Genetic and clinical characterization of BRCA-associated hereditary breast and ovarian cancer in Navarra (Spain)

Ainara Ruiz De Sabando,Lourdes Morales Garofalo,Maria A Ramos-Arroyo,Edurne Urrutia Lafuente,Fermín García-Amigot,Eva Ardanaz,Sira Moreno,Angel Alonso Sánchez

doi:10.1186/s12885-019-6277-x

Ainara Ruiz De Sabando, Lourdes Morales Garofalo + Show 6 more

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https://doi.org/10.1186/s12885-019-6277-x

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Abstract

BackgroundGenetic testing for BRCA1/2 genes is widely used as a strategy to reduce incidence and morbidity of hereditary breast and ovarian cancer (HBOC). The purpose of this study is to analyse the demographic and molecular characteristics of BRCA germline mutations in Navarra, Spain, and to investigate the clinical profile of hereditary and sporadic breast cancer (BC) and ovarian cancer (OC) in the Community.MethodsThe study includes 1246 individuals assessed for BRCA1/2 genetic testing in Navarra, during 2000–2016, and a cohort of BC (n = 4384) and OC (n = 561) from the population-based Navarra Cancer Registry. Distribution and molecular characteristics of BRCA1/2 mutations, as well as, comparative analysis of the clinical course, pathologic features and overall survival (OS) of patients in different risk groups were investigated.ResultsBRCA mutation detection rate was 16%, with higher proportion (63%) of BRCA2 families. Nineteen per cent of mutations were recurrent, one of which, BRCA2 c.6024dupG, showed high association to OC. BRCA carriers had double risk (95% CI = 1.04–4.33) of developing multiple malignancies than low risk families and were diagnosed at a much earlier age (16.6 and 11.7 years difference for BC and OC, respectively) when compared to the general population. For BC, BRCA carriers showed a more advanced histological stage, higher risk of bilateral neoplasms (OR = 4.3; 95% CI = 1.3–11.4, for BRCA2 carriers) and worse OS rate at 5-, 10- and 15- years, than women with sporadic tumors. For OC, over 70% of patients of all risk groups showed advanced stages at diagnosis, with the highest among BRCA1 carriers (91%). Furthermore, they also had higher probability of developing ovarian bilateral tumors (OR = 7.8, 95% CI = 1.7–55.7, for BRCA1 carriers) than the general population. Five-year OS rate was worse among women with sporadic OC than BRCA carriers, but it levelled out over the 15-year period.ConclusionsIn addition to national similarities in the HBOC-BRCA1/2 associated mutational spectrum, we identified a recurrent BRCA2 pathogenic variant (c.6024dupG), highly associated to OC in Navarra. Carriers of BRCA1/2 mutations showed a more severe BC and OC phenotype and had a worse overall prognosis when compared to a large cohort of women with sporadic counterpart tumors.

Highlights

Genetic testing for BRCA1/2 genes is widely used as a strategy to reduce incidence and morbidity of hereditary breast and ovarian cancer (HBOC)
Families are classified as high-risk families, if they meet the criteria established by the Breast Cancer Committee of the Complejo Hospitalario de Navarra (CHN) (Additional file 1: Figure S1), or as low-risk families, if not
Hereditary breast/ovarian cancer study (2000–2016) Among the 751 evaluated families, residents of Navarra, with clinical and family history that suggested HBOC, 233 were classified as low-risk families, with no further analysis, and 518 others as high-risk families, for which mutational analysis was performed in the index affected member (Table 1)

Summary

Introduction

Genetic testing for BRCA1/2 genes is widely used as a strategy to reduce incidence and morbidity of hereditary breast and ovarian cancer (HBOC). The purpose of this study is to analyse the demographic and molecular characteristics of BRCA germline mutations in Navarra, Spain, and to investigate the clinical profile of hereditary and sporadic breast cancer (BC) and ovarian cancer (OC) in the Community. Survival has substantially improved over the past few years due to screening and the improvement of treatments, BC is the leading cause of cancer death among Spanish women, with about 6500 deaths in 2017, and OC is the fifth, with 2000 [4]. Between 5 and 10% [5] of all BC and 13–15% of OC [6, 7] are hereditary and approximately 25% are associated with the Hereditary breast/ovarian cancer (HBOC) syndrome, caused by abnormalities in the DNA repair genes BRCA1 and BRCA2 [8]. Clinical findings regarding the prognostic role of BRCA mutational status are still controversial

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