Clinical Genetics

Hereditary cancer predispositions: Comparison of multigene panel sequencing on fresh‐frozen breast/ovarian tumor versus blood

Abstract In breast or ovarian cancer (BC/OC) patients with evocative personal and/or family history, multigene panel sequencing is performed on blood to diagnose hereditary predispositions. Additionally, BRCA1 / BRCA2 testing can be performed on tumor sample for therapeutic purpose. The accuracy of multigene panel tumor analysis on BC/OC to detect predisposing germline pathogenic variants (gPV) has not been precisely assessed. By comparing sequencing data from blood and fresh‐frozen tumor we show that tumor genomic instability causes pitfalls to consider when performing tumor testing to detect gPV. Even if loss of heterozygosity increases germline signal in most cases, somatic copy number variants (CNV) can mask germline CNV and collapse point gPV variant allele frequency (VAF). Moreover, VAF does not allow an accurate distinction between germline and somatic pathogenic variants.

BRCA2 c.156_157insAlu Founder Variant in Northern Portugal: An Insight Into Hereditary Breast and Ovarian Cancer Genetic Risk and Management

ABSTRACT The BRCA2 c.156_157insAlu variant is a Portuguese founder mutation implicated in hereditary breast and ovarian cancer (HBOC). This study aims to determine its occurrence and clinical implications in the northern interior region of Portugal. A retrospective study of 571 individuals referred for HBOC genetic counseling and testing between 2021 and 2024 was conducted. Genetic screening was performed using next‐generation sequencing of 27 hereditary cancer genes, with confirmatory PCR for BRCA2 c.156_157insAlu. Pathogenic or likely pathogenic variants were detected in 19.8% of participants, with BRCA1/2 variants accounting for 5.4%. The BRCA2 c.156_157insAlu variant was identified in 6 individuals (25% of all BRCA2 pathogenic variants identified), including breast cancer patients and asymptomatic carriers. Clinically, it was associated with early onset and contralateral breast cancer. Cascade testing and genetic counseling were offered to at‐risk relatives. The BRCA2 c.156_157insAlu variant remains a significant contributor to HBOC in northern Portugal. Its high local proportion among BRCA2 variants supports the implementation of targeted genetic testing strategies, enhancing early detection and personalized cancer risk management.

Patterns and predictors of genetic referral among ovarian cancer patients at a National Cancer Institute‐Comprehensive Cancer Center

Abstract Germline mutations (eg, BRCA1 / 2 ) have prognostic and treatment implications for ovarian cancer (OVCA) patients. Thus, national guidelines recommend genetic testing for OVCA patients. The present study examines patterns and predictors of genetics referral in OVCA patients. Electronic medical record data were abstracted retrospectively from 557 OVCA patients treated from 1 January 2001 to 31 December 2015. Logistic regression models identified sociodemographic characteristics, disease/treatment characteristics, family history data, provider characteristics, and survival data that predicted genetics referral. Overall, 27.5% of patients received referral. Eleven variables predicting referral were selected during stepwise regression: younger age, White race, not having private insurance, professional school education, year of OVCA diagnosis, platinum sensitivity, female gynecologic oncologist, chemotherapy administered by a gynecologic oncologist, clinical trial enrollment, longer overall survival, and family history of OVCA. Genetics referral among OVCA patients was similar to rates reported nationwide. Unique predictive factors will contribute to quality improvement and should be validated at a multi‐institutional level to ensure guideline concordant care is provided to all OVCA patients. Future research should identify both patient‐level and provider‐level factors associated with genetics referral.

Epithelial ovarian cancer risk: A review of the current genetic landscape

Abstract Ovarian cancer is the fourth most common cause of cancer‐related death in women in the developed world, and one of the most heritable cancers. One of the most significant risk factors for epithelial ovarian cancer (EOC) is a family history of breast and/or ovarian cancer. Combined risk factors can be used in models to stratify risk of EOC, and aid in decisions regarding risk‐reduction strategies. Germline pathogenic variants in EOC susceptibility genes including those involved in homologous recombination and mismatch repair pathways are present in approximately 22% to 25% of EOC. These genes are associated with an estimated lifetime risk of EOC of 13% to 60% for BRCA1 variants and 10% to 25% for BRCA2 variants, with lower risks associated with remaining genes. Genome‐wide association studies have identified single nucleotide polymorphisms (SNPs) thought to explain an additional 6.4% of the familial risk of ovarian cancer, with 34 susceptibility loci identified to date. However, an unknown proportion of the genetic component of EOC risk remains unexplained. This review comprises an overview of individual genes and SNPs suspected to contribute to risk of EOC, and discusses use of a polygenic risk score to predict individual cancer risk more accurately.

Clinical management among individuals with variant of uncertain significance in hereditary cancer: A systematic review and meta‐analysis

Abstract Improper medical use of variant of uncertain significance (VUS) remains a concern in hereditary cancer genetic testing. The goal of this study was to assess the association between pathogenic and likely pathogenic (P/LP), VUS, and benign and likely benign (B/LB) genetic test results and cancer‐related surgical and screening management. Systematic searches of Medline, Embase, EBSCO CINAHL Plus, and PsycINFO were conducted from 1946 to August 26, 2020. Eligible studies included individuals with cancer genetic test result and surgical or screening management outcomes. We reviewed 885 abstracts and 22 studies that reported relevant surgical and screening outcomes were included. Meta‐analysis revealed significantly higher surgical rates among individuals with P/LP than among those with VUS for therapeutic mastectomy with contralateral prophylactic mastectomy (OR = 7.35, 95% CI, 4.14–13.64), prophylactic mastectomy (OR = 3.05, 95% CI, 1.5–6.19), and oophorectomy (OR = 6.46, 95% CI, 3.64–11.44). There were no significant differences in therapeutic mastectomy, or breast conservation or lumpectomy rates between individuals with P/LP and VUS, or in any outcomes between patients with VUS and B/LB. Studies evaluating screening outcomes were limited, and results were conflicting. Comprehensive analysis do not indicate that a significant number of individuals with VUS results undergo inappropriate clinical management.

Further delineation of the NTHL1 associated syndrome: A report from the French Oncogenetic Consortium

Abstract Biallelic pathogenic variants in the NTHL1 (Nth like DNA glycosylase 1) gene cause a recently identified autosomal recessive hereditary cancer syndrome predisposing to adenomatous polyposis and colorectal cancer. Half of biallelic carriers also display multiple colonic or extra‐colonic primary tumors, mainly breast, endometrium, urothelium, and brain tumors. Published data designate NTHL1 as an important contributor to hereditary cancers but also underline the scarcity of available informations. Thanks to the French oncogenetic consortium (Groupe Génétique et Cancer), we collected NTHL1 variants from 7765 patients attending for hereditary colorectal cancer or polyposis (n = 3936) or other hereditary cancers (n = 3829). Here, we describe 10 patients with pathogenic biallelic NTHL1 germline variants, that is, the second largest NTHL1 series. All carriers were from the “colorectal cancer or polyposis” series. All nine biallelic carriers who underwent colonoscopy presented adenomatous polyps. For digestive cancers, average age at diagnosis was 56.2 and we reported colorectal, duodenal, caecal, and pancreatic cancers. Extra‐digestive malignancies included sarcoma, basal cell carcinoma, breast cancer, urothelial carcinoma, and melanoma. Although tumor risks remain to be precisely defined, these novel data support NTHL1 inclusion in diagnostic panel testing. Colonic surveillance should be conducted based on MUTYH recommendations while extra‐colonic surveillance has to be defined.

Tooth agenesis: What do we know and is there a connection to cancer?

Abstract Like all developmental processes, odontogenesis is highly complex and dynamically regulated, with hundreds of genes co‐expressed in reciprocal networks. Tooth agenesis (missing one or more/all teeth) is a common human craniofacial anomaly and may be caused by genetic variations and/or environmental factors. Variants in PAX9 , MSX1 , AXIN2 , EDA , EDAR , and WNT10A genes are associated with tooth agenesis. Currently, variants in ATF1 , DUSP10 , CASC8 , IRF6 , KDF1 , GREM2 , LTBP3 , and components and regulators of WNT signaling WNT10B , LRP6 , DKK, and KREMEN1 are at the forefront of interest. Due to the interconnectedness of the signaling pathways of carcinogenesis and odontogenesis, tooth agenesis could be a suitable marker for early detection of cancer predisposition. Variants in genes associated with tooth agenesis could serve as prognostic or therapeutic targets in cancer. This review aims to summarize existing knowledge of development and clinical genetics of teeth. Concurrently, the review proposes possible approaches for future research in this area, with particular attention to roles in monitoring, early diagnosis and therapy of tumors associated with defective tooth development.

The risks of breast and ovarian cancer associated with the Ashkenazi Jewish founder allele BRCA2 6174delT

Abstract Approximately 1% of the Ashkenazi Jewish population carries the BRCA2 6174delT (c.5946del) pathogenic variant. It is important to have accurate knowledge of the risks of breast and ovarian cancer associated with this specific variant so that women may be counseled accordingly. In this prospective study, we estimated the risks of breast and ovarian cancer associated with the 6174delT variant compared with the risks for other pathogenic variants in the BRCA2 gene. The annual risk for developing breast cancer was significantly lower in 246 women who carried the 6174delT variant compared with 721 non‐Jewish women who carried a variant at any other locus in BRCA2 (1.2% per year vs. 2.4% per year, p  = 0.003). We estimated the cumulative risk of breast cancer from age 30 to 70 to be 39% for carriers of the BRCA2 6174delT variant and 61% for carriers of other BRCA2 variants. The annual risk for ovarian or fallopian tube cancer was 0.51% per year for the 233 women who carried the 6174delT variant compared to 0.22% per year for the 1128 carriers of other BRCA 2 variants; the difference was not significant. Lower risks for breast cancer associated with 6174delT may not impact screening and prevention choices, however, the discussion should be based on accurate risk assessment.

Feedback of extended panel sequencing in 1530 patients referred for suspicion of hereditary predisposition to adult cancers

Abstract High‐throughput sequencing analysis represented both a medical diagnosis and technological revolution. Gene panel analysis is now routinely performed in the exploration of hereditary predisposition to cancer, which is becoming increasingly heterogeneous, both clinically and molecularly. We present 1530 patients with suspicion of hereditary predisposition to cancer, for which two types of analyses were performed: a) oriented according to the clinical presentation ( n = 417), or b) extended to genes involved in hereditary predisposition to adult cancer ( n = 1113). Extended panel analysis had a higher detection rate compared to oriented analysis in hereditary predisposition to breast / ovarian cancer ( P  < .001) and in digestive cancers ( P  < .094) (respectively 15% vs 5% and 19.3%, vs 12.5%). This higher detection is explained by the inclusion of moderate penetrance genes, as well as the identification of incident mutations and double mutations. Our study underscores the utility of proposing extended gene panel analysis to patients with suspicion of hereditary predisposition to adult cancer.

Dominant‐negative pathogenic variant BRIP1 c. 1045G >C is a high‐risk allele for non‐mucinous epithelial ovarian cancer: A case‐control study

Abstract BRIP1 is a moderate susceptibility epithelial ovarian cancer (EOC) gene. Having identified the BRIP1 c.1045G>C missense variant in a number of families with EOC, we aimed to investigate the frequency of this and BRIP1 .2392C>T pathogenic variant in patients with breast cancer (BC) and/or EOC. A case‐control study of 3767 cases and 2043 controls was undertaken investigating the presence of these variants using Sanger sequencing and gene panel data. Individuals with BC and/or EOC were grouped by family history. BRIP1 c.1045G>C was associated with increased risk of BC/EOC (OR = 37.7; 95% CI 5.3–444.2; P  = 0.0001). The risk was highest for women with EOC (OR = 140.8; 95% CI 23.5–1723.0; P  < 0.0001) and lower for BC (OR = 11.1; 95% CI 1.2–106.5; P  = 0.1588). BRIP1 c.2392C>T was associated with smaller risks for BC/EOC (OR = 5.4; 95%CI 2.4–12.7; P  = 0.0003), EOC (OR = 5.9; 95% CI 1.3–23.0; p  = 0.0550) and BC (OR = 5.3; 95%CI 2.3–12.9; P  = 0.0009). Our study highlights the importance of BRIP1 as an EOC susceptibility gene, especially in familial EOC. The variant BRIP1 c.1045G>C, rs149364097, is of particular interest as its dominant‐negative effect may confer a higher risk of EOC than that of the previously reported BRIP1 c.2392C>T nonsense variant. Dominant‐negative missense variants may confer higher risks than their loss‐of‐function counterparts.