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

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.

Clinical manifestations of colorectal cancer patients from a large multicenter study in Colombia.

Colorectal cancer (CRC) is a major public health problem, and its incidence is rising in developing countries. However, studies characterizing CRC clinicopathological features in cases from developing countries are still lacking. The goal of this study was to evaluate clinicopathological and demographic features in one of the largest CRC studies in Latin America.The study involved over 1525 CRC cases recruited in a multicenter study in Colombia between 2005 and 2014 as part of ongoing genetic and epidemiological studies. We gathered clinicopathological data such as age at diagnosis, sex, body mass index, tobacco and alcohol consumption, family history of cancer, and tumor features including location, histological type, and stage. Statistical analyses were performed to test the association between age of onset, sex, and clinical manifestations.The average age at CRC diagnosis was 57.4 years, with 26.5% of cases having early-onset CRC (diagnosed by age 50 years). Most cases were women (53.2%; P = 0.009), 49.2% were overweight or obese, 49.1% were regular alcohol drinkers, 52% were smokers/former smokers, and 12.2% reported relatives with cancer. Most tumors in the study were located in the rectum (42.7%), were adenocarcinomas (91.5%), and had advanced stage (T3-T4, 79.8%). Comparisons by sex found that male cases were more likely to be obese (36.5% vs 31.1%; P = 0.001), less likely to have a family history of cancer (9.7% vs 15.3%; P = 0.016), and more likely to have advanced-stage tumors (83.9% vs 76.1%; P = 0.036). Comparisons by age of onset found that early-onset cases were more likely to be women (59.3% vs 51.0%; P = 0.005) and report a family history of cancer (17.4% vs 10.2%; P = 0.001).To our knowledge, our study is the largest report of clinicopathological characterization of Hispanic CRC cases, and we suggest that further studies are needed to understand CRC etiology in diverse Hispanic populations.

The 8q24 rs6983267G variant is associated with increased thyroid cancer risk.

The G allele of the rs6983267 single-nucleotide polymorphism, located on chromosome 8q24, has been associated with increased risk of several cancer types. The association between rs6983267G and thyroid cancer (TC) has been tested in different populations, mostly of European ancestry, and has led to inconclusive results. While significant associations have been reported in the British and Polish populations, no association has been detected in populations from Spain, Italy and the USA. To further investigate the role of rs6983267G in TC susceptibility, we evaluated rs6983267 genotypes in three populations of different continental ancestry (British Isles, Colombia and Japan), providing a total of 3067 cases and 8575 controls. We detected significant associations between rs6983267G and TC in the British Isles (odds ratio (OR)=1.19, 95% CI: 1.11-1.27, P=4.03×10(-7)), Japan (OR=1.20, 95% CI: 1.03-1.41, P=0.022) and a borderline significant association of similar effect direction and size in Colombia (OR=1.19, 95% CI: 0.99-1.44, P=0.069). A meta-analysis of our multi-ethnic study and previously published non-overlapping datasets, which included a total of 5484 cases and 12 594 controls, confirmed the association between rs6983267G and TC (P=1.23×10(-7), OR=1.13, 95% CI: 1.08-1.18). Our results therefore support the notion that rs6983267G is a bona fide TC risk variant that increases the risk of disease by ∼13%.