Abstract
Breast and ovarian cancers are some of the most common tumors in females, and the genetic predisposition is emerging as one of the key risk factors in the development of these two malignancies. BRCA1 and BRCA2 are the best-known genes associated with hereditary breast and ovarian cancer. However, recent advances in molecular techniques, Next-Generation Sequencing in particular, have led to the identification of many new genes involved in the predisposition to breast and/or ovarian cancer, with different penetrance estimates. TP53, PTEN, STK11, and CDH1 have been identified as high penetrance genes for the risk of breast/ovarian cancers. Besides them, PALB2, BRIP1, ATM, CHEK2, BARD1, NBN, NF1, RAD51C, RAD51D and mismatch repair genes have been recognized as moderate and low penetrance genes, along with other genes encoding proteins involved in the same pathways, possibly associated with breast/ovarian cancer risk. In this review, we summarize the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and the associated genetic disorders. Furthermore, we discuss the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.
Highlights
Breast cancer (BC) and ovarian cancer (OC) are the first and the eighth most common tumors for both incidence and mortality in females, respectively [1]
BRCA1 [7] and BRCA2 [8] are the main genes involved in Hereditary Breast and Ovarian Cancer syndrome (HBOC) [9], but other genes have been associated with BC and OC risk [10,11,12,13,14,15,16,17]
Given the high risk of developing BC, the National Comprehensive Cancer Network (NCCN) guidelines suggest that women with TP53 pathogenic variant (PV)/likely-pathogenic variant (LPV) should undergo clinical breast examination every 6–12 months starting at the age of 20, annual breast magnetic resonance imaging (MRI) screening with contrast from 20 to 75 years, and mammography with consideration of tomosynthesis from 30 to 75 years
Summary
Breast cancer (BC) and ovarian cancer (OC) are the first and the eighth most common tumors for both incidence and mortality in females, respectively [1]. In the last few years, the advent of Next-Generation Sequencing (NGS) has enabled the analysis of a great number of genes with the advantage of lower costs and wider access to molecular tests for patients with suspected genetic syndromes [18]. In this complex scenario, one of the main issues is to define how many and which genes should be tested in patients with a suspicion of a genetic predisposition to cancer. A genetic variant is usually defined with high penetrance when the RR for the carrier is ≥10.0, with medium-high penetrance when the RR is between 5.0 and 10.0, with moderate penetrance when the RR is between 2.0 and 5.0, and with low penetrance when the RR is between 1.0 and 2.0 [19]
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