Germline breast cancer susceptibility gene mutations and breast cancer outcomes

Abstract

BackgroundIt is unclear whether germline breast cancer susceptibility gene mutations affect breast cancer related outcomes. We wanted to evaluate mutation patterns in 20 breast cancer susceptibility genes and correlate the mutations with clinical characteristics to determine the effects of these germline mutations on breast cancer prognosis.MethodsThe study cohort included 480 ethnic Chinese individuals in Taiwan with at least one of the six clinical risk factors for hereditary breast cancer: family history of breast or ovarian cancer, young age of onset for breast cancer, bilateral breast cancer, triple negative breast cancer, both breast and ovarian cancer, and male breast cancer. PCR-enriched amplicon-sequencing on a next generation sequencing platform was used to determine the germline DNA sequences of all exons and exon-flanking regions of the 20 genes. Protein-truncating variants were identified as pathogenic.ResultsWe detected a 13.5% carrier rate of pathogenic germline mutations, with BRCA2 being the most prevalent and the non-BRCA genes accounting for 38.5% of the mutation carriers. BRCA mutation carriers were more likely to be diagnosed of breast cancer with lymph node involvement (66.7% vs 42.6%; P = 0.011), and had significantly worse breast cancer specific outcomes. The 5-year disease-free survival was 73.3% for BRCA mutation carriers and 91.1% for non-carriers (hazard ratio for recurrence or death 2.42, 95% CI 1.29–4.53; P = 0.013). After adjusting for clinical prognostic factors, BRCA mutation remained an independent poor prognostic factor for cancer recurrence or death (adjusted hazard ratio 3.04, 95% CI 1.40–6.58; P = 0.005). Non-BRCA gene mutation carriers did not exhibit any significant difference in cancer characteristics or outcomes compared to those without detected mutations. Among the risk factors for hereditary breast cancer, the odds of detecting a germline mutation increased significantly with having bilateral breast cancer (adjusted odds ratio 3.27, 95% CI 1.64–6.51; P = 0.0008) or having more than one risk factor (odds ratio 2.07, 95% CI 1.22–3.51; P = 0.007).ConclusionsWithout prior knowledge of the mutation status, BRCA mutation carriers had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. Optimal approach to breast cancer treatment for BRCA mutation carriers warrants further investigation.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4229-5) contains supplementary material, which is available to authorized users.

BRCAness Combined With a Family History of Cancer Is Associated With a Poor Prognosis for Breast Cancer Patients With a High Risk of BRCA Mutations

“…These results might be because we focused on a limited population of early-onset and TNBC patients. However, these findings have confirmed the results reported by Slattery et al 41 and Wang et al 42 Moreover, we evaluated the combination of BRCAness and FH. We found no overall significant association between the presence of BRCAness and a positive FH.…”

Differentially expressed genes and key molecules of BRCA1/2-mutant breast cancer: evidence from bioinformatics analyses

“…Furthermore, some genes were further verified by the identification between wild-type BC and normal tissue, which showed that a total of 43 genes had not only significant changes of expression level in BC patients but further more obvious changes in BRCA1/2-mutant BC patients. This demonstrated specific expression alternation of genes in our study, including TTK, EXO1, TICRR (TOBPPI interacting checkpoint and replication regulation) and so on, would be closely associated with BRCA1/2 mutations, providing a clue for further understanding the certain characteristic of BRCA1/2-mutant BC (for example, increased risk of distant metastasis and more aggressive nature) (Wang et al, 2018) and clarifying its pathogenesis.…”

Development of PARP and Immune-Checkpoint Inhibitor Combinations

“…The data in this regard are mixed, with a number of large metaanlayses demonstrating improved prognosis for patients with ovarian cancer harboring mutations in BRCA1/2 (79,80), possibly due to the relationship between BRCA1/2 mutations and platinum sensitivity. However, the data in patients with breast cancer are more mixed, with some studies indicating poorer prognosis in BRCA1/2-mutant patients (81,82).…”