Identification of Eleven Novel BRCA Mutations in Tunisia: Impact on the Clinical Management of BRCA Related Cancers

Abstract

BackgroundBreast cancer is the world’s most common cancer among women. It is becoming an increasingly urgent problem in low- and middle-income countries (LMICs) where a large fraction of women is diagnosed with advanced-stage disease and have no access to treatment or basic palliative care. About 5-10% of all breast cancers can be attributed to hereditary genetic components and up to 25% of familial cases are due to mutations in BRCA1/2 genes. Since their discovery in 1994 and 1995, as few as 18 mutations have been identified in BRCA genes in the Tunisian population. The aim of this study is to identify additional BRCA mutations, to estimate their contribution to the hereditary breast and ovarian cancers in Tunisia and to investigate the clinicopathological signatures associated with BRCA mutations.MethodsA total of 354 patients diagnosed with breast and ovarian cancers, including 5 male breast cancer cases, have been investigated for BRCA1/2 mutations using traditional and/or next generation sequencing technologies. Clinicopathological signatures associated with BRCA mutations have also been investigated.ResultsIn the current study, 16 distinct mutations were detected: 10 in BRCA1 and 6 in BRCA2, of which 11 are described for the first time in Tunisia including 3 variations that have not been reported previously in public databases namely BRCA1_c.915T>A; BRCA2_c.-227-?_7805+? and BRCA2_c.249delG. Early age at onset, family history of ovarian cancer and high tumor grade were significantly associated with BRCA status. BRCA1 carriers were more likely to be triple negative breast cancer compared to BRCA2 carriers. A relatively high frequency of contralateral breast cancer and ovarian cancer occurrence was observed among BRCA carriers and was more frequent in patients carrying BRCA1 mutations.ConclusionOur study provides new insights into breast and ovarian cancer genetic landscape in the under-represented North African populations. The prevalence assessment of novel and recurrent BRCA1/2 pathogenic mutations will enhance the use of personalized treatment and precise screening strategies by both affected and unaffected North African cancer cases.

Spectrum of Genetic Diseases in Tunisia: Current Situation and Main Milestones Achieved

“…Furthermore, breast and cervical cancer screening has been integrated into basic health care services within the framework of national cancer control plans (Ministère de la Santé, Direction de Santé, Plan pour la lutte contre le cancer 2015-2019) (Tunis: Ministère de la Santé, 2015). In addition, the establishment of an NGS platform in Institut Pasteur de Tunis, allowed the setting up of molecular diagnosis of familial cancers, thus contributing to the better characterization and widening of the mutation spectrum of BRCA1/2 genes in the Tunisian population [99]. The increased prevalence of cystic fibrosis (CF) among Tunisian children and the potentially severe complications associated with this disease justify the management of CF by a multidisciplinary team of clinicians in the child pulmonology referral unit in Bechir Hamza children's Hospital of Tunis [54].…”

Pathologically confirmed women's breast cancer: A descriptive study of Tunisian and Algerian series

“…It remains only in the framework of research of germline BRCA mutations. 52,53 This study has some limitations. Menopausal status, comorbid-…”

“…Some authors suggested that these differences could be partly explained by genetic influences, ethnicity and race factors. 52,53 51 In Tunisia and Algeria, the use of NGS is not applied in routine. It remains only in the framework of research of germline BRCA mutations.…”

“…High rates of triple negative BCs among Sub‐Saharan African women are not well understood. Some authors suggested that these differences could be partly explained by genetic influences, ethnicity and race factors 52,53 . Differences in rates of BC categories may be related also to variations in immunohistochemistry techniques and interpretation.…”

“…In Tunisia and Algeria, the use of NGS is not applied in routine. It remains only in the framework of research of germline BRCA mutations 52,53 …”