The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications

Abstract

Cancer arising in carriers of mutations in the BRCA1 and BRCA2 genes differs from sporadic breast cancer of age-matched controls and from non-BRCA1/2 familial breast carcinomas in its morphological, immunophenotypic and molecular characteristics. Most BRCA1 carcinomas have the basal cell phenotype, a subtype of highgrade, highly proliferating, estrogen receptor-and HER2-negative breast carcinomas, characterized by the expression of basal or myoepithelial markers such as basal keratins, P-cadherin, epidermal growth factor receptor, etc. This phenotype is rarely found in BRCA2 carcinomas, which are of higher grade than sporadic age-matched controls, but tend to be estrogen receptor-and progesterone receptor-positive. The expression of the cell-cycle proteins cyclins A, B1 and E and SKP2 is associated with a BRCA1 phenotype, whereas cyclin D1 and p27 expression is associated with BRCA2 carcinomas. Recent studies have shown that hereditary carcinomas that are not attributable to BRCA1/2 mutations have phenotypic similarities to BRCA2 tumors, but tend to be of lower grade and proliferation index. Somatic mutations in the BRCA genes are rarely found in hereditary tumors; by contrast, BRCA1 and BRCA2 loss of heterozygosity (LOH) is found in almost all BRCA1 and BRCA2 carcinomas, respectively. Furthermore, all types of hereditary breast carcinomas have a low frequency of HER2 expression. Finally, comparative genomic hybridization studies have revealed differences in chromosomal gains and losses between genotypes. The pathological and molecular features of hereditary breast cancer can drive specific treatments and influence the process of mutation screening. In addition, detecting molecular changes such as BRCA1/2 LOH in nonatypical cells obtained by random fine-needle aspiration, ductal lavage or nipple aspirate fluid may help to earlier identify carrier women who are at an even higher risk of developing breast carcinoma. Keywords: hereditary breast cancer; BRCA1; BRCA2; molecular pathology; histopathology; immunohistochemistry It is currently estimated that 5-10% of all breast cancers are hereditary and attributable to mutations in high-penetrance susceptibility genes, but only two of these have been identified: BRCA1 (OMIM 113705) 1 and BRCA2 (OMIM 600185). 2 BRCA1 mutations are associated with families with breast and ovarian cancer, while families with male breast tumors are associated with mutations in the BRCA2 gene.While early estimates suggested that BRCA1 and BRCA2 mutations were responsible for 75% of multiple-case breast cancer families and for the majority of families with multiple breast and ovarian cancers, 3,4 recent data have shown that these percentages may have been overestimated. In fact, the percentage of high-risk families associated with mutations in these genes seems to be around 25% in all series investigated, including the Spanish population. 5 Mutations are found in a high percentage (about 45%) of families with breast and ovarian tumors, while the mutation rate in families with only breast can...

The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

“…The p53 tumour suppressor protein is involved in the DDR and, -like BRCA1, it is also a direct substrate of the ATM kinase (Kastan and Bartek, 2004). Furthermore, like ATM, p53 was also found activated in early human lesions as part of the anticancer barrier (Bartkova et al, 2005a) and it is a marker which is reportedly elevated in BRCA1-deficient breast cancer and the triple-negative subset of breast tumours (Honrado et al, 2005;Cleator et al, 2007). As can be seen from the data in Table 2, there was no significant association of p53 overabundance (scored as positive when 20% or more cancer cells in a tumour were stained) with normal or aberrantly reduced ATM among the non-BRCA1/2 series.…”

Basal-like breast cancer and the BRCA1 phenotype

“…BRCA1 tumours are usually characterized by high histological grade, atypical medullary features, high proliferation indices, pushing borders and conspicuous lymphocytic infiltrate (Marcus et al, 1996;Armes et al, 1998;Lakhani et al, 1998;Quenneville et al, 2002;Honrado et al, 2005a. Similarities with basal-like phenotype at the immunohistochemical level are equally striking: the large majority of BRCA1 mutation cancers also lack ER, PgR and HER2 expression and frequently show p53 immunoexpression and TP53 somatic mutations (Crook et al, 1998;Armes et al, 1999;Lakhani et al, 2002;Quenneville et al, 2002;Palacios et al, 2005).…”

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes

“…However, most of FBC patients do not carry mutations in these genes, and are known as non-BRCA1/2 or BRCAX cases. BRCA1-associated tumors can be differentiated from BRCA2, BRCAX and SBC based on their immunohistochemical (IHC) profiles (see reviews (Honrado et al, 2005a;Lacroix and Leclercq, 2005)). Most reports suggest that BRCA1-associated tumors have a basal-like phenotype because they share many expression, IHC and clinical features with basal-like cancers (see reviews (Tischkowitz and Foulkes, 2006;).…”