BRCA1/BRCA2 Mutations Shaped by Ancient Consanguinity Practice in Southern Mediterranean Populations

摘要

The aim of this study is to investigate the involvement of consanguinity on BRCA1/2 mutation incidence in SouthernMediterranean populations and to confirm their low penetrance by comparison of their recurrence in sporadic and familialbreast cancer in a context of ancient consanguinity practice. Our study comprises of two parts: First, a comparison ofthe consanguinity rates of the South Mediterranean countries in a relationship with the frequency of BRCA1 deleteriousmutations in breast cancer families and the recurrence of these mutations. Second, we investigated 23patients with afamily history of breast cancer, 51 patients without a family history of breast cancer using next-generation sequencingof BRCA2 and then confirmed by Sanger sequencing for the novel mutation. As results, we clearly show a strongrelationship between the frequency of BRCA1 deleterious mutations in breast cancer families and rate of consanguinity,since they are significantly inversely correlated. Four deleterious mutations were found in BRCA2 gene including anovel frame-shift mutationc.9382_9383dup in a patient with familial breast cancer and three other frame-shift mutationsc.6591_6592del, c.1310_1313del and c.7654dup in patients with sporadic breast cancer.These results are discussedin a context of selective pressure of ancient consanguinity practice. In conclusion, the study of BRCA1/2 gene inSouthern Mediterranean countries revealed low penetrance recurrent mutations in sporadic and familial breast cancer.These mutations have been selected in a context of ancient consanguinity practice along with protective genetic andenvironmental factors.