Miriam J Smith

Effects of higher-than-expected control population allele frequency on classification of loss-of-function variants in cancer susceptibility genes

A query was sent to the cancer predisposition gene variant database Cancer Variant Interpretation Group UK, on the nonsense variant in NM_032043.3(BRIP1):c.2392C>T,p.(Arg798Ter). The submitter classified this as a variant of uncertain significance, providing very strong variant effect evidence with the intention of adding supporting pedigree information, according to the guidelines used for classification. However, the relatively high population frequency in the UKB cohort of 367/439 920 (0.083%) was a concern as it is higher than expected for the disease frequency, which would reduce the predicted pathogenicity score. This situation highlights the increasing concerns over the use of population data in pathogenicity classification of truncating/loss-of-function (LoF) variants in known cancer predisposition genes, particularly since the addition of UKB control data. Here, we have conducted a series of case-control comparisons for common truncating variants in known breast/ovarian cancer-associated genes, as well as LZTR1-related schwannomatosis, to address this issue using our Manchester cancer screening population compared with controls in UKB data. Our data show strong ORs for these common truncating variants. We propose that for truncating variants in cancer susceptibility genes with a significant case-control OR, apparently conflicting population frequency evidence criteria should be avoided.

Association between genetic polymorphisms and endometrial cancer risk: a systematic review

Introduction Endometrial cancer is one of the most commonly diagnosed cancers in women. Although there is a hereditary component to endometrial cancer, most cases are thought to be sporadic and lifestyle related. The aim of this study was to systematically review prospective and retrospective case–control studies, meta-analyses and genome-wide association studies to identify genomic variants that may be associated with endometrial cancer risk. Methods We searched MEDLINE, Embase and CINAHL from 2007 to 2019 without restrictions. We followed PRISMA 2009 guidelines. The search yielded 3015 hits in total. Following duplicate exclusion, 2674 abstracts were screened and 453 full-texts evaluated based on our pre-defined screening criteria. 149 articles were eligible for inclusion. Results We found that single nucleotide polymorphisms (SNPs) in HNF1B, KLF, EIF2AK, CYP19A1, SOX4 and MYC were strongly associated with incident endometrial cancer. Nineteen variants were reported with genome-wide significance and a further five with suggestive significance. No convincing evidence was found for the widely studied MDM2 variant rs2279744. Publication bias and false discovery rates were noted throughout the literature. Conclusion Endometrial cancer risk may be influenced by SNPs in genes involved in cell survival, oestrogen metabolism and transcriptional control. Larger cohorts are needed to identify more variants with genome-wide significance.

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.

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.