ArticlesPathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases
Introduction
A small proportion of breast-cancer cases, in particular cancers diagnosed in young patients are attributable to a hereditary predisposition to the disease, which is transmitted as a highly penetrant autosomal dominant trait. There has been considerable progress in the identification of the genes responsible. The BRCA1 gene is located on chromosome 17q21 and encodes a protein of 1863 aminoacid residues, which includes a zinc-finger domain.1, 2 Mutations in BRCA1 are associated with a risk of breast cancer of about 80% and a risk of ovarian cancer of 40% by age 70.3, 4 The BRCA2 gene is located on chromosome 13q12-q13 and encodes a protein of 3418 aminoacid residues without extensive sequence similarity to other known proteins.5, 6, 7 Early estimates suggest that mutations in BRCA2 are associated with a similar risk of breast cancer to BRCA1, but that the risk of ovarian cancer is lower and the risk of breast cancer in male carriers is higher (Ford and colleagues, unpublished data). Mutations in BRCA1 and BRCA2 together account for about 80% of families with four or more cases of breast cancer diagnosed in patients younger than 60 years. Other genes that are known to raise the risk of breast cancer include the TP53 gene,8 the gene on chromosome 10q22-23 responsible for Cowden's disease,9 and, in men, the androgen-receptor gene.10 Abnormalities in these genes are rare compared with mutations in BRCA1 and BRCA2. In addition, certain alleles of the H-RAS1 gene, which are common compared with disease-associated variants of BRCA1 and BRCA2, may slightly raise the risk of breast and other cancers.11
Medullary carcinoma, tubular carcinoma, invasive lobular carcinoma, and lobular carcinoma in situ have all been reported as more commonly associated with a family history of breast cancer than other cancer subtypes.12, 13, 14, 15, 16, 17 Interpretation of these studies is often complicated by small numbers of cases, variable family histories and changes in the criteria for diagnosis and classification of breast cancer. No clear agreement has emerged that any particular type is more commonly associated with a family history than any other. Nevertheless, in a histological review of the populationbased series of 4071 breast cancers diagnosed between ages 20 and 54 years in the Cancer and Steroid Hormone Study,18 a higher familial risk was reported for lobular carcinoma in situ than for other subtypes. In a separate study of the Utah Population Database,19 a greater degree of familiality was detected for invasive lobular cancer than for breast cancer overall. Since the localisation and identification of breast-cancer susceptibility genes, there have been suggestions that cancers arising in breast-cancer families, and specifically those due to BRCA1, are of higher grade than sporadic cases.20, 21, 22, 23 We examined the pathology of breast cancers related to BRCA1 and BRCA2 in a large, collaborative study organised through the Breast Cancer Linkage consortium and compared the histological findings with those of controls unselected for a family history of the disease.
Section snippets
Breast-cancer specimens
From familial breast-cancer specimens in paraffin blocks, 5 μm sections, unstained or stained with haemotoxylin and eosin, were obtained from participating groups in the UK, USA, Ireland, France, Germany, Iceland, Switzerland, and the Netherlands. Each group gathered specimens from several histopathology departments. As controls, specimens from 187 apparently sporadic female breast-cancer cases diagnosed when the women were younger than 40, 144 diagnosed between the ages of 40 and 49, and 216
Results
440 cases of familial breast cancer were included in the study. The age distribution of the control and familial groups was similar (table 1). 118 (27%) familial cases were classified as attributable to BRCA1, 78 (18%) as attributable to BRCA2, and 244 (55%) as unknown. 113 cases were classified as BRCA1, because of a clear disease-causing mutation, and five cases after geneticlinkage analysis. 67 cases were classified as BRCA2 because of a clear disease-causing mutation and 11 cases after
Discussion
This study shows that the histological characteristics of breast cancers due to BRCA1 and, to a lesser extent, BRCA2 mutations differ from those of sporadic breast cancers. Moreover, our results show that cancers associated with BRCA1 and BRCA2 mutations differ from each other. The differences were detectable despite the incomplete agreement between pathologists, which indicates that the true associations are, in fact, stronger than those observed. For BRCA1, the data were based on 42 different
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