Prevalence of the BRCA1 founder mutation c.5266dupin Brazilian individuals at-risk for the hereditary breast and ovarian cancer syndrome.

Ingrid P Ewald,Aishameriane Schmidt,Sara Hamaguchi,Aline S Moreira,Suzi A Camey,Patrícia Koehler-Santos,Fernando R Vargas,Patrícia Izetti,Miguel Am Moreira,Carlos A Moreira-Filho,Roberto Giugliani,Maira Caleffi,Danielle R Cunha,Patricia Ashton-Prolla

doi:10.1186/1897-4287-9-12

Abstract

About 5-10% of breast and ovarian carcinomas are hereditary and most of these result from germline mutations in the BRCA1 and BRCA2 genes. In women of Ashkenazi Jewish ascendance, up to 30% of breast and ovarian carcinomas may be attributable to mutations in these genes, where 3 founder mutations, c.68_69del (185delAG) and c.5266dup (5382insC) in BRCA1 and c.5946del (6174delT) in BRCA2, are commonly encountered. It has been suggested by some authors that screening for founder mutations should be undertaken in all Brazilian women with breast cancer. Thus, the goal of this study was to determine the prevalence of three founder mutations, commonly identified in Ashkenazi individuals in a sample of non-Ashkenazi cancer-affected Brazilian women with clearly defined risk factors for hereditary breast and ovarian cancer (HBOC) syndrome. Among 137 unrelated Brazilian women from HBOC families, the BRCA1c.5266dup mutation was identified in seven individuals (5%). This prevalence is similar to that encountered in non-Ashkenazi HBOC families in other populations. However, among patients with bilateral breast cancer, the frequency of c.5266dup was significantly higher when compared to patients with unilateral breast tumors (12.1% vs 1.2%, p = 0.023). The BRCA1 c.68_69del and BRCA2 c.5946del mutations did not occur in this sample. We conclude that screening non-Ashkenazi breast cancer-affected women from the ethnically heterogeneous Brazilian populations for the BRCA1 c.68_69del and BRCA2 c.5946del is not justified, and that screening for BRCA1c.5266dup should be considered in high risk patients, given its prevalence as a single mutation. In high-risk patients, a negative screening result should always be followed by comprehensive BRCA gene testing. The finding of a significantly higher frequency of BRCA1 c.5266dup in women with bilateral breast cancer, as well as existence of other as yet unidentified founder mutations in this population, should be further assessed in a larger well characterized high-risk cohort.

Highlights

Breast cancer is the most common non-cutaneous malignancy in Brazilian women of all ages
A significant proportion of individuals with hereditary breast cancer have mutations in the tumor suppressor genes Breast Cancer 1 (BRCA1) (OMIM # 113705) and Breast Cancer 2 (BRCA2) (OMIM # 600185) [5]. Carriers of such mutations are usually predisposed to breast, ovarian, prostate and other cancers at an early age, a syndrome known as Hereditary Breast and Ovarian Cancer (HBOC) [6]
A significant family history of HBOC was defined as presence of either: (a) the American Society of Clinical Oncology (ASCO) criteria for HBOC [19] or (b) a prior probability of harboring a BRCA mutation ≥ 30% by pedigree analysis using the Myriad mutation prevalence tables or the Penn II mutation prediction model [20,21,22]

Summary

Introduction

Breast cancer is the most common non-cutaneous malignancy in Brazilian women of all ages. In the Southern and Southeastern States of Brazil, the estimated breast cancer incidence rates for 2010 reached 64.54 and 64.30 per 100,000 women, the highest in the country [1]. A significant proportion of individuals with hereditary breast cancer have mutations in the tumor suppressor genes BRCA1 (OMIM # 113705) and BRCA2 (OMIM # 600185) [5]. Carriers of such mutations are usually predisposed to breast, ovarian, prostate and other cancers at an early age, a syndrome known as Hereditary Breast and Ovarian Cancer (HBOC) [6]

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