Hereditary breast cancer: syndromes, tumour pathology and molecular testing

Abstract

Hereditary factors account for a significant proportion of breast cancer risk. Approximately 20% of hereditary breast cancers are attributable to pathogenic variants in the highly penetrant BRCA1 and BRCA2 genes. A proportion of the genetic risk is also explained by pathogenic variants in other breast cancer susceptibility genes, including ATM, CHEK2, PALB2, RAD51C, RAD51D and BARD1, as well as genes associated with breast cancer predisposition syndromes - TP53 (Li-Fraumeni syndrome), PTEN (Cowden syndrome), CDH1 (hereditary diffuse gastric cancer), STK11 (Peutz-Jeghers syndrome) and NF1 (neurofibromatosis type 1). Polygenic risk, the cumulative risk from carrying multiple low-penetrance breast cancer susceptibility alleles, is also a well-recognised contributor to risk. This review provides an overview of the established breast cancer susceptibility genes as well as breast cancer predisposition syndromes, highlights distinct genotype-phenotype correlations associated with germline mutation status and discusses molecular testing and therapeutic implications in the context of hereditary breast cancer.

Keywords: BRCA1; BRCA2; cancer syndromes; familial breast cancer; genotype-phenotype correlation.

Figure 1

Examples of tumour pathology in hereditary breast cancer. A, BRCA1‐associated invasive carcinoma of no special type with medullary pattern; B, CDH1‐associated breast cancer is characteristically invasive lobular carcinoma; C, invasive carcinoma with apocrine differentiation can be associated with germline PTEN mutations (Cowden syndrome).