Molecular Genetics & Genomic Medicine

Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family

AbstractBackgroundGermline variants in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) cause Lynch syndrome, an autosomal dominant hereditary cancer susceptibility syndrome. The risk for endometrial cancer is significantly higher in women with MSH6 pathogenic/likely pathogenic (P/LP) variants compared with that for MLH1 or MSH2 variants.MethodsThe proband was tested via a clinical testing, Memorial Sloan Kettering‐Integrated Mutation Profiling of Actionable Cancer Targets (MSK‐IMPACT). RT‐PCR was performed using patient's blood DNA and cDNA was analyzed by DNA sequencing and a cloning approach.ResultsWe report a 56‐year‐old female with endometrial cancer who carries a germline variant, MSH6 c.4001G > C, located at the last nucleotide of exon 9. While the pathogenicity of this variant was previously unknown, functional studies demonstrated that this variant completely abolished normal splicing and caused exon 9 skipping, which is expected to lead to a prematurely truncated or abnormal protein.ConclusionOur results indicate that this variant likely contributes to cancer predisposition through disruption of normal splicing, and is classified as likely pathogenic.

The effect of a single SMARCA4 exon deletion on RNA splicing: Implications for variant classification

AbstractBackgroundExon deletions are generally considered pathogenic, particularly when they are located out of frame. Here, we describe a pediatric, female patient presenting with hypercalcemia and a small cell carcinoma of the ovary, hypercalcemic type, and carrying a germline de novo SMARCA4 exon 14 deletion.MethodsThe SMARCA4 deletion was identified by whole genome sequencing, and the effect on the RNA level was examined by gel‐ and capillary electrophoresis and nanopore sequencing.ResultsThe deletion was in silico predicted to be truncating, but RNA analysis revealed two major transcripts with deletion of exon 14 alone or exon 14 through 15, where the latter was located in‐frame. Because the patient's phenotype matched that of other patients with pathogenic germline variants in SMARCA4, the deletion was classified as likely pathogenic.ConclusionWe propose to include RNA analysis in classification of single‐exon deletions, especially if located outside of known functional domains, as this can identify any disparate effects on the RNA and DNA level, which may have implications for variant classification using the American College of Medical Genetics and Genomics guidelines.

Correlation between heparanase gene polymorphism and susceptibility to endometrial cancer

AbstractBackgroundEndometrial cancer is one of the three most common malignancies in the female genital tract. Previous studies have demonstrated the association between heparanase (HPSE, OMIM 604,724) single‐nucleotide polymorphism (SNP) and cancer risk in several cancers. However, its role in endometrial cancer remains unclear. The present study investigated the effects of HPSE SNPs on the susceptibility and clinicopathological parameters in patients with endometrial cancer.MethodsHPSE SNPs of rs4693608 (G > A) and rs4364254 (C > T) were analyzed using polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) assay in 270 endometrial cancer patients and 320 healthy controls.ResultsThe investigation indicated that the HPSE SNP rs4693608 with GG showed a protective effect from EC in both codominant (adjusted OR = 0.41, 95%CI = 0.21–0.81, p = .026) and recessive models (adjusted OR = 0.43, 95%CI = 0.22–0.82, p = .0076). No significant differences were found in the incidences of EC patients with the rs4364254 polymorphisms compared to controls. Moreover, a significantly increased distribution of A/A (rs4693608) was observed in patients with grade ≥ 2 (p = .03) and in patients with positive cervical invasion (p = .042) while patients with T/C (rs4364254) had lower tumor grade.ConclusionOur study suggested that HPSE SNP of rs4693608 correlated strongly with susceptibility to EC, and HPSE SNPs might be a potential biomarker for prognosis of endometrial cancer.

Prevalence and clinical implications of germline mutations among Jordanian patients with ovarian cancer. The Jordanian exploratory cancer genetics (Jo‐ECAG) ovarian study

AbstractBackgroundOvarian cancer is one of the most common gynecological malignancies. Due to the absence of effective screening methods, ovarian cancer is usually diagnosed at late stages. Patients with pathogenic and likely‐pathogenic germline variants (PGVs) in BRCA1 or BRCA2 harbor elevated risk of developing both ovarian and breast cancers. Identifying PGVs may help in both cancer prevention and active disease treatment. Worldwide prevalence of PGVs varies and the matter is poorly addressed among Arab patients.MethodsPatients with epithelial ovarian, fallopian tube or primary peritoneal cancers were offered the universal 20 or 84‐multi‐gene panel testing as per standard guidelines. Cascade family screening was also offered to all first and second‐degree relatives of PGV positive patients. Genetic testing was done at a referral lab using a next generation sequencing (NGS)‐based platform.ResultsDuring the study period, 152 patients, median age (range): 50 (18–79) years old, were tested. The majority (n = 100, 65.8%) had high‐grade serous carcinoma, and 106 patients (69.7%) had metastatic disease at presentation. In total, 38 (25.0%) had PGVs, while 47 (30.9%) others had variants of uncertain significance (VUS). PGVs were mostly in BRCA1 (n = 21, 13.8%) and in BRCA2 (n = 12, 7.9%), while 6 (3.9%) others had PGVs in non‐BRCA1/2 genes. PGV rates were significantly higher among 15 patients with a positive family history of ovarian cancer (60.0%, p = .022) and among 52 patients with a positive family history of breast cancer (40.4%, p = .017).ConclusionsPGVs are common among Jordanian women with ovarian cancer, and mostly occur in BRCA1/2. Given its clinical impact on disease prevention and precision therapy, universal testing should be routinely offered.

Germline mutations in Chinese ovarian cancer with or without breast cancer

AbstractBackgroundOvarian and breast cancers are known to have significant genetic components. Considering the differences in the mutation spectrum across ethnicity, it is important to identify hereditary breast and ovarian cancer (HBOC) genes mutation in Chinese for clinical management.MethodsTwo cohorts of 451 patients with ovarian cancer only (OV) and 93 patients with both breast and ovarian (BROV) cancers were initially screened for BRCA1, BRCA2, TP53, and PTEN. 109 OV and 43 BROV patients with extensive clinical risk and were being tested negative, were then further characterized by 30‐gene panel analysis.ResultsPathogenic BRCA1/2 variants were identified in 45 OV patients and 33 BROV patients, giving a prevalence of 10% and 35.5%, respectively. After the extended screening, mutations in other HBOC genes were identified in an additional 12.8% (14/109) of the OV cohort and 14% (6/43) in the BROV cohort. The most commonly mutated genes in the OV cohort were MSH2 (4.6%) while in the BROV cohort were MSH2 (4.7%) and PALB2 (4.7%). With this extended multigene testing strategy, pathogenic mutations were detected in 12.8% of OV patients (BRCAs: 10%; additional genes: 12.8%) and 40.9% (BRCAs: 35.5%; additional genes: 14%) of BROV patients.ConclusionExtended characterization of the contributions of HBOC genes to OV and BROV patients has significant impacts on further management in patients and their families, expanding the screening net for more asymptomatic individuals.

Identification of key genes and pathways of diagnosis and prognosis in cervical cancer by bioinformatics analysis

AbstractBackgroundCervical cancer as one of the most common malignant tumors lead to bad prognosis among women. Some researches already focus on the carcinogenesis and pathogenesis of cervical cancer, but it is still necessary to identify more key genes and pathways.MethodsDifferentially expressed genes were identified by GEO2R from the gene expression omnibus (GEO) website, then gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyzed by DAVID. Meanwhile, protein–protein interaction network was constructed by STRING, and both key genes and modules were found in visualizing network through Cytoscape. Besides, GEPIA did the differential expression of key genes and survival analysis. Finally, the expression of genes related to prognosis was further explored by UNLCAN, oncomine, and the human protein atlas.ResultsTotally 57 differentially expressed genes were founded, not only enriched in G1/S transition of mitotic cell cycle, mitotic nuclear division, and cell division but also participated in cytokine–cytokine receptor interaction, toll‐like receptor signaling pathway, and amoebiasis. Additionally, 12 hub genes and 3 key modules were screened in the Cytoscape visualization network. Further survival analysis showed that TYMS (OMIM accession number 188350), MCM2 (OMIM accession number 116945), HELLS (OMIM accession number 603946), TOP2A (OMIM accession number 126430), and CXCL8 (OMIM accession number 146930) were associated with the prognosis of cervical cancer.ConclusionThis study aim to better understand the characteristics of some genes and signaling pathways about cervical cancer by bioinformatics, and could provide further research ideas to find new mechanism, more prognostic factors, and potential therapeutic targets for cervical cancer.

Clinicopathological and immunological characterization of RNA m6A methylation regulators in ovarian cancer

AbstractBackgroundN6‐methyladenosine (m6A) modification is one of the critical gene regulatory mechanisms implicated in cancer biology. However, the roles of m6A regulators in ovarian cancer are still poorly understood.MethodsWe integrated multiple databases including Gene Expression Omnibus (GEO), ROC Plotter, Kaplan‐Meier Plotter, and Tumor Immune Estimation Resource (TIMER) to explore clinicopathological significance of m6A regulators in ovarian cancer.ResultsWe showed that alterations in the expression of m6A regulators were related to the malignancy and poor prognosis of ovarian cancer. We found decreased YTHDC1 and increased RBM15 expressions were associated with ovarian cancer cell metastases and HNRNPC was a predictor of paclitaxel resistance. Moreover, dysregulated m6A regulators were enriched in the activation of cancer‐related pathways. Our results further demonstrated that the level of immune cell infiltration and the expression of various immune gene markers were closely associated with the expressions of specific m6A regulators (RBM15B, ZC3H13, YTHDF1, and IGF2BP1).ConclusionsOur study establishes a new prognostic profile of ovarian cancer patients based on m6A regulators, and highlights the potential roles of m6A regulators in ovarian cancer development.

A novel BRCA2 splice variant identified in a young woman

AbstractBackgroundBRCA1/2 VUSs represent an important clinical issue in risk assessment for the breast/ovarian cancer families (HBOC) families. Among them, some occurring within the intron‐exon boundary may lead to aberrant splicing process by altering or creating de novo splicing regulatory elements or unmasking cryptic splice site. Defining the impact of these potential splice variants at functional level is important to establish their pathogenic role.MethodsGenomic DNA was extracted from peripheral blood sample of a young woman affected with breast cancer belonging to a HBOC family and the entire coding regions of the BRCA1 and BRCA2 genes were amplified using the Ion AmpliSeq BRCA1 and BRCA2 Panel. The BRCA2 c.682‐2delA variant has been characterized by RT‐PCR analysis performed on mRNA extracted from blood and lymphoblastoid cell line.ResultsWe demonstrated that a novel BRCA2 c.682‐2delA variant at the highly conserved splice consensus site in intron 8 disrupts the canonical splice acceptor site generating a truncated protein as predicted by several bioinformatics tools. Segregations analysis in the family and LOH performed on proband breast cancer tissue further confirmed its classification as pathogenic variant.ConclusionCombining different methodologies, we characterized this new BRCA2 variant and provided findings of clinical utility for its classification as pathogenic variant.

Evaluating the role of NTHL1 p.Q90* allele in inherited breast cancer predisposition

ABSTRACTBackgroundRare protein truncating variants of NTHL1 gene are causative for the recently described, recessively inherited NTHL1 tumor syndrome that is characterized by an increased lifetime risk for colorectal cancer, colorectal polyposis, and breast cancer. Although there is strong evidence for breast cancer being a part of the cancer spectrum in these families, the role of pathogenic NTHL1 variants in breast cancer susceptibility in general population remains unclear.MethodsWe tested the prevalence of NTHL1 nonsense variant c.268C>T, p.Q90*, which is the major allele in NTHL1 families and also shows enrichment in the Finnish population, in a total of 1333 breast cancer patients. Genotyping was performed for DNA samples extracted from peripheral blood by using high‐resolution melt analysis.ResultsSixteen NTHL1 p.Q90* heterozygous carriers were identified (1.2%, p = 0.61): 5 in hereditary cohort (n = 234, 2.1%, p = 0.39) and 11 in unselected cohort (n = 1099, 1.0%, p = 0.36). This frequency is equal to that in the general population (19/1324, 1.4%). No NTHL1 p.Q90* homozygotes were identified.ConclusionOur results indicate that NTHL1 p.Q90* heterozygous carriers do not have an increased risk for breast cancer and that the variant is unlikely to be a significant contributor to breast cancer risk at the population level.

BRCA2 c.8827C>T pathogenic mutation in a consanguineous Chinese family with hereditary breast cancer

AbstractBackgroundMutations in the BRCA2 DNA repair associated gene (BRCA2) are associated with the development of breast cancer, with different ethnic mutations at different sites. Based on different types of BRCA2 variants, the underlying mechanism remains still elusive.MethodsNext‐generation sequencing (NGS) was performed to detect germ line mutations in BRCA2. The expressions of BRCA2 mRNA and BRCA2 protein were detected by Real‐time PCR and Western blot, respectively.ResultsIn a consanguineous Chinese family with hereditary breast cancer, one woman had unilateral breast cancer, two women had bilateral asynchronous breast cancer, and one man had prostate cancer. We identified a mutation site (NM_000059.4: c.8827C>T, NP_ 000050.3: p.(Gln2943*)) in BRCA2 gene, which was a nonsense mutation that predicted disrupting peptide chain synthesis and limiting BRCA2 protein production, validated by the decreased expressions of both BRCA2 mRNA and BRCA2 protein.ConclusionIn this study, we identified a BRCA2 c.8827C>T nonsense mutation with a truncated BRCA2 protein in a consanguineous Chinese Han family, suggesting individuals with this mutation should be regularly screened for malignancies such as breast, prostate, and ovarian cancer. Our study verified the function of this BRCA2 mutation site and provided a new target for the precise treatment of such patients.

A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect

AbstractBackgroundRAD51C is important in DNA repair and individuals with pathogenic RAD51C variants have increased risk of hereditary breast and ovarian cancer syndrome (HBOC), an autosomal dominant genetic predisposition to early onset breast and/or ovarian cancer.MethodsFive female HBOC probands sequenced negative for moderate‐ and high‐risk genes but shared a recurrent variant of uncertain significance in RAD51C (NM_058216.3: c.571 + 4A > G). Participant recruitment was followed by haplotype and case/control analyses, RNA splicing analysis, gene and protein expression assays, and Sanger sequencing of tumors.ResultsThe RAD51C c.571 + 4A > G variant segregates with HBOC, with heterozygotes sharing a 5.07 Mbp haplotype. RAD51C c.571 + 4A > G is increased ~52‐fold in the Newfoundland population compared with the general Caucasian population and positive population controls share disease‐associated alleles, providing evidence of a founder effect. Splicing analysis confirmed in silico predictions that RAD51C c.571 + 4A > G causes exon 3 skipping, creating an immediate premature termination codon. Gene and protein expression were significantly reduced in a RAD51C c.571 + 4G > A heterozygote compared with a wild‐type relative. Sanger sequencing of tumors from two probands indicates loss‐of‐heterozygosity, suggesting loss of function.ConclusionThe RAD51C c.571 + 4A > G variant affects mRNA splicing and should be re‐classified as pathogenic according to American College of Medical Genetics and Genomics guidelines.

Gonadoblastoma in Turner syndrome with puberty delay: A case report and literature review

AbstractBackgroundY chromosome material stands as an independent risk determinant for the onset of gonadoblastoma (GB) and subsequent gonadal germ cell tumours in individuals with Turner syndrome (TS). However, the delayed and underestimated identification of Y chromosome material through karyotyping within primary care settings exacerbates the intricacies of managing these patients over the long term.MethodsWe present a case involving TS accompanied by Y chromosome material, wherein puberty delay and GB were identified during prophylactic gonadectomy. Subsequently, we delve into the literature to explore the GB‐related malignancy risk in TS patients with Y chromosome material, the incidence of Y chromosome presence in TS patients using methodologies beyond routine chromosomal testing, and the diagnosis and treatment of puberty delay in TS patients, all based on our case.ResultsA spectrum of more sensitive molecular techniques, including polymerase chain reaction (PCR) and fluorescence in situ hybridisation, effectively augments the detection of Y chromosome material alongside karyotyping. In addition to gonadectomy, the implementation of appropriate oestrogen therapy and a holistic, multidisciplinary approach to care can enhance the quality of life, while mitigating the long‐term morbidity and mortality risks for TS patients harbouring Y chromosome material.ConclusionsBeyond gonadectomy, adopting a multifaceted approach the Y chromosome material detection, prompt initiation of puberty, tailored oestrogen therapy, and coordinated multidisciplinary management significantly contributes to the comprehensive health oversight of TS patients with Y chromosome material.

A Maternal Loss‐of‐Function Variant in KHDC3L Gene Causes a Range of Adverse Pregnancy Outcomes: A Case Report

ABSTRACTBackgroundThe KHDC3L gene encodes a component of the subcortical maternal complex (SCMC). Biallelic mutations in this gene cause 5%–10% of biparental hydatidiform moles (BiHM), and a few maternal deletions in KHDC3L have been identified in women with recurrent pregnancy loss (RPL).MethodIn this study, we had a patient with a history of 10 pregnancy or neonatal losses, including spontaneous abortions, neonatal deaths, and molar pregnancy. Whole‐exome sequencing (WES) was performed for genetic diagnostic testing.ResultsWe found a homozygous deleterious variant in the start codon of KHDC3L (c. 1A>G, p.M1V), which probably results in non‐translation or the production of a truncated protein.ConclusionThis is the first report of a maternal loss‐of‐function variant in KHDC3L gene in a patient experiencing various types of pregnancy loss. This case report broadens the understanding of KHDC3L's pathogenic variants and phenotypic spectrum, consistent with its crucial role during human pre‐ and post‐implantation development.

Clinical approach for managing patients with unexpected CDH1 mutations: A case report

AbstractBackgroundHereditary diffuse gastric cancer (HDGC) (OMIM# 137215) is an autosomal dominant cancer syndrome associated with CDH1 (OMIM# 192090) mutations. Prophylactic total gastrectomy (PTG) is the most recommended preventive treatment when a pathogenic mutation is found. However, the increasing use of genetic testing has led to the identification of incidental CDH1 mutations in individuals without a family history of gastric cancer. It remains unclear whether these patients should undergo prophylactic total gastrectomy.MethodsGermline DNA, obtained from peripheral blood, was analysed by NGS.ResultsA 47‐year‐old woman was diagnosed with high‐grade serous ovarian carcinoma, FIGO stage IIIC, with a Homologous Recombination Deficiency (HRD) GIS status of 78 (positive, cut‐off: 43). She received chemotherapy and niraparib treatment. A multigene panel test revealed no pathogenic mutations in BRCA1 (OMIM# 113705)/BRCA2 (OMIM# 600185) genes, but a de novo deletion of exon 16 in CDH1 was found incidentally. She had no previous family history of gastric or breast cancer. The patient was enrolled in a surveillance program involving periodic endoscopy and was diagnosed with diffuse gastric cancer through biopsies of a pale area in the antrum after 1 year of close endoscopic follow‐up.ConclusionThis case presents supportive evidence for the pathogenic classification of the loss of the last exon of CDH1.

From a variant of unknown significance to pathogenic: Reclassification of a large novel duplication in BRCA2 by high‐throughput sequencing

AbstractBackgroundGermline mutations in BRCA1/2 significantly contribute to hereditary breast and/or ovarian cancer. Here, we report a novel BRCA2 duplication of exons 22–24 in a female patient with bilateral breast cancer at age 35 and 44. The duplicated region was initially detected by gene panel sequencing and multiplex ligation‐dependent probe amplification. However, the location and orientation of the duplicated region was unknown. Therefore, it was initially classified as a variant of unknown significance.MethodsThe spatial directional characterization of the BRCA2 duplication was achieved by targeted enrichment of the whole‐genomic BRCA2 locus including exons and introns, and subsequent high‐throughput sequencing. Subsequently, bioinformatics tools and a breakpoint‐spanning PCR were used for identification of location and orientation of the duplication.ResultsThe duplicated region was arranged in tandem and direct orientation (Chr13(GRCh37):g.32951579_32960394dup; NM_000059.3 c.8754 + 651_9256+6112dup p.(Ala3088Phefs*3)). It is predicted to result in a frameshift and a premature stop codon likely triggering nonsense‐mediated mRNA decay. Consequently, it is regarded as pathogenic.ConclusionThis case study demonstrates that a comprehensive characterization of a structural variant by breakpoint assessment is crucial for its correct classification. Therefore, sequencing strategies including non‐coding regions might be necessary to identify cancer predispositions in affected families.

Evaluation of family history in individuals with heterozygous BRCA pathogenic variants diagnosed with breast or ovarian cancer in a single center in Italy

AbstractBackgroundBRCA1 and BRCA2 gene mutations are responsible for 5% of breast cancer (BC) and 10–15% of ovarian cancer (EOC). The presence of a germline mutation and therefore the identification of subjects at high risk of developing cancer should ideally precede the onset of the disease, so that appropriate surveillance and risk‐reducing treatments can be proposed. In this study, we revisited the family history (FH) of women who tested positive for BRCA mutations after being diagnosed with BC or EOC.MethodsThe National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®), and the Italian Association of Medical Oncology (AIOM) guidelines were applied to the FH of 157 women who were referred to San Gerardo Hospital for genetic counseling.ResultsAlmost 85% of women had an FH of BRCA‐related cancer. 63.7% and 52.2% of women could have undergone genetic testing according to NCCN and AIOM testing criteria (p < .05) before tumor diagnosis. An FH of EOC was the most frequent NCCN criterion, followed by BC diagnosed <45 years old. Sixty‐five percent of deceased women could have undergone genetic testing before developing cancer.ConclusionsFH is a powerful tool to identify high‐risk individuals eligible for genetic counseling and testing. Testing of healthy individuals should be considered when an appropriately affected family member is unavailable for testing.

KCNQ1OT1 promotes ovarian cancer progression via modulating MIR‐142‐5p/CAPN10 axis

AbstractBackgroundLong non‐coding RNA (lncRNA) has been regarded as crucial regulator for cancer progression. Roles of KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) in cancers including osteosarcoma and colon cancer have been previously reported. However, its role in ovarian cancer (OC) remains unclear.MethodsExpression level of KCNQ1OT1 on OC cells and normal cell was analyzed with quantitative real‐time PCR. Gain and loss‐of‐function experiments were performed to analyze the biological roles of KCNQ1OT1 in OC. Moreover, whether KCNQ1OT1 functions its role via mediating MICRORNA‐142‐5p (MIR‐142‐5p)/calpain 10 (CAPN10) axis was analyzed. In addition, effects of KCNQ1OT1, MIR‐142‐5p, and CAPN10 on overall survival of OC patients were analyzed at Kaplan–Meier plotter website.ResultsWe showed KCNQ1OT1 was elevated expression in OC cells and indicated poorer overall survival of OC patients. Besides, we found KCNQ1OT1 could promote OC cell proliferation and migration in vitro. Moreover, MIR‐142‐5p was found reduced expression, while CAPN10 was found elevated expression in OC cells compared with normal cell. Kaplan–Meier curve analysis showed low MIR‐142‐5p or high CAPN10 expression were indicators for poorer overall survival of OC patients. At length, we showed KCNQ1OT1 could regulate OC development via MIR‐142‐5p/CAPN10 axis.ConclusionsTaken together, KCNQ1OT1 upregulates CAPN10 expression via sponging MIR‐142‐5p, thus promoting the proliferation and migration of OC.

Case report of bilateral ovarian fibromas associated with de novo germline variants in PTCH1 and SMARCA4

AbstractBackgroundOvarian sex cord‐stromal tumors (OSCTs) are rare ovarian tumors that can develop from sex cord, stromal cells, or both. OSCTs can be benign or malignant. Bilateral and/or unilateral ovarian fibromas, a type of OSCT of the stromal cells, have been reported in individuals diagnosed with nevoid basal cell carcinoma syndrome (NBCCS). Calcified ovarian fibromas have been reported in 15–25% of individuals diagnosed with NBCCS while 75% of those cases occur bilaterally. The average age at diagnosis of OSCT/ovarian fibromas in patients with NBCSS is in the second to third decade compared with age 50 in the general population. Ovarian tumors are rare in pediatric populations.MethodsThe patient is a 5‐year‐old female diagnosed with bilateral ovarian fibromas at age 4. Multigene panel for the patient and subsequent targeted molecular evaluation of parents were completed. Histological evaluations on the surgically resected ovaries were performed for microscopic characterization of fibromas.ResultsGermline testing identified de novo heterozygous novel likely pathogenic variants in PTCH1 gene, exon 12 deletion, and an SMARCA4 splicing variant c.2002‐1G > A. Microscopic examination of bilateral tumors was consistent with an ovarian fibroma.ConclusionsTo our knowledge, this is the first report of bilateral benign ovarian fibroma in a child with a diagnosis of nevoid basal cell carcinoma syndrome (NBCCS) with a potential predisposition to Rhabdoid Tumor Predisposition Syndrome (RTPS).

CASC15 polymorphisms are correlated with cervical cancer susceptibility in Chinese women

AbstractBackgroundCervical cancer is a frequent, common cancer in women, and causes high cancer‐related deaths among women in our world. Accumulating studies provided an important evidence for long noncoding RNA (lncRNA) polymorphisms in the susceptibility of various cancer. Here, we recruited 494 cervical cancer cases and 504 unrelated controls to assess the relationship between CASC15 (OMIM# 616610) polymorphisms and cervical cancer susceptibility.MethodsAgena MassARRAY platform was conducted to genotype CASC15 polymorphisms. Odds ratios (ORs) and 95% confidence intervals (CIs) were analyzed through logistic regression to adjust for confounding factors, such as age and gender.ResultsOur study suggested that rs12212674 (NC_000006.12:g.22086845T>A) “A” allele was significantly associated with an increased risk of cervical cancer (OR = 1.31, 95% CI = 1.01–1.69, p = .041). The result was demonstrated in the log‐additive model (OR = 1.32, 95% CI = 1.02–1.72, p = .037). After age stratification, we also found that the “TT” genotype of rs4712653 (NC_000006.11:g.22125964T>C) in CASC15 was interaction with a higher cervical cancer risk in subjects aged ≤51 years in the co‐dominant model (OR = 2.08, 95% CI = 1.02–4.25, p = .044) and the recessive model (OR = 2.11, 95% CI = 1.05–4.24, p = .036). Whereas no significant correlation was found among other SNPs of CASC15 polymorphisms and the risk of cervical cancer. MDR analysis illustrated that the interaction between rs7740084 (NC_000006.11:g.21727531G>A), rs1555529 (NC_000006.11:g.21691704A>G), and rs12212674 had a certain effect on the progress of cervical cancer.ConclusionOur results revealed a potential interaction between CASC15 polymorphisms and cervical cancer susceptibility. The results provided important insights into CASC15 function in the development of cervical cancer.

The SNP rs4846048 of MTHFR enhances the cervical cancer risk through association with miR‐522: A preliminary report

AbstractBackgroundThe present research was designed to explore the association between single nucleotide polymorphisms (SNPs) at the 3′‐untranslated region (3′‐UTR) of methylenetetrahydrofolate reductase (MTHFR) and the risk of cervical cancer (CC).MethodsFrom May 2015 to October 2016, a total of 197 patients (diagnosed with CC and precancerous lesions, and underwent surgical treatments) were enrolled in the study. Meanwhile, a total of 80 healthy cases were used as the controls. PCR‐DNA analysis was used to explore the genotype of the SNPs (rs4846048 and rs55763075) of the MTHFR 3′‐UTR as well as the association between allelic frequencies and the CC risk. Then, the role of rs4846048 SNPs in the association of microRNA‐522 (miR‐522) and MTHFR was evaluated through luciferase reporter assay. Meanwhile, the modulatory influence of miR‐522 on cell apoptosis and viability of Hela cells was also detected by flow cytometry and MTT assay.ResultsThe rs4846048 AG and G allele frequencies were significantly higher in CC subgroup compared with the control group. Methylenetetrahydrofolate reductase rs4846048 A/G alleles contributed to miR‐522 binding, and miR‐522 negatively modulated the expressions of MTHFR. Furthermore, miR‐522 overexpression increased cell viability but decreased apoptotic cells in Hela cells.ConclusionThe preliminary report revealed that the SNP rs4846048 of MTHFR enhanced the risk of CC through association with miR‐522, which further regulated cell viability and apoptosis in Hela cells.