Non-BRCA1/2 Breast Cancer Susceptibility Genes: A New Frontier with Clinical Consequences for Plastic Surgeons

Abstract

Summary:Twenty percent of breast cancer cases may be related to a genetic mutation conferring an increased risk of malignancy. The most common and prominent breast cancer susceptibility genes are BRCA1 and BRCA2, found in nearly 40% of such cases. However, continued interest and investigation of cancer genetics has led to the identification of a myriad of different breast cancer susceptibility genes. Additional genes, each with unique significance and associated characteristics, continue to be recognized. Concurrently, advanced genetic testing, while still controversial, has become more accessible and cost-effective. As oncologic and reconstructive advances continue to be made in prophylactic breast reconstructive surgery, patients may present to plastic surgeons with an increasingly more diverse array of genetic diagnoses to discuss breast reconstruction. It is therefore imperative that plastic surgeons be familiar with these breast cancer susceptibility genes and their clinical implications. We, therefore, aim to review the most common non-BRCA1/2 breast cancer susceptibility genetic mutations in an effort to assist plastic surgeons in counseling and managing this unique patient population. Included in this review are syndromic breast cancer susceptibility genes such as TP53, PTEN, CDH1, and STK11, among others. Nonsyndromic breast cancer susceptibility genes herein reviewed include PALB2, CHEK2, and ataxia telangiectasia mutated gene. With this knowledge, plastic surgeons can play a central role in the diagnosis and comprehensive treatment, including successful breast reconstruction, of all patients carrying genetic mutations conferring increased risk for breast malignancies.

Educational Case: Hereditary breast and ovarian cancers

“…Although the BRCA genes are the most common and prominent genes associated with breast cancer, mutations in several other genes have also been linked to malignancy. These include genes associated with syndromic manifestations, including TP53 , PTEN , CDH1 , STK11 , and mismatch repair genes, as well as non-syndromic genes such as PALB2 , CHEK2 , and ATM 10 , 11 (see Table 1 ) . Those with mutations in these genes are at risk of certain types of cancers, and unique screening regimens must be followed in these patients.…”

“…Deleterious mutations in these genes cause increased risk of breast cancer, as well as other types of cancers. 10 , 11 Gene Encoded protein Normal function Syndrome Associated tumors/conditions BRCA1 BRCA1 Tumor suppressor Hereditary breast and ovarian cancer syndrome Breast, tubo-ovarian, endometrial, peritoneal, prostate, pancreatic, & male breast cancer. BRCA2 BRCA2 Tumor suppressor Hereditary breast and ovarian cancer syndrome Breast, tubo-ovarian, endometrial, peritoneal, prostate, pancreatic, & male breast cancer TP53 p53 Tumor suppressor Li-Fraumeni syndrome Breast, lung, and briain cancer; sarcomas; leukemia PTEN PTEN Tumor suppressor Cowden syndrome Hamartomatous polyps, lipomas, & ganglioneuromas.…”

Factors that impact risk management decisions among women with pathogenic variants in moderate penetrance genes associated with hereditary breast cancer

“…Research and evidence are lacking with respect to the occurrence of second primary breast cancers in carriers of PV in moderate penetrance genes (Bernstein, Concannon, & Group, 2017;Weiss, Garber, & King, 2018). Previous studies have suggested that the decision to proceed with surgery must take into consideration the personal and family risk factors unique to each patient (Frey, Salibian, Schnabel, Choi, & Karp, 2017).…”

Implementation of Risk-Stratified Breast Cancer Prevention With a Polygenic Risk Score Test in Clinical Practice

“…9 Genetic factors include rare pathogenic variants (PV) in high-and moderate-risk cancer predisposition genes (BRCA1, BRCA2, etc), having effects large enough to warrant monogenic testing. [10][11][12] However, only a fraction (5%-10%) of BC cases are caused by these rare PVs. 13 A considerable part of BC risk variation is explained by variants outside these highrisk genes in the form of BC-associated common single-nucleotide polymorphisms (SNPs), identified by genome-wide association studies (GWAS).…”