Inherited and acquired alterations in development of breast cancer

Abstract

Breast cancer is the most common cancer among women, accounting for about 30% of all cancers. In contrast, breast cancer is a rare disease in men, accounting for less than 1% of all cancers. Up to 10% of all breast cancers are hereditary forms, caused by inherited germ-line mutations in "high-penetrance," "moderate-penetrance," and "low-penetrance" breast cancer susceptibility genes. The remaining 90% of breast cancers are due to acquired somatic genetic and epigenetic alterations. A heterogeneous set of somatic alterations, including mutations and gene amplification, are reported to be involved in the etiology of breast cancer. Promoter hypermethylation of genes involved in DNA repair and hormone-mediated cell signaling, as well as altered expression of micro RNAs predicted to regulate key breast cancer genes, play an equally important role as genetic factors in development of breast cancer. Elucidation of the inherited and acquired genetic and epigenetic alterations involved in breast cancer may not only clarify molecular pathways involved in the development and progression of breast cancer itself, but may also have an important clinical and therapeutic impact on improving the management of patients with the disease.

Keywords: acquired alterations; breast cancer; epigenetics; inherited susceptibility.

Figure 1

Genetic susceptibility in hereditary breast cancer. Up to 10% of all breast cancers are caused by inherited germ-line mutations in breast cancer susceptibility genes. High-penetrance genes (BRCA1 and BRCA2) contribute to 25% of hereditary breast cancer, moderate-penetrance genes (CHEK2, ATM, PALB2, BRIP1, RAD51C) contribute less than 5% to the risk of breast cancer. The great majority of hereditary breast cancer may be due to common low-penetrance alleles or other still unknown genetic factors. Abbreviation: BC, breast cancer.

Figure 2

Somatic mutations in breast cancer. The great majority of somatic mutations are single base substitutions, mainly missense mutations; missense changes account for about 60% of somatic alterations; the remaining somatic mutations result in stop codon (5.1%) or in alterations of splice site (2.8%) and only a few percentages of these are insertions, deletions, or duplications (5.6%).