ABSTRACT
Burak Yılmaz, MS, Catherine A. Moroski-Erkul, MS, Omer Faruk Hatipoglu, PhD, Esra Gunduz, DMD, PhD, Debmalya Barh, MSc, MTech, MPhil, PhD, and Mehmet Gunduz, MD, PhD
ABSTRACT Breast cancer (BC) is classied as sporadic, familial, or hereditary. In familial BC, an unusual high number of members in a family are affected by breast, ovarian, or a related cancer. Family history is crucial in determining an individual’s BC susceptibility. A person’s risk of developing BC increases with an increasing number of affected family members. Only 5%–10% of all BC appears to have strong inheritance. Of these, 4%–5% is caused by genes with high penetrance and transmitted in an autosomal dominant manner. Testing for well-characterized mutations in blood based on a clinical suspicion of familial cancer is a well-known approach for genetic testing in cancer susceptibility. This review summarizes known genetic biomarkers,
CONTENTS
5.1 Introduction ........................................................................................................................ 168 5.1.1 What is Familial Breast Cancer? .......................................................................... 168 5.1.2 Why Is It Important? ............................................................................................. 168 5.1.3 Early Detection of Familial BC ............................................................................ 169 5.1.4 Genetics of BC ........................................................................................................ 170
5.2 High-Risk Genes ................................................................................................................ 170 5.2.1 BRCA1 ...................................................................................................................... 170
5.2.1.1 Clinical Features of BRCA1 ................................................................... 171 5.2.2 BRCA2 (FANCD1) .................................................................................................. 173
5.2.2.1 Clinical Features of BRCA2 ................................................................... 173 5.2.3 TP53.......................................................................................................................... 174 5.2.4 PTEN ........................................................................................................................ 175 5.2.5 STK11 ....................................................................................................................... 176 5.2.6 E-Cadherin (CDH1) ................................................................................................ 176
5.3 Moderate Penetrance Genes ............................................................................................. 176 5.3.1 ATM ......................................................................................................................... 176 5.3.2 CHEK2 (CHK2) ....................................................................................................... 177 5.3.3 BRIP1/BACH1 (FANCJ) ......................................................................................... 178 5.3.4 PALB2 (FANCN)..................................................................................................... 178
5.4 Low-Penetrance BC Genes ................................................................................................ 179 5.5 Conclusion and Future Directions .................................................................................. 179 References ..................................................................................................................................... 181
which may be used for early diagnosis of familial BC. Genes that serve as biomarkers for hereditary BC can be classied according to penetrance. BRCA1 and BRCA2, two BC-associated genes with high penetrance, account for about 5% of all BCs, and mutation rates of these genes are variable across populations. Other BC susceptibility genes that have been described as having high to moderate penetrance are CHEK2, PTEN, TP53, ATM, STK11/LKB1, CDH1, NBS1, RAD50, BRIP1, and PALB2. A further 20 low-penetrance BC risk-modifying alleles have been identied to date. These genes all likely play a role in the development and progression in the wide spectrum of observed hereditary BCs.
