RESUMO
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.
Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Haplótipos , Polimorfismo de Nucleotídeo Único , África/epidemiologia , Brasil/epidemiologia , Chile/epidemiologia , Cromossomos Humanos Par 17/genética , Colômbia/epidemiologia , Feminino , Efeito Fundador , Estudo de Associação Genômica Ampla/métodos , Humanos , Portugal/epidemiologia , Espanha/epidemiologiaRESUMO
Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2+ tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07-1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2+ tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer. SIGNIFICANCE: The positive association between Indigenous American genetic ancestry and HER2+ breast cancer suggests that the high incidence of HER2+ subtypes in Latinas might be due to population and subtype-specific genetic risk variants.
Assuntos
Neoplasias da Mama/química , Neoplasias da Mama/etnologia , Hispânico ou Latino/genética , Receptor ErbB-2/análise , Adulto , Idoso , Povo Asiático/etnologia , Povo Asiático/estatística & dados numéricos , População Negra/etnologia , População Negra/estatística & dados numéricos , Neoplasias da Mama/genética , Colômbia/etnologia , Feminino , Humanos , Indígenas Norte-Americanos , Indígenas Sul-Americanos , América Latina/etnologia , Modelos Lineares , Modelos Logísticos , México/etnologia , Pessoa de Meia-Idade , Peru/etnologia , Receptor ErbB-2/genética , Receptores de Estrogênio/sangue , Receptores de Progesterona/sangue , Estados Unidos , População Branca/etnologia , População Branca/estatística & dados numéricos , Adulto JovemRESUMO
Thyroid cancer (TC) is the second most common cancer among Hispanic women. Recent genome-wide association (GWA) and candidate studies identified 6 single nucleotide polymorphisms (SNPs; rs966423, rs2439302, rs965513, rs6983267, rs944289, and rs116909374), associated with increased TC risk in Europeans but their effects on disease risk have not been comprehensively tested in Hispanics. In this study, we aimed to describe the main clinicopathological manifestations and to evaluate the effects of known SNPs on TC risk and on clinicopathological manifestations in a Hispanic population.We analyzed 281 nonmedullary TC cases and 1146 cancer-free controls recruited in a multicenter population-based study in Colombia. SNPs were genotyped by Kompetitive allele specific polymerase chain reaction (KASP) technique. Association between genetic variants and TC risk was assessed by computing odds ratios (OR) and confidence intervals (CIs).Consistent with published data in U.S. Hispanics, our cases had a high prevalence of large tumors (>2âcm, 43%) and a high female/male ratio (5:1). We detected significant associations between TC risk and rs965513A (ORâ=â1.41), rs944289T (ORâ=â1.26), rs116909374A (ORâ=â1.96), rs2439302G (ORâ=â1.19), and rs6983267G (ORâ=â1.18). Cases carried more risk alleles than controls (5.16 vs. 4.78, Pâ=â4.8â×â10). Individuals with ≥6 risk alleles had >6-fold increased TC risk (ORâ=â6.33, Pâ=â4.0â×â10) compared to individuals with ≤2 risk alleles. rs944289T and rs116909374A were strongly associated with follicular histology (ORsâ=â1.61 and 3.33, respectively); rs2439302G with large tumors (ORâ=â1.50); and rs965513A with regional disease (ORâ=â1.92).To our knowledge, this is the first study of known TC risk variants in South American Hispanics and suggests that they increase TC susceptibility in this population and can identify patients at higher risk of severe disease.