Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations

Abstract

Tumors arising in BRCA1 and BRCA2 mutation carriers appear to have specific pathological and gene expression profiles, which show a high level of concordance. BRCA1 tumors are high-grade, negative for hormone receptors, have a high proliferation rate, and are positive for some cell cycle promoter genes. BRCA2 tumors present a phenotype opposite to BRCA1 tumors but very similar to sporadic tumors, except that BRCA2 overexpress some DNA repair markers such as CHEK2, show high cytoplasmic expression of RAD51, and are negative for HER-2 amplification and expression. Some of these characteristics have also been found in cDNA expression studies, although more analysis are necessary in order to obtain new markers that can be associated with a germ line mutation in BRCA1 or BRCA2. In this way, some studies in normal tissues of BRCA1/2 carriers suggest that differences exist in the level of expression of some genes when compared with noncarriers. Finally, IHC studies in tumors carrying a mutation in CHEK2 are rare and show contradictory results, probably due to the low number of these cases. However, they represent an example showing how different mutations of the same gene may be associated with specific histological subtypes of cancer.

Differential Expression of Genes Related to Androgen and Estrogen Metabolism in Hereditary versus Sporadic Prostate Cancer

“…BRCA1 breast cancers exhibit a down-regulation of both ERA and ERA target genes, and BRCA1 regulates ERA gene transactivation (26). These data support the concept that some susceptibility genes may regulate hormone receptor expression in familial breast cancer.…”

Effect of Reproductive Factors and Oral Contraceptives on Breast Cancer Risk inBRCA1/2Mutation Carriers and Noncarriers: Results from a Population-Based Study

“…Some differences between BRCA1-and BRCA2-related tumors exist; these include that BRCA1-related tumors are more likely to be estrogen receptor/progesterone receptor-negative than sporadic tumors, whereas BRCA2-related tumors are not (51). However, it is not clear how this could explain the different roles of lowdose oral contraceptive use between the BRCA1 mutation carriers and the BRCA2 mutation carriers.…”

Clinical and pathologic characteristics of BRCA-positive and BRCA-negative male breast cancer patients: results from a collaborative multicenter study in Italy

“…In particular, BRCA1-related BCs have distinct morphology and show a triple negative (ER-, PR-, HER2-) phenotype [8]. By contrast, BRCA2-related BCs are a heterogeneous group not fully characterized [9][10][11].…”