Abstract
Families with breast and ovarian cancer are often tested for disease associated sequence variants in BRCA1 and BRCA2. Pathogenic sequence variants (PVs) in these two genes are known to increase breast and ovarian cancer risks in females. However, in most families no PVs are detected in these two genes. Currently, several studies have identified other genes involved in hereditary breast and ovarian cancer (HBOC). To identify genetic risk factors for breast and ovarian cancer in a Norwegian HBOC cohort, 101 breast and/or ovarian cancer patients negative for PVs and variants of unknown clinical significance (VUS) in BRCA1/2 were screened for PVs in 94 genes using next-generation sequencing. Sixteen genes were closely scrutinized. Nine different deleterious germline PVs/likely pathogenic variants (LPVs) were identified in seven genes in 12 patients: three in ATM, and one in CHEK2, ERCC5, FANCM, RAD51C, TP53 and WRN. Additionally, 32 different VUSs were identified and these require further characterization. For carriers of PV/LPV in many of these genes, there are no national clinical management programs in Norway. The diversity of genetic risk factors possibly involved in cancer development show the necessity for more knowledge to improve the clinical follow-up of this genetically diverse patient group.
Highlights
A total of 3,589 new female breast cancer (BC) cases and 520 new ovarian cancer (OC) cases were reported in Norway in 20171, 5–10% are thought to be due to inherited pathogenic variants (PVs)[2]
Half (48.5%) of the identified Pathogenic sequence variants (PVs)/likely pathogenic variants (LPVs) were located in BRCA1 and BRCA2, meaning that more than half (51.5%) of all pathogenic findings were in other genes
A total of 101 BC and/or OC patients with no BRCA1/2 PVs, LPVs or variants of unknown clinical significance (VUS) were included in the study (Supplementary Table S1)
Summary
A total of 3,589 new female breast cancer (BC) cases and 520 new ovarian cancer (OC) cases were reported in Norway in 20171, 5–10% are thought to be due to inherited pathogenic variants (PVs)[2]. The largest study of its kind, so far, investigated 35,409 women with a single breast cancer diagnosis, where 93.2% met the National Comprehensive Cancer Network (NCCN) guidelines for HBOC genetic testing[9] These patients were screened for PVs using a 25-gene panel, and identified PVs/LPVs in 9.3%. Genes www.nature.com/scientificreports encoding proteins involved in homologous recombination repair, the same pathway in which BRCA1 and BRCA2 are involved, are frequently reported with pathogenic findings in HBOC cases. These genes include the previously mentioned CHEK2, ATM and PALB2, together with NBN, RAD50, RAD51C, RAD51D and BRIP19,10,12–14. We included Norwegian women diagnosed with BC and/or OC, for whom no BRCA1 or BRCA2 PV/LPV/variant of unknown clinical significance (VUS) have been identified
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