Genetic markers in breast tumors with hereditary predisposition

Abstract

Although epidemiological evidence supports certain risk factors (e.g., age, residence in Western countries, obesity, nulliparity, early menarche, alcohol consumption, ionizing radiation, hormone replacement therapy, mammographic density), a family history of breast cancer remains the strongest risk factor for the disease. Familial forms comprise approximately 1520% of all breast cancers and apparently have a distinctive pathogenesis determined by the particular susceptibility-gene involved [1, 2]. While the susceptibility-genes in most breast cancers developing in familial clusters have not been identified (Fig. 4-1), it is estimated that between 4046% are caused by germ-line mutations in the BRCA1 and BRCA2 genes, or by rare hereditary cancer syndromes caused by mutations in other tumor suppressor genes (TSG), CHEK2, p53, PTEN or ATM, or by germ-line mutations in BRIP1, PALB2, NBS1, RAD50 or mismatch repair genes MSH2 and MLH1, all of which are critical to genomic integrity [2, 3]. Recently, common breast cancer susceptibility alleles in CASP8 and TGFB1 have been identified [4] (Table 4-1). Inherited breast cancer has several distinctive clinical features: early age at onset, higher prevalence of bilateral breast cancer, presence of associated tumors (ovarian, colon, prostate, endometrial carcinomas, and sarcomas) [5]. Characterization of hereditary breast cancers at the molecular level is a research priority for those who wish to understand its etiology and pathogenesis and ultimately incorporate this knowledge into improved diagnosis and targeted treatment. The general information about known genes contributing to inherited breast cancer syndromes is provided in Table 4-1. For information about mutations in breast cancer susceptibility genes, their functions and interacting proteins, we direct the reader to recent comprehensive reviews [3, 614]. In this chapter, we focus on the secondary genetic alterations, cooperative oncogenes, TSGs, and other potential markers that are characteristic of BRCA1/2-associated hereditary breast cancers, as these appear to be the best characterized. © 2008 Humana Press Inc.