A Review of the Hereditary Component of Triple Negative Breast Cancer: High- and Moderate-Penetrance Breast Cancer Genes, Low-Penetrance Loci, and the Role of Nontraditional Genetic Elements

Abstract

Triple negative breast cancer (TNBC), representing 10-15% of breast tumors diagnosed each year, is a clinically defined subtype of breast cancer associated with poor prognosis. The higher incidence of TNBC in certain populations such as young women and/or women of African ancestry and a unique pathological phenotype shared between TNBC and BRCA1-deficient tumors suggest that TNBC may be inherited through germline mutations. In this article, we describe genes and genetic elements, beyond BRCA1 and BRCA2, which have been associated with increased risk of TNBC. Multigene panel testing has identified high- and moderate-penetrance cancer predisposition genes associated with increased risk for TNBC. Development of large-scale genome-wide SNP assays coupled with genome-wide association studies (GWAS) has led to the discovery of low-penetrance TNBC-associated loci. Next-generation sequencing has identified variants in noncoding RNAs, viral integration sites, and genes in underexplored regions of the human genome that may contribute to the genetic underpinnings of TNBC. Advances in our understanding of the genetics of TNBC are driving improvements in risk assessment and patient management.

Development of Radiotracers for Breast Cancer—The Tumor Microenvironment as an Emerging Target

“…Furthermore, at the time of diagnosis, the tumor is larger in size and higher-graded comparing to the other BCa types [ 9 ]. This phenotype usually shows a poorly differentiated histology and tends to develop more frequently lymph node metastases with a higher affinity for lung and brain metastases [ 9 , 10 ]. The heterogeneity of TNBC is reflected in the six molecular subtypes which include two basal-like, an immunomodulatory, a mesenchymal, a mesenchymal stem-like, and a luminal androgen receptor subtype.…”

Should Genetic Testing for Cancer Predisposition Be Standard-of-Care for Women with Invasive Breast Cancer? The Murtha Cancer Center Experience

“…During the 25 year period since the BRCA1 and BRCA2 genes were identified, a number of additional breast cancer genes have been identified [11]. Management of breast cancer patients who harbor germline mutations in cancer predisposition genes may differ from those patients with sporadic breast cancer.…”

Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes

“…Noteworthy, gBRCA1/2 mutations have been identified in 10-20% of TNBCs, while somatic mutations are rarely reported (3-5% of cases) [15]. BRCA1 mutated TNBC patients are commonly younger than those harboring BRCA2 mutations, with a median age at diagnosis of 47.2 years and 58.8 years, respectively [16]. The relationship between these genomic scars and race/ethnicity has been widely studied, showing the lowest and the highest prevalence of gBRCA1/2 mutations in the Asian group (0.5%) and in the Ashkenazi Jewish (AJ) population (10.2%), respectively [17].…”