Haplotype analysis of the internationally distributed BRCA1 c.3331_3334delCAAG founder mutation reveals a common ancestral origin in Iberia

Abstract

Càncer de mama; Mutació fundadora; Haplotip

Cáncer de mama; Mutación fundadora; Haplotipo

Breast cancer; Founder mutation; Haplotype

Background The BRCA1 c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry. Methods BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity around BRCA1 c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surrounding BRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia. Results The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was ~ 100 generations in Iberia and that it was introduced to South America early during the European colonization period. Conclusions Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening.

AMDEA was supported with graduate Fellowships from UC Davis T32 Biotechnology Program. MB, ME, and LGC-C received funding from GSK Oncology and from “Oficina de Desarrollo a la Docencia de la Universidad del Tolima, Convocatoria 2010”. AC and AEF received funding from the Colciencias program “Becas Doctorales Nacionales, Convocatorias 528-2011 and 647-2015”. JB received funding from the Colciencias program “Formación de Capital Humano de Alto Nivel para el Departamento de Tolima- 2016, convocatoria 755”. BRCA1/2 genotyping of the Brazilian patients was performed in part with grants from CNPq (408313/2016-1), FAPERGS and Fundo de Incentivo a Pesquisa (FIPE) do Hospital de Clínicas de Porto Alegre, Brazil. AV received funding from CIBERER (grant ER17P1AC7112/2017). PC received funding from FONDEF grant #CA12I10152. CL was Supported by the Carlos III National Health Institute funded by FEDER funds—a way to build Europe—[PI19/00553; PI16/00563; PI16/01898; SAF2015-68016-R and CIBERONC]; the Government of Catalonia [Pla estratègic de recerca i innovació en salut (PERIS_MedPerCan and URDCat projects), 2017SGR1282 and 2017SGR496]. BR received funding from the National Institutes of Health (R01GM123306). The contents of this article are solely the responsibility of the authors and do not reflect the official views of the National Institutes of Health. LGC-C received from the V Foundation for Cancer Research and from The Auburn Community Cancer Endowed Chair in Basic Science.