Prevalence and Prognostic Role of BRCA1/2 Variants in Unselected Chinese Breast Cancer Patients

Abstract

BackgroundThe prevalence of BRCA1/2 variants in Chinese breast cancer patients varies among studies. Germline or somatic BRCA1/2 mutations are associated with sensitivity to poly(ADP-ribose) polymerase-1 inhibitors and DNA-damaging agents. We aimed to investigate the distribution of both somatic and germline BRCA1/2 variants in unselected Chinese breast cancer patients, and explore their roles in tumor phenotype and disease prognosis.Methods507 breast cancer patients, unselected for family history of breast cancer or age at diagnosis, were prospectively enrolled from West China Hospital between Feb. 2008 and Feb. 2014. BRCA1/2 variants in the exons/flanking regions were detected in fresh-frozen tumors using next-generation sequencing and confirmed by independent methods. Germline/somatic status was validated by Sanger sequencing in paired blood/normal tissue.ResultsBRCA1/2 pathogenic or likely pathogenic (P/LP) variants were detected in 50 patients (9.9%), including 40 germline carriers (18 in BRCA1, 22 in BRCA2), 9 patients with somatic variants (3 in BRCA1, 6 in BRCA2), and 1 patient with concurrent germline/somatic variants in BRCA2. The triple-negative (21.4%) and Luminal B (9.7%) subtypes had higher rates of BRCA1/2 variants. In patients with disease stage 0~II, presence of a germline or somatic BRCA1 P/LP variant increased the risk of relapse as compared to non-carriers [univariate hazard ratio (HR): 3.70, P = 0.04]. Germline BRCA1 P/LP variants, which were associated with aggressive tumor phenotypes, predicted worse disease-free survival in the subgroup of stage 0~II (HR: 4.52, P = 0.02) and N0 (HR: 5.4, P = 0.04) compared to non-carriers.ConclusionA high frequency of germline and somatic BRCA1/2 P/LP variants was detected in unselected Chinese breast cancer patients. Luminal B subtype should be considered as a high-risk population of BRCA1/2 mutation, in addition to triple-negative breast cancer. BRCA1 status was associated with aggressive tumor phenotype and worse disease progression in early stage breast cancer patients.

Network Meta‐Analysis on the Effects of DNA Damage Response‐Related Gene Mutations on Overall Survival of Breast Cancer Based on TCGA Database

“…PARP1 is essential for the proper dynamic assembly of DSB sensors and for recruiting the key components of the early ATM dependent signaling pathway, which provided a new insight into the dynamic nature of protein interaction networks in the nucleus of living cells [Mangone et al, 2012]. BRCA1 and BRCA2 are well-studied genes and their mutations are thought to be associated closely to the worse disease prognosis in BC patients [Koumarianou et al, 2016, Zhong et al, 2016. Aberrancies of the ATR gene were one of the most TABLE V. HR and 95%CI of Twelve Mutated Genes for Overall Survival in Breast Carcinoma Hazard ratio (95%CI) If the confidence interval does not contain 1, there is a significant difference.…”

The role of BRCA status on prognosis in patients with triple-negative breast cancer

“…BRCA testing was performed using germline DNA (from blood) and somatic DNA (from tumor tissue). Details of the comprehensive NGS workflow for testing and analyzing tumor BRCA1/2 variants were described in our previous work [ 49 ]. Germline mutation were interpreted according to the American College of Medical Genetics and Genomics (ACMG) and other studies [ 50 ].…”

“…Briefly, variants that produce premature termination codons which are associated with non-functional or truncated proteins were classified as pathogenic (P) variants in our study: such as nonsense mutations, frameshift mutations, splice site mutations and exonic deletions. Similarly, inactivating somatic variants were considered as pathogenic variants: such as nonsense mutations and frameshift mutations [ 49 ]. The results were categorized as either positive or negative for a deleterious mutation.…”

Molecular Subtypes and Prognosis in Young Mexican Women With Breast Cancer

“…32 Another potential reason may be the fact that many patients may have received hormonal therapy without ovarian suppression, and the future implementation of new treatment strategies including ovarian suppression may possibly lead to changes in this outcome. 33 Finally, young patients with Luminal B tumors may be more likely to carry BRCA mutations, 34 and their survival could potentially be improved by implementing interventions such as oophorectomy. 35 This study has some limitations.…”