy and communication skills in oncology healthcare professionals discussing genetic testing with breast and ovarian cancer patients. Further evidence from a randomised trial is needed to evaluate effects on changing clinical practice, improving patient outcomes, and cost-effectiveness.

A comprehensive reference for BRCA1/2 genes pathogenic variants in Iran: published, unpublished and novel

BRCA1 and BRCA2 are two prominent genes that account for about 20-40% of inherited breast cancer. Mutations in these genes are often associated with clustering of especially early-onset cancers in the family. The spectrum of BRCA variants showed a significant difference between geographic regions and ethnicities. The frequency and spectrum of BRCA mutations in Iran, a country in southwest Asia, have not yet been thoroughly studied. Here, for the first time, all published and not published BRCA pathogenic variants are presented. Among 1040 high risk families (1258 cases) which were detected, 116 families were found to carry pathogenic variants in either BRCA1 or BRCA2. Altogether 89 distinct types of pathogenic variants have been detected in Iran, including 41 in BRCA1 and 48 in BRCA2. 16 out of 89 mutations had not been previously reported in Iran and are presented for the first time in this article, among which 4 mutations are novel worldwide. 20% of families had one of the seven most commonly observed mutations, including c.81-1G > C, c.66_67delAG, c.4609C>T, c.1568delT, c.1961delA, in BRCA1 and: c.3751_3752insA, c.8585dupT in BRCA2. Combining the data from published articles and our study which has not been published before, a comprehensive table is created as a reference for entire BRCA pathogenic variants and their frequencies in Iran.

Knowledge and psychosocial impact of genetic counseling and multigene panel testing among individuals with ovarian cancer

In a sample of individuals with ovarian cancer, we aimed to (a) identify factors associated with the psychosocial impact of genetic counseling and multigene panel testing, (b) identify factors associated with cancer genetics knowledge, and (c) summarize patient-reported recommendations to improve the genetic counseling and multigene panel testing process. Eligible participants in this secondary analysis of quantitative and qualitative survey data were English-speaking adults with ovarian cancer. Psychosocial impact was assessed using the Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire. Knowledge of cancer genetics was assessed using the KnowGene scale. Significant predictors of MICRA and KnowGene scores were identified using multiple regression. Open-ended survey item responses were analyzed using conventional content analysis. Eighty-seven participants met eligibility criteria. A positive genetic test result was associated with greater adverse psychosocial impact (B = 1.13, p = 0.002). Older age (B = - 0.07, p = 0.044) and being a member of a minority racial or ethnic group (B = - 3.075, p = 0.033) were associated with lower knowledge, while a personal history of at least one other type of cancer (B = 1.975, p = 0.015) was associated with higher knowledge. In open-ended item responses, participants wanted clinicians to assist with family communication, improve result disclosure, and enhance patient and family understanding of results. A subset of individuals with ovarian cancer who receive a positive genetic test result may be at risk for adverse psychosocial outcomes. Tailored cancer genetics education is necessary to promote the equitable uptake of targeted ovarian cancer treatment and risk-reducing therapies. Interventions to enhance patient-clinician communication in this setting are a research priority.

Barriers to completion of cascade genetic testing: how can we improve the uptake of testing for hereditary breast and ovarian cancer syndrome?

Cascade testing for familial cancer syndromes has historically been difficult to execute. As part of a facilitated cascade testing pathway, we evaluated barriers to completion of cascade testing. Our previously published study evaluated a facilitated cascade testing pathway whereby a genetics team facilitated at-risk relative (ARR) cascade testing through telephone genetic counseling and mailed saliva kit testing. This follow-up study evaluated barriers to completion of cascade genetic testing through six-month follow-up telephone interviews. Probands identified 114 ARRs, of whom 97 were successfully contacted by telephone. Among those contacted, 83 (86%) reported interest in genetic testing and 14 (14%) declined. Among those reporting interest in testing, 71% (69/83) completed testing. Follow-up telephone interviews revealed that 14 ARRs did not complete testing despite reporting interest for the following reasons: concern about genetic discrimination, fear of a positive result and belief that the pathogenic variant was not relevant to his/her health. Five ARRs reported that they remained interested in testing and the telephone call prompted completion of testing. Even when facilitated by a medical team with prioritization of relative convenience, significant barriers to cascade testing ARRs for hereditary breast and ovarian cancer syndrome persist due to concern about genetic discrimination, cost, and fear of positive test results.

A pilot study investigating feasibility of mainstreaming germline BRCA1 and BRCA2 testing in high-risk patients with breast and/or ovarian cancer in three tertiary Cancer Centres in Ireland

In the Republic of Ireland (ROI), BRCA1/BRCA2 genetic testing has been traditionally undertaken in eligible individuals, after pre-test counselling by a Clinical Geneticist/Genetic Counsellor. Clinical Genetics services in ROI are poorly resourced, with routine waiting times for appointments at the time of this pilot often extending beyond a year. The consequent prolonged waiting times are unacceptable where therapeutic decision-making depends on the patient's BRCA status. "Mainstreaming" BRCA1/BRCA2 testing through routine oncology/surgical clinics has been implemented successfully in other centres in the UK and internationally. We aimed to pilot this pathway in three Irish tertiary centres. A service evaluation project was undertaken over a 6-month period between January and July 2017. Eligible patients, fulfilling pathology and age-based inclusion criteria defined by TGL clinical, were identified, and offered constitutional BRCA1/BRCA2 testing after pre-test counselling by treating clinicians. Tests were undertaken by TGL Clinical. Results were returned to clinicians by secure email. Onward referrals of patients with uncertain/pathogenic results, or suspicious family histories, to Clinical Genetics were made by the treating team. Surveys assessing patient and clinician satisfaction were sent to participating clinicians and a sample of participating patients. Data was collected with respect to diagnostic yield, turnaround time, onward referral rates, and patient and clinician feedback. A total of 101  patients underwent diagnostic germline BRCA1/BRCA2 tests through this pathway. Pathogenic variants were identified in 12 patients (12%). All patients in whom variants were identified were appropriately referred to Clinical Genetics. At least 12 additional patients with uninformative BRCA1/BRCA2 tests were also referred for formal assessment by Clinical Geneticist or Genetic Counsellor. Issues were noted in terms of time pressures and communication of results to patients. Results from a representative sample of participants completing the satisfaction survey indicated that the pathway was acceptable to patients and clinicians. Mainstreaming of constitutional BRCA1/BRCA2 testing guided by age- and pathology-based criteria is potentially feasible for patients with breast cancer as well as patients with ovarian cancer in Ireland.

Prevalence of FANCM germline variants in BRCA1/2 negative breast and/or ovarian cancer patients from Pakistan

The Fanconi anemia complementation group M (FANCM) gene is a potential candidate for breast/ovarian cancer susceptibility in European populations. Here, we examined the contribution of FANCM germline variants to hereditary breast and/or ovarian cancer in Pakistan. Comprehensive FANCM variant screening was performed in 201 BRCA1 and BRCA2 (BRCA1/2) negative Pakistani patients with and without triple-negative breast cancer (TNBC) and/or ovarian cancer, using denaturing high-performance liquid chromatography analysis (DHPLC) followed by DNA sequencing. Novel variants were tested for their potential effect on protein function using in silico tools. Reverse transcription (RT)-PCR analysis of RNA extracted from one deletion/insertion (delins) variant (p.K1780delinsNGIT) carrier and three non-carriers was performed to evaluate the impact of this variant on splicing. Furthermore, potentially functional variants were evaluated in 200 healthy female controls. A missense variant (p.V1857M) was identified in a 50-year-old TNBC patient with a family history of breast cancer. It was also identified in the index patient´s daughter, who was diagnosed with osteosarcoma at 15 years of age. Further, one delins variant (p.K1780delinsNGIT) was identified in a 45-year-old non-TNBC patient, but not detected in her brother, who was diagnosed with Hodgkin's lymphoma at 38 years of age. Based on in silico and RNA analyses, p.V1857M and p.K1780delinsNGIT were predicted as variants of uncertain significance (VUS), respectively. Both variants were absent in 200 healthy controls. Our findings suggest a marginal contribution of FANCM variants to hereditary breast/ovarian cancer in Pakistan, which need to be confirmed in larger studies.

Founder vs. non-founder BRCA1/2 pathogenic alleles: the analysis of Belarusian breast and ovarian cancer patients and review of other studies on ethnically homogenous populations

The spectrum of BRCA1/2 mutations demonstrates significant interethnic variations. We analyzed for the first time the entire BRCA1/2 coding region in 340 Belarusian cancer patients with clinical signs of BRCA1/2-related disease, including 168 women with bilateral and/or early-onset breast cancer (BC), 104 patients with ovarian cancer and 68 subjects with multiple primary malignancies involving BC and/or OC. BRCA1/2 pathogenic alleles were detected in 98 (29%) women, with 67 (68%) of these being represented by founder alleles. Systematic comparison with other relevant studies revealed that the founder effect observed in Belarus is among the highest estimates observed worldwide. These findings are surprising, given that the population of Belarus did not experience geographic or cultural isolation throughout history.

Physicians’ experience, practice and education, on genetic testing and genetic counseling: a nationwide survey study in Greece

Genetic testing has been implemented in clinical practice. However, data on physician's practices and education related to cancer genetics, risk assessment and clinical management in Greece, is limited. In Greece, genetic counseling is performed by treating physicians in collaboration with clinical laboratory geneticists due to the absence of medical geneticists and genetic counsellors. We evaluated treating physicians' experience on genetic testing for hereditary cancer and counseling practices in Greece, thus providing critical areas for improvement of genetic counseling processes. A 28-question survey was used to assess physicians' experience with genetic testing practices, factors that affect their clinical management and decision making and limitations in their education. Of 250 physicians, 208 (83%) completed the survey; of whom 89 (42.8%) were medical oncologists, 88 general surgeons (42.3%), 26 gynecologists (12.5%) and 5 (2.4%) of other specialties. Overall, 91.8% of participants referred patients for genetic testing, with 51.8% recommending multigene panel testing. While most clinicians (84%) reported lack of a clinical genetics department at their institution, 75.7% referred patients for genetic counseling at available departments or healthcare professionals with expertise in genetic counseling. Overall, 68.8% of respondents reported no training or moderate training on cancer genetics. A higher proportion of medical oncologists reported sufficient/very satisfactory training (40.9%) compared to general surgeons (27.3%) or gynecologists (11.5%) (p = 0.012). Time spent on pre- and post-testing sessions varied significantly among respondents. Of 199 physicians, 70% would manage patients with BRCA1 VUS as patients with pathogenic variants, mainly surgeons (83.1%) and gynecologists (80%), compared to oncologists (52.3%) (p < 0.001). Additionally, 64% of physicians treating patients with breast and ovarian cancer would recommend an intervention based on the presence of a BRCA1 VUS. Most respondents (87%) were interested in receiving additional education on cancer risk assessment. Limited consensus was observed during physicians' genetic testing, counseling practices and clinical management of patients with increased predisposition to cancer. Our findings highlight the need for improvement in physician education on cancer risk assessment and increase of genetic counseling resources and services.

Comparison of universal screening in major lynch-associated tumors: a systematic review of literature

Lynch syndrome (LS) is associated with an increased lifetime risk of several cancers including colorectal (CRC), endometrial (EC), ovarian (OC), urinary (UT) and sebaceous tumors (ST). The benefit for universal screening in CRC and EC is well known. However, this benefit in other major lynch-associated tumors is unclear. We performed a systematic review of all published articles in the MEDLINE database between 2005 to 2017 to identify studies performing universal screening for LS in unselected CRC, EC, OC, UT and ST. All cases with MSI-H (instability in two or more markers) or missing one or more proteins on IHC testing were considered screening positive. Cases with MLH1 promoter hypermethylation or BRAF mutation positive were considered to have somatic mutations. A total of 3788 articles were identified in MEDLINE yielding 129 study arms from 113 studies. The overall pooled yield of universal LS screening and germline mismatch gene mutation was significantly different across the major LS-associated tumors (Mann Whitney test, p < 0.001). The pooled screening yield was highest in ST [52.5% (355/676), 95% CI 48.74-56.26%] followed by EC [22.65% (1142/5041), 95% CI 21.54-23.86%], CRC [11.9% (5649/47,545), 95% CI 11.61-12.19%], OC [11.29% (320/2833), 95% CI 10.13-12.47%] and UT [11.2% (31/276), 95% CI 7.48-14.92%]. ST also had the highest pooled germline positivity for mismatch repair gene mutation [18.8%, 33/176, 95%CI 13.03-24.57], followed by EC [2.6% (97/3765), 95% CI 2.09-3.11], CRC [1.8% (682/37,220), 95% CI 1.66-1.94%], UT [1.8%(3/164), 95% CI - 0.24-3.83%] and OC [0.83%(25/2983), 95% CI 0.48-1.12%]. LS screening in EC yielded significantly higher somatic mutations compared to CRC [pooled percentage 16.94% [(538/3176), 95%CI 15.60-18.20%] vs. 5.23% [(1639/26,152), 95% CI 4.93-5.47%], Mann Whitney test, p < 0.0001. Universal LS testing should be routinely performed in OC, UT and STs in addition to CRC and EC. Our findings also support consideration for IHC and somatic mutation testing before germline testing in EC due to higher prevalence of somatic mutations as well as germline testing in all patients with ST. Our results have implications for future design of LS screening programs and further studies are needed to assess the cost effectiveness and burden on genetic counselling services with expanded universal testing for LS.

Evaluation of implementation of risk management guidelines for carriers of pathogenic variants in mismatch repair genes: a nationwide audit of familial cancer clinics

This nationwide study assessed the impact of Lynch syndrome-related risk management guidelines on clinicians' recommendations of risk management strategies to carriers of pathogenic variants in mismatch repair genes and the extent to which carriers took up strategies in concordance with guidelines. Clinic files of 464 carriers (with and without colorectal cancer) were audited for carriers who received their genetic testing results in July 2008-July 2009 (i.e. before guideline release), July 2010-July 2011 and July 2012-July 2013 (both after guideline release) at 12 familial cancer clinics (FCCs) to ascertain the extent to which carriers were informed about risk management in accordance with guidelines. All carriers captured by the audit were invited to participate in interviews; 215 were interviewed to assess adherence to recommended risk management guidelines. The rates of documentation in clinic files increased significantly from pre- to post-guideline for only two out of eight risk management strategies. The strategies with the highest compliance of carriers post-guidelines were: uptake of one or two-yearly colonoscopy (87%), followed by hysterectomy to prevent endometrial cancer (68%), aspirin as risk-reducing medication (67%) and risk-reducing salpingo-oophorectomy (63%). Interrater reliability check for all guidelines showed excellent agreement (k statistics = 0.89). These results indicate that there is scope to further increase provision of advice at FCCs to ensure that all carriers receive recommendations about evidence-based risk management. A multi-pronged behaviour change and implementation science approach tailored to specific barriers is likely to be needed to achieve optimal clinician behaviours and outcomes for carriers.

Primary fallopian tube carcinoma (PFTC) in a BRIP-1 mutation carrier: the first case report

Some hereditary ovarian cancer cases can be associated with a mutation of a gene involved in the DNA double-strand break repair system other than BRCA, such as BRIP1. This mutation is an emerging indication for prophylactic risk-reducing salpingo-oophorectomy (RRSO): however, anomalous tubal pathologic lesions have not yet been reported during RRSO performed for this specific indication (BRIP1), as largely reported for BRCA mutation carriers. An asymptomatic 64-year-old woman with a family history of ovarian and breast cancer agreed to undergo RRSO for a pathogenic variant of the BRIP1 gene (heterozygous NM_032043.2: c.124delT, p. Cys42Valfs) with normal BRCA genes. Histological examination showed the presence of high-grade serous carcinoma of the fimbria of the right tube of a maximum diameter of 0.4 cm (final FIGO stage IIB). The pathogenic mechanism that leads to the development of high-grade serous ovarian/fallopian tube cancer in patients with mutations of BRIP1 should be the same as for patients with mutations of BRCA1 and 2. Our case confirms to consider BRIP1 mutation to be sufficient to justify RRSO at 45-50 years old.

Non-serous ovarian cancer in PTEN Hamartoma Tumor Syndrome: additional evidence for increased risk

Abstract Increased hereditary cancer risk is one of the hallmarks of PTEN Hamartoma Tumor Syndrome (PHTS) which is caused by a pathogenic germline variant in PTEN. Case reports and some cohort studies have described ovarian cancer (OC) in PHTS patients. Previously, we observed an enrichment of non-serous OC in PHTS compared to sporadic cases (3% vs 1%). However, ovarian cancer is currently not considered a PHTS-related cancer. The aim of this study was to describe five PHTS patients with a pathogenic germline variant in PTEN with non-serous OC. Three of the non-serous OCs were mucinous carcinomas (49, 51 and 52 years) and two were malignant germ cell tumors (8 and 15 years) and all were diagnosed before genetic testing and PHTS diagnosis. In addition to OC, the described patients developed other PHTS-related benign and malignant lesions. We provide further evidence that non-serous ovarian cancer, especially mucinous, endometrioid and malignant germ cell tumors should be further investigated as potential PHTS-related cancers.

Identifying the BRCA1 c.-107A &gt; T variant in Dutch patients with a tumor BRCA1 promoter hypermethylation

AbstractAn inherited single nucleotide variant (SNV) in the 5′UTR of the BRCA1 gene c.-107A &gt; T was identified to be related to BRCA1 promoter hypermethylation and a hereditary breast and ovarian cancer phenotype in two UK families. We investigated whether this BRCA1 variant was also present in a Dutch cohort of breast and ovarian cancer patients with tumor BRCA1 promoter hypermethylation. We selected all breast and ovarian cancer cases that tested positive for tumor BRCA1 promoter hypermethylation at the Netherlands Cancer Institute and Sanger sequenced the specific mutation in the tumor DNA. In total, we identified 193 tumors with BRCA1 promoter hypermethylation in 178 unique patients. The wild-type allele was identified in 100% (193/193) of sequenced tumor samples. In a large cohort of 178 patients, none had tumors harboring the previously identified c.-107A &gt; T SNV in BRCA1. We therefore can conclude that the germline SNV is not pervasive in patients with tumor BRCA1 promoter hypermethylation.

Optimizing the detection of hereditary predisposition in women with epithelial ovarian cancer: nationwide implementation of the Tumor-First workflow

AbstractGenetic testing in patients with ovarian carcinoma (OC) is crucial, as around 10–15% of these women have a genetic predisposition to OC. Although guidelines have recommended universal germline testing for all patients with OC for a decade, implementation has proved challenging, thus resulting in low germline-testing rates (around 30–50%). Many new initiatives to improve genetic-testing rates have emerged, but most have been carried out at the local level, leading to differences in workflows within and between countries. We present an example of a nationwide implementation project that has successfully led to a uniform, high-quality genetic-testing workflow for women with OC. Nationwide multidisciplinary meetings generated consensus on the preferred workflow for OC genetic testing: the “Tumor-First” workflow. This workflow means starting by testing the tumor DNA for the presence of pathogenic variants in OC-risk genes, thus providing a prescreen to germline testing while yielding information on the effectiveness of treatment with PARP inhibitors. This new workflow efficiently stratifies genetic counseling and germline testing and reduces healthcare costs. Although challenging, the nationwide implementation of this workflow was successful, resulting in tumor-DNA testing rates exceeding 80%. In this article, we present our structured implementation approach, illustrate our implementation strategies—which were tailored to identified factors important to implementation—and share the lessons learned from the Tumor-First implementation project. This knowledge could facilitate the future implementation of workflows aimed at optimizing the recognition of hereditary cancers.

Cascade screening in HBOC and Lynch syndrome: guidelines and procedures in a UK centre

AbstractIn the 33 years since the first diagnostic cancer predisposition gene (CPG) tests in the Manchester Centre for Genomic Medicine, there has been substantial changes in the identification of index cases and cascade testing for at-risk family members. National guidelines in England and Wales are usually determined from the National Institute of healthcare Evidence and these have impacted on the thresholds for testing BRCA1/2 in Hereditary Breast Ovarian Cancer (HBOC) and in determining that all cases of colorectal and endometrial cancer should undergo screening for Lynch syndrome. Gaps for testing other CPGs relevant to HBOC have been filled by the UK Cancer Genetics Group and CanGene-CanVar project (web ref. https://www.cangene-canvaruk.org/). We present time trends (1990–2020) of identification of index cases with germline CPG variants and numbers of subsequent cascade tests, for BRCA1, BRCA2, and the Lynch genes (MLH1, MSH2, MSH6 and PMS2). For BRCA1/2 there was a definite increase in the proportion of index cases with ovarian cancer only and pre-symptomatic index tests both doubling from 16 to 32% and 3.2 to &gt; 8% respectively. A mean of 1.73–1.74 additional family tests were generated for each BRCA1/2 index case within 2 years. Overall close to one positive cascade test was generated per index case resulting in &gt; 1000 risk reducing surgery operations. In Lynch syndrome slightly more cascade tests were performed in the first two years potentially reflecting the increased actionability in males with 42.2% of pre-symptomatic tests in males compared to 25.8% in BRCA1/2 (p &lt; 0.0001).

A mosaic pathogenic variant in MSH6 causes MSH6-deficient colorectal and endometrial cancer in a patient classified as suspected Lynch syndrome: a case report

Abstract Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. However, mosaic variants in the MMR genes have been rarely described. We identified a likely de novo mosaic MSH6 :c.1135_1139del p.Arg379* pathogenic variant in a patient diagnosed with suspected Lynch syndrome/Lynch-like syndrome. The patient developed MSH6-deficient EC and CRC at 54 and 58 years of age, respectively, without a detectable germline MMR pathogenic variant. Multigene panel sequencing of tumor and blood-derived DNA identified an MSH6 somatic mutation ( MSH6 :c.1135_1139del p.Arg379*) common to both the EC and CRC, raising suspicion of mosaicism. A droplet digital polymerase chain reaction (ddPCR) assay detected the MSH6 variant at 5.34% frequency in normal colonic tissue, 3.49% in saliva and 1.64% in blood DNA, demonstrating the presence of the MSH6 variant in all three germ layers. This study highlights the utility of tumor sequencing to guide sensitive ddPCR testing to detect low-level mosaicism in the MMR genes. Further investigation of the prevalence of MMR mosaicism is needed to inform routine diagnostic approaches and genetic counselling.

Reliability and validity of the multidimensional impact of cancer risk assessment (MICRA) questionnaire: Japanese version

Abstract This study aimed to develop and validate a Multidimensional Impact of Cancer Risk Assessment questionnaire–Japanese version (MICRA-J) as an assessment of the psychosocial impact of genetic testing. The MICRA was translated into Japanese using standardized translation procedures. The reliability and validity of the MICRA-J were evaluated in individuals who underwent BRCA1/2 testing for hereditary breast and ovarian cancer diagnosis. The 72 respondents included patients with BRCA1/2 pathogenic variants (n = 20), BRCA1/2 negative (n = 35), variants of uncertain significance (VUS, n = 6), participants with cascade testing positive (n = 7), and participants with cascade testing negative (n = 4). Total MICRA-J scores were positively correlated with Hospital Anxiety and Depression Scale (HADS) scores and negatively correlated with the 36-item short-form version 2 acute (SF-36v2 acute) scores (P &lt; 0.05). The MICRA-J showed good internal consistency coefficients (α &gt; 0.70). Furthermore, high test–retest correlations were obtained when the 64 participants responded to the MICRA-J twice within a short period (Pearson’s correlation coefficient = 0.85). The MICRA-J Total score was higher in the groups with BRCA1/2 pathogenic variant carriers than in the BRCA1/2 negative group, whereas the HADS and SF36v2 acute did not differ significantly. These results suggest that the reliability and validity of the MICRA-J have been established. The MICRA-J, similar to the MICRA in other languages, is considered a useful tool to specifically measure the psychosocial impact of genetic testing.

Gastric-type endocervical adenocarcinoma in situ as the presenting feature in a mosaic STK11 pathogenic variant carrier with a Peutz-Jeghers syndrome child

We present the first documented case of gastric-type endocervical adenocarcinoma in situ in a mosaic STK11 pathogenic variant carrier, who delivered a child with classic Peutz-Jeghers syndrome (PJS). A 53-year-old woman presented with persistent watery vaginal discharge for 2 years. Histopathology confirmed gastric-type endocervical adenocarcinoma in situ. Familial genetic investigation was initiated after her son's diagnosis of PJS with an apparent de novo STK11 germline variant [NM_000455.4:c.842del (p.Pro281Argfs*6)]. Comprehensive STK11 screening via Sanger sequencing of peripheral blood from both parents showed no pathogenic variants. Following multidisciplinary tumor board review, ultra-deep next-generation sequencing was performed on multiple tissue specimens. Molecular analysis revealed low-level mosaicism for the familial STK11 variant in cervical tissue with no detectable mutations in blood, saliva, urine, or ovarian stroma. This case demonstrates three key clinical insights: (1) parental mosaicism may underlie apparent de novo PJS cases, (2) tissue-specific STK11 mosaicism can manifest as localized neoplastic transformation without classic PJS manifestations, and (3) ultra-deep sequencing may be considered in genetic counseling paradigms for parents of children with "de novo" cancer predisposition syndromes. These findings highlight the importance of considering mosaic phenomena in tumor prevention for hereditary cancer syndrome families.

Risk-reducing salpingectomy with delayed oophorectomy to prevent ovarian cancer in women with an increased inherited risk: insights into an alternative strategy

AbstractEpithelial ovarian cancer (EOC) is the most lethal type of gynaecological cancer, due to lack of effective screening possibilities and because the disease tends to metastasize before onset of symptoms. Women with an increased inherited risk for EOC are advised to undergo a risk-reducing salpingo-oophorectomy (RRSO), which decreases their EOC risk by 96% when performed within guideline ages. However, it also induces premature menopause, which has harmful consequences. There is compelling evidence that the majority of EOCs originate in the fallopian tube. Therefore, a risk-reducing salpingectomy with delayed oophorectomy (RRS with DO) has gained interest as an alternative strategy. Previous studies have shown that this alternative strategy has a positive effect on menopause-related quality of life and sexual health when compared to the standard RRSO. It is hypothesized that the alternative strategy is non-inferior to the standard RRSO with respect to oncological safety (EOC incidence). Three prospective studies are currently including patients to compare the safety and/or quality of life of the two distinct strategies. In this article we discuss the background, opportunities, and challenges of the current and alternative strategy.

Ovarian carcinoma in children with constitutional mutation of SMARCA4: single-family report and literature review

AbstractOvarian carcinoma is an extremely rare malignancy in children, often developing on the underlying inherited background. Female carriers of pathogenic germline mutations of SMARCA4 are at risk of an aggressive type of undifferentiated ovarian cancer called small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Regardless of age of the patient, stage of the disease, and oncological treatment, the prognosis for SCCOHT is poor. Therefore, early intervention with risk-reducing surgeries is recommended for these patients. In this study, we report genetic testing of a family with two children carrying pathogenic germline mutations of SMARCA4 and summarize the course of SCCOHT in all pediatric patients reported in the literature with constitutional defects identified within the SMARCA4 locus.

Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a multisystem disorder caused by germline heterozygous NF1 loss-of-function variants. The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein, which functions by down-regulating RAS/RAF/MAPK-signalling pathways. Somatic NF1 aberrations frequently occur in sporadic ovarian cancer (OC), but the incidence of OC in NF1 patients is rare. Here we report the germline and somatic findings for two unrelated patients with NF1 and high-grade serous OC. Germline testing revealed a heterozygous NF1 pathogenic variant in each patient, c.7096_7101del (p.Asn2366_Phe2367del) and c.964delA (p.Ile322Leufs*54), respectively. No germline variants in well-established OC predisposition genes were detected, including BRCA1 and BRCA2. Tumor loss-of-heterozygosity analysis demonstrated loss of the wild type NF1 allele for both patients. Biallelic NF1 inactivation occurs as part of OC pathogenesis in NF1 patients. Although the penetrance of NF1-associated OC is insufficient to warrant risk-reducing interventions, our findings highlight the potential for therapies targeting the RAS/RAF/MAPK-signalling pathway for these cases.

Analysis of 3297 individuals suggests that the pathogenic germline 5′-UTR variant BRCA1 c.-107A &gt; T is not common in south-east Germany

In this study we aim to determine the prevalence of the recently identified pathogenic BRCA1 variant c.-107A > T in the south-east German population. This variant causes the epigenetic silencing of the BRCA1 promotor and has been detected in two independent families from the UK without a germline BRCA1 or BRCA2 pathogenic variant. A total of 3297 individuals with suspicion of hereditary breast and ovarian cancer and fulfilling the clinical criteria necessary for genetic testing in Germany were analyzed for presence of the variant by a Kompetitive Allele-Specific PCR (KASP) assay or direct Sanger sequencing. Since we did not detect an individual carrying the variant we conclude that BRCA1 c.-107A > T is not a common variant in the south-east German population.

Lack of evidence for CDK12 as an ovarian cancer predisposing gene

CDK12 variants were investigated as a genetic susceptibility to ovarian cancer in a series of 416 unrelated and consecutive patients with ovarian carcinoma and who carry neither germline BRCA1 nor BRCA2 pathogenic variant. The presence of CDK12 variants was searched in germline DNA by massive parallel sequencing on pooled DNAs. The lack of detection of deleterious variants and the observed proportion of missense variants in the series of ovarian carcinoma patients as compared with all human populations strongly suggests that CDK12 is not an ovarian cancer predisposing gene.

Pilot study of a decision aid on BRCA1/2 genetic testing among Orthodox Jewish women

Orthodox Jewish women face unique social, cultural, and religious factors that may influence uptake of BRCA1/2 genetic testing. We examined the impact of a web-based decision aid (DA) on BRCA1/2 genetic testing intention/completion among Orthodox Jewish women. We conducted a single-arm pilot study among 50 Orthodox Jewish women who were given access to a web-based DA entitled RealRisks and administered serial surveys at baseline and 1 and 6 months after exposure to the DA. Descriptive statistics were conducted for baseline characteristics and study measures. Comparisons were made to assess changes in study measures over time. Fifty Orthodox Jewish women enrolled in the study with a mean age of 43.9 years (standard deviation [SD] 14.6), 70% Modern Orthodox, 2% with personal history of breast cancer, and 68% and 16% with a family history of breast or ovarian cancer, respectively. At baseline, 27 (54%) participants intended to complete genetic testing. Forty-three participants (86%) completed RealRisks and the 1-month survey and 38 (76%) completed the 6-month survey. There was a significant improvement in BRCA1/2 genetic testing knowledge and decrease in decisional conflict after exposure to the DA. At 1 month, only 20 (46.5%) completed or intended to complete genetic testing (p = 0.473 compared to baseline). While the DA improved genetic testing knowledge and reduced decisional conflict, genetic testing intention/completion did not increase over time. Future interventions should directly address barriers to BRCA1/2 genetic testing uptake and include input from leaders in the Orthodox Jewish community. NCT03624088 (8/7/18).

Functional and phenotypic consequences of an unusual inversion in MSH2

A de novo germline pathogenic BRCA1 variant identified following an osteosarcoma pangenomic molecular analysis

Cascade testing in Italian Hereditary Breast Ovarian Cancer families: a missed opportunity for cancer prevention?

Healthy carriers of BRCA1/2 pathogenic variants (PVs) may benefit from risk-reducing measures of proven efficacy. The main approach to identify these individuals is cascade testing, and strategies to support this complex process are under investigation. In Italy, cascade testing has received little attention; therefore, we analyzed the uptake and characteristics of BRCA1/2 cascade testing in families diagnosed with HBOC between 2017 and 2019 at two Italian genetics centers. All blood relatives aged 18 years or older at September 2022 and who could be involved in the first step of cascade testing (i.e., all the living relatives closest to the proband) were included. In addition to first-degree relatives, individuals who were second-, third- or fourth-degree relatives were included if the closest relative(s) was/were deceased. Overall, 213 families were included (103, Genoa; 110, Bologna). Most probands were women affected by breast and/or ovarian cancer (86.4%, Genoa; 84.5%, Bologna), and the branch segregating the PV was known/suspected in 62% of families (62.1%, Genoa; 60.9%, Bologna). Overall, the uptake of cascade testing was 22.8% (25.8%, Genoa; 19.9%, Bologna; OR = 0.59: 95%CI 0.43-0.82). It was strongly associated with female gender (OR = 3.31, 95%CI 2.38-4.59), age ≤ 70 years (< 30 years OR = 3.48, 95%CI 1.85-6.56; 30-70 years OR = 3.08, 95%CI 2.01-4.71), first-degree relationship with the proband (OR = 16.61, 95%CI 10.50-26.28) and segregation of the PV in both the maternal (OR = 2.54, 95%CI 1.72-3.75) and the paternal branch (OR = 4.62, 95%CI 3.09-6.91). These real-world data may be important to inform the design and implementation of strategies aimed at improving the uptake of HBOC cascade testing in Italy.

Impact of hormonal contraception on endometrial histology in patients with Lynch syndrome, a retrospective pilot study

Hormonal contraception (HC) is a well-recognized protection against endometrial cancer (EC) in the general population. It has not been established if this is also applicable to women with Lynch syndrome (LS), a condition associated with a up to 50% lifetime risk of developing EC. The objective of this study was to evaluate if the use of HC influences the incidence of endometrial hyperplasia and EC in women with LS by comparing the histology of annual endometrial biopsies obtained in patients with LS who are using HC versus non-users. This is a retrospective cohort study conducted with endometrial biopsies obtained in women 30 to 50 years of age with LS. The Pearson Chi-square test was performed to compare the prevalence of cancer and hyperplasia in the HC users and in the non-HC users groups. A total of 164 endometrial biopsies obtained among 75 women were suitable for analysis. Among the 86 biopsies obtained in the non-HC group, 81.4% (70/86) were normal. Two cases of endometrial carcinoma (2.3%) and 6 endometrial hyperplasia without atypia were found (7.0%). Among the 78 biopsies performed in patients using HC, 78.2% (61/78) were normal. Three endometrial hyperplasia without atypia (3.8%) and three cases of EC were diagnosed (3.8%). This study suggests that, in women of 30 to 50 years of age with LS, the use of hormonal contraception does not seem to decrease the occurrence of endometrial hyperplasia/carcinoma on annual endometrial histology.

Genetic testing for hereditary breast and ovarian cancer in the Murcian population using a comprehensive NGS panel

Traditionally, hereditary breast and ovarian cancer syndrome (HBOC) has been associated with germline pathogenic or likely pathogenic variants (PV/LPV) in BRCA1 and BRCA2. However, growing evidence indicates that this condition is genetically heterogeneous, and that PV/LPV in additional cancer predisposition genes also contribute significantly to disease susceptibility. In this study, 414 HBOC index cases (ICs) from the Region of Murcia, who fulfilled the 2019 Spanish Society of Medical Oncology (SEOM) criteria, were analyzed using next-generation sequencing (NGS). A 50-gene panel was applied, containing a total of 20 clinically actionable genes recommended by the National Comprehensive Cancer Network (NCCN) for HBOC. The study achieved a diagnostic yield of 15% based solely on the 20 clinically actionable genes included in the panel, with the highest detection rate observed among patients with co-occurring breast and high-grade serous epithelial ovarian cancer. Notably, applying only criteria involving a personal history of breast cancer from the 2019 SEOM guidelines limited the identification of HBOC patients carrying PV/LPV. It was also observed that BRCA genes contributed more to HBOC than non-BRCA genes (60% and 40%, respectively). Finally, re-evaluation of variants of uncertain significance (VUS) led to a substantial reduction in their number, with 25.38% of the initially identified VUS reclassified as benign or likely benign and 6 of the 97 remaining variants (6.2%) prioritized after applying a prioritization algorithm. This study confirms the importance of limiting HBOC genetic testing to clinically actionable genes in routine clinical practice. The re-evaluation and the prioritization of VUS are also essential, since they allow clinical laboratories to manage their resources more efficiently.

Use and feasibility of a Lynch Syndrome predictive model for inherited colorectal and endometrial cancer in a low-middle income country

While universal tumor testing for Lynch Syndrome (LS) is recommended in all new diagnoses of colorectal cancer (CC) and endometrial cancer (EC), the cost and availability of this test in low-resource settings poses challenges. The PREdiction Model for gene Mutations (PREMM