Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls

Abstract

Objectives Given the lack of adequate screening modalities, knowledge of ovarian cancer risks for carriers of pathogenic alterations in predisposition genes is important for decisions about risk-reduction by salpingo-oophorectomy. We sought to determine which genes assayed on multi-gene panels are associated with ovarian cancer, the magnitude of the associations, and for which clinically meaningful associations could be ruled out. Methods 7768 adult ovarian cancer cases of European ancestry referred to a single clinical testing laboratory underwent multi-gene panel testing for detection of pathogenic alterations in known or suspected ovarian cancer susceptibility genes. A targeted capture approach was employed to assay each of 19 genes for the presence of pathogenic or likely pathogenic alterations. Mutation frequencies in ovarian cancer cases were compared to mutation frequencies in individuals from the Exome Aggregation Consortium (ExAC). Analyses stratified by family and personal history of other cancers and age at diagnosis were also performed. Results Significant associations (p < 0.001) were identified between alterations in 11 genes and ovarian cancer, with eight of these displaying ≥5-fold increased risk (BRCA1, BRCA2, BRIP1, MSH2, MSH6, RAD51C, RAD51D). Relative risks of ovarian cancer greater than two-fold were also observed for ATM, but could reliably be ruled out for RAD50 and CHEK2. Conclusions These results will inform clinical management of women found to carry pathogenic alterations in genes tested on multi-gene panels. The knowledge that some genes are not associated with OC can reduce concerns of women found to carry pathogenic alterations in those genes.

Diagnosis of Li-Fraumeni Syndrome: Differentiating TP53 germline mutations from clonal hematopoiesis

“…Subsequent studies have elucidated that such events are enriched in the peripheral blood of patients with prior chemotherapy (Coombs et al, 2017). In our study sample, 24 out of 523 patients (4.6%) carried truncating variants affecting the PPM1D gene ( Lilyquist et al (2017) in the AGO-TR1 study was 25.2% (132 out of 523) (Harter et al, 2017). In the subgroup of patients showing variants with low VFs in the CH-associated genes TP53 and PPM1D, the proportion of germline mutation carriers was elevated (41.7%, 10/24; Table 3) compared with the overall patient sample, though not reaching levels of significance.…”

“…Notably, the overall prevalence of pathogenic germline mutations in validated OC predisposition genes ATM (MIM# 607585), BRCA1 (MIM# 113705), BRCA2 (MIM# 600185), BRIP1 (MIM# 605882), MSH2 (MIM# 609309), MSH6 (MIM# 600678), RAD51C (MIM# 602774), RAD51D (MIM# 602954) according to Lilyquist et al. () in the AGO‐TR1 study was 25.2% (132 out of 523) (Harter et al., ). In the subgroup of patients showing variants with low VFs in the CH‐associated genes TP53 and PPM1D , the proportion of germline mutation carriers was elevated (41.7%, 10/24; Table 3) compared with the overall patient sample, though not reaching levels of significance.…”

Gene panel testing of 5589 BRCA1/2‐negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

“…PTVs were defined as nonsense, frameshift, or essential splice‐site variants affecting the invariant splice sites or the last nucleotide of an exon. As suggested by Lilyquist et al., protein truncating variants in the last exon or within the last 55 bp of the penultimate exon were classified as VUS, unless a known functional domain was disrupted . For the identification of potentially damaging, rare missense variants we employed two in silico prediction tools (SIFT and MutationTaster).…”

The role of menopausal hormone therapy in women with or at risk of ovarian and breast cancers: Misconceptions and current directions

“…In patients diagnosed with ovarian cancer, up to 24% will be identified as having a hereditary predisposition. Pathogenic mutations in BRCA1 and BRCA2 are found in 10% to 15% and account for up to 40% of heritable cases of ovarian cancer, but a number of other genes (including BRIP1 , RAD51C , and RAD51D ) have been identified as well . A model of ovarian carcinogenesis that divides surface epithelial tumors into 5 main histologically defined subtypes (high‐grade serous [70%], low‐grade serous [<10%], endometrioid [<10%], clear cell [<10%], and mucinous ovarian carcinoma [3%]) has emerged.…”