Genetic Determinants of Breast Cancer Risk: A Review of Current Literature and Issues Pertaining to Clinical Application

Abstract

Despite major advances in breast cancer therapy, annual mortality remains significant with a sizeable proportion of patients eventually succumbing to metastatic disease. Clearly, optimizing approaches for identification and management of women at heightened risk for breast cancer will reduce overall morbidity and mortality from the disease. Over the past few decades, advances in molecular genetics and linkage analyses have allowed for the identification of specific germline mutations underlying a significant fraction of hereditary breast cancer. Genome-wide association studies have been developed as a powerful tool in identifying lower penetrance mutations, and it is believed that such genome-level variations may act in concert to give rise to the majority of inherited breast cancer risk. Controversies and uncertainties remain in clinical application of newly identified genomic loci that confer genetic susceptibility. This article reviews the well-characterized breast cancer susceptibility genes, highlights recent publications pertaining to the less well known and lower penetrance genetic polymorphisms, summarizes challenges in translating research findings to the clinical scenario, and offers some recommendations for clinical practice.

Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment

“…12,14,31 Furthermore, the practical clinical effect of the recently introduced practice guidelines pertaining to low-and moderate-risk HBOC genes is unknown. 1 We asked whether, under current consensus practice guidelines, finding a non-BRCA1/2 mutation would alter the management recommendations that would otherwise be made based on personal and family history alone.…”

“…12,13 In particular, many of the tested genes are low-to moderate-risk genes for which consensus management guidelines have not been established or have been introduced only very recently. 1,14 In the absence of an identified mutation, recommendations for cancer-specific screening and prevention approaches for patients and family members are typically based on personal and/or family cancer history. Thus, it is uncertain whether identifying such low-to moderate-risk gene mutations would change individual clinical management recommendations in patients referred for genetic testing, most or all of whom are already established to have a clinically significant personal or family history.…”

Identification of p130Cas/ErbB2-dependent invasive signatures in transformed mammary epithelial cells

“…23 Several studies have been designed to assess the genetic alterations associated with breast cancer recurrence and progression. 24 Despite these studies, a detailed molecular characterization of breast cancer progression is still missing. In this study, by inducing ErbB2 activation in the presence or in the absence of p130Cas overexpression, we provided an in vitro cell model for the understanding of the genetic changes that are associated with the shift from a non-invasive to an invasive mammary tumor.…”

Insight into the mechanisms of action of estrogen receptor β in the breast, prostate, colon, and CNS

“…Prolonged exposure to estrogen is a wellestablished risk factor for breast cancer in postmenopausal women (Darbre & Charles 2010, Fernandez & Russo 2010. The combination of multiple gene mutations (BRCA1, TP53, and ERBB2) together with the expression of ERa determines the final course and progression of the tumor (Njiaju & Olopade 2012). About 70% of breast cancers are ERa-positive and respond to anti-estrogen therapies such as tamoxifen, raloxifene, or other SERMs and aromatase inhibitors (Musgrove & Sutherland 2009).…”