Researchers used large-scale, whole-exome sequencing to take a closer look at non-BRCA predisposition gene associations with breast cancer (BC) and ovarian cancer (OV), according to a new study published in JAMA Oncology.
“Since the discovery of BRCA1 and BRCA2, multiple high- and moderate-penetrance genes have been reported as risk factors for hereditary breast cancer, ovarian cancer, or both; however, it is unclear whether these findings represent the complete genetic landscape of these cancers,” wrote researchers, led by Hsiao-Mei Lu, PhD, Ambry Genetics, Aliso Viejo, California.
At least 3% of cancer cases are due to hereditary variation in cancer predisposition genes, with between 5% and 20% of BC and OV cases tied to genetic abnormalities.
In the 1990s, researchers employed family-based genetic linkage studies to discover that BRCA1 and BRCA2 heightened the risk for BC and OV. Despite the emergence of rapid next-generation sequencing, only 11 new BC and OV cancer susceptibility genes are well characterized. Consequently, only between about 10% and 24% of patients are assessed for BC or OV risk.
Although mismatch repair genes (MMR) are widely recognized and treated as OV susceptibility genes, limited data support their contributions to BC and OV. Furthermore, several genes that have been identified as being associated with BC lack supporting large-scale evidence.
“Further investigation of cancer risks associated with less well-characterized genes is imperative, particularly as multigene panel testing that includes moderate-risk genes are increasingly used in oncology practice,” wrote the authors.
In the current study, researchers conducted whole-exome sequencing on 11,416 patients with BC, OV, or both, as well as 3,988 controls. Patients with a self-reported history of cancer were excluded from the study.
The team found increased risk of BC was associated the following four non-BRCA genes:
- ATM (OR: 2.97; 95% CI: 1.67-5.68)
- CHEK2 (OR: 2.19; 95% CI :1.40-3.56)
- PALB2 (OR: 5.53; 95% CI: 2.24-17.65)
- MSH6 (OR: 2.59; 95% CI: 1.35-5.44)
The following four genes were associated with elevated OV risk:
- MSH6 (OR: 4.16; 95% CI: 1.95-9.47)
- RAD51C (OR: not estimable; false-discovery rate-corrected P=0.004)
- TP53 (OR: 18.50; 95% CI: 2.56-808.10)
- ATM (OR: 2.85; 95% CI: 1.30-6.32)
No association was found between MRN complex genes or CDKN2A and elevated risk of BC or OV.
“The findings also do not support previously reported breast cancer associations with the ovarian cancer susceptibility genes BRIP1, RAD51C, and RAD51D, or mismatch repair genes MSH2 and PMS2,” wrote the researchers.
On the basis of their findings, the investigators suggested that MSH6 is a moderate-risk BC predisposition gene, and ATM is a moderate-risk OV predisposition gene. This finding is particularly salient because, to date, estimations of associations between these moderate-risk predisposition genes and BC and OV have been hampered by mixed or insufficient data.
Overall, the results of the current study bolstered several well-known BC or OV gene associations and concurred with previous research.
According to the researchers, one potential limitation of this study was that self-reported personal disease history of the controls could have been incomplete, and some these patients could have had a history of BC or OV.
“The results have the potential to add to our understanding of the genomic landscape of BC and OV predisposition and to inform comprehensive genetic testing in the context of patient care,” wrote the investigators.
This study was funded by Ambry Genetics Inc.