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

Abstract

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.

Sociodemographic, Clinical, and Variation Outcomes for Breast Cancer and Breast Cancer-Related Mutations in a Ten-Year Cohort From Neiva, Huila, Colombia

“…These findings may contribute to genetic screening test strategies, support efforts to understand uncertain clinically significant variants, and involve laboratories, clinicians, patients, and relatives [27]. The European origin of the mutation was introduced early in the country's colonization, resulting in a high mutation prevalence in the population, mainly in the department of Huila (Southern Colombia) [28]. In our study cohort, 105 BRCA1/2 P/LP mutation carriers were identified.…”

Hereditary Breast Cancer in the Brazilian State of Ceará (The CHANCE Cohort): Higher-Than-Expected Prevalence of Recurrent Germline Pathogenic Variants

“…The most prevalent one was c.3331_3334del, corresponding to 38.7% of the BRCA1 P/LP variants. This frameshift alteration was previously described as the second most commonly identified pathogenic BRCA1 variant in Brazil ( 13 ), was originated in Iberia and was later introduced to Colombia and South America at the time of Spanish colonization ( 24 ). The second most prevalent BRCA1 P/LP variant described in this cohort was c.5074+2T>C, corresponding to 25.8% of the cases.…”

Systematic review of the molecular basis of hereditary breast and ovarian cancer syndrome in Brazil: the current scenario

“…Represented in different populations, it was first described in Canadian families [ 52 ]. To know the origin of this mutation, a study conducted in 2020 by Tuazon and collaborators [ 53 ] performed haplotype analysis with populations from Colombia, Spain, Portugal, Chile, Africa and Brazil and suggested that this mutation had a single origin in the Iberian Peninsula and was introduced in Colombia and South America at the time of Spanish colonization. This mutation was responsible for 10.2% of BRCA1 mutations found in Brazil in this review.…”