Novel mutations in the BRCA1 and BRCA2 genes in Iranian women with early-onset breast cancer.

Iraj Harirchi,Ann Dalton,Mohammad A Mohagheghi,Vahid R Yassaee,Sirous Zeinali,Soghra Jarvandi,David P Hornby

doi:10.1186/bcr443

Abstract

Breast cancer is the most common female malignancy and a major cause of death in middle-aged women. So far, germline mutations in the BRCA1 and BRCA2 genes in patients with early-onset breast and/or ovarian cancer have not been identified within the Iranian population. With the collaboration of two main centres for cancer in Iran, we obtained clinical information, family history and peripheral blood from 83 women under the age of 45 with early-onset breast cancer for scanning of germline mutations in the BRCA1 and BRCA2 genes. We analysed BRCA1 exons 11 and BRCA2 exons 10 and 11 by the protein truncation test, and BRCA1 exons 2, 3, 5, 13 and 20 and BRCA2 exons 9, 17, 18 and 23 with the single-strand conformation polymorphism assay on genomic DNA amplified by polymerase chain reaction. Ten sequence variants were identified: five frameshifts (putative mutations - four novel); three missense changes of unknown significance and two polymorphisms, one seen commonly in both Iranian and British populations. Identification of these novel mutations suggests that any given population should develop a mutation database for its programme of breast cancer screening. The pattern of mutations seen in the BRCA genes seems not to differ from other populations studied. Early-onset breast cancer (less than 45 years) and a limited family history is sufficient to justify mutation screening with a detection rate of over 25% in this group, whereas sporadic early-onset breast cancer (detection rate less than 5%) is unlikely to be cost-effective.

Highlights

Worldwide, breast cancer is the most common cancer in women, excluding skin cancers [1], with a lifetime risk of 10% in the general population [2]
Mutations are scattered throughout both BRCA1 and BRCA2, some coding regions were chosen for several reasons: first, it has been shown that they have a significant role in protein function [27]; second, exons 10 and 11 cover a large segment of the gene; third, many putative mutations have been reported in these regions; and fourth, the coding regions listed above have been shown in other significant studies [28,29,30,31,32] to be most likely to harbour germline BRCA1 and BRCA2 mutations
We have identified ten sequence variants in this cohort: five frameshifts, four of which were novel (Figs 1 and 2), three missense changes of unknown significance and two polymorphisms

Summary

Introduction

Breast cancer is the most common cancer in women, excluding skin cancers [1], with a lifetime risk of 10% in the general population [2]. Many efforts are under way to reduce the high incidence and mortality associated with breast and ovarian cancer by the early detection of women at high risk. These women, once identified, can be targeted for more aggressive prevention programs. Germline mutations in the BRCA1 and BRCA2 genes in patients with early-onset breast and/or ovarian cancer have not been identified within the Iranian population. Methods: With the collaboration of two main centres for cancer in Iran, we obtained clinical information, family history and peripheral blood from 83 women under the age of 45 with early-onset breast cancer for scanning of germline mutations in the BRCA1 and BRCA2 genes. Early-onset breast cancer (less than 45 years) and a limited family history is sufficient to justify mutation screening with a detection rate of over 25% in this group, whereas sporadic early-onset breast cancer (detection rate less than 5%) is unlikely to be cost-effective

Methods

Discussion

Conclusion