RESUMO
BACKGROUND: Colorectal cancer (CRC) is the first cause of cancer deaths among Puerto Ricans. The incidence and mortality of CRC in Puerto Rico continue to be on the rise. The burden of CRC in Puerto Rico is higher than among US Hispanics and is second only to African Americans, thus supporting the importance of studying this CRC health disparity. The genetic background of the Puerto Rican population is a mix of European, African, and Amerindian races, which may account, in part, for the differences observed in the CRC mortality rates among Puerto Ricans. The objective of the study was to assess the role of genetic ancestry in CRC risk and its association with clinicopathological features of CRC tumors in Puerto Ricans. RESULTS: We used a validated panel of 105 ancestry informative markers (AIMs) to estimate genetic ancestry in 406 Puerto Rican CRC cases and 425 Puerto Rican controls. We examined the association of genetic ancestry with CRC risk and tumor clinicopathological characteristics. CONCLUSIONS: The mean ancestry proportions in the study population were 61% European, 21% African, and 18% Amerindian. No association was observed between genetic ancestry and risk of CRC. However, African ancestry was associated with an increased risk of developing rectal tumors (OR = 1.55, 95% CI 1.04-2.31). Additional studies are needed to fully elucidate the role of African ancestry in CRC carcinogenesis.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Negro ou Afro-Americano/genética , Idoso , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Hispânico ou Latino/genética , Humanos , Indígenas Centro-Americanos/genética , Masculino , Pessoa de Meia-Idade , Porto Rico , População Branca/genéticaRESUMO
BACKGROUND: The Puerto Rican (PR) population is a racially admixed population that has a high prostate cancer (PCa) mortality rate. We hypothesized in this pilot study that West African Ancestry (WAA) was associated with PCa in this heterogeneous (PR) population. METHODS: A case/case and case/control study was performed. Controls, 207 African American (AA) and 133 PR were defined as men with no PCa, a serum PSA < 2.5 ng/mL and a negative rectal examination. Cases were patients with pathological specimens from radical prostatectomies (RP) (291 PR and 200 AA). DNA was extracted from whole blood of controls and from paraffin embedded normal seminal vesicle from the RPs. We assessed the association of PCa and aggressiveness with genetic ancestry using an ancestry informative marker panel (AIMs) and Wilcoxon rank-sum test and the association of PCa and aggressiveness with 15 previously PCa associated SNPs using Chi square test. Gleason Score (GS) and tumor stage (TS) were used to define low risk (GS ≤ 7[3 + 4]), TS ≤ pT2) and high risk (GS≥ 7[4 + 3], TS > pT2) PCa. Statistical analyses were done using SAS. RESULTS: No difference in overall percent WAA was found between PR cases and controls. Among PR or AA cases WAA was not associated with disease severity based upon risk group, Gleason score or stage. Among AA controls WAA was significantly higher than in cases. The SNP rs7824364 (chromosome 8q24) PCa risk allele was significantly increased among cases versus controls for both AA (P < 0.0001) and PR (P = 0.0001) men. PR men with ≥1 risk allele exhibited a higher percent of WAA (39% vs 29%, P = 0.034). CONCLUSION: The SNP rs7824364, a local marker of WAA in the 8q24 region was associated with PCa among both AA and PR men and with increased WAA among PR men. This novel relationship of PCA risk loci, WAA with PCa and its phenotype among PR men deserves further study.
Assuntos
Negro ou Afro-Americano/genética , Hispânico ou Latino/genética , Próstata/patologia , Prostatectomia/métodos , Neoplasias da Próstata , Idoso , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: The study of genetic variants alone is not enough to explain a complex disease like cancer. Alterations in DNA methylation patterns have been associated with different types of tumor. In order to detect markers of susceptibility for the development of cutaneous melanoma and breast cancer in the Uruguayan population, we integrated genetic and epigenetic information of patients and controls. METHODS: We performed two case-control studies that included 49 individuals with sporadic cutaneous melanoma and 73 unaffected controls, and 179 women with sporadic breast cancer and 209 women controls. We determined the level of global leukocyte DNA methylation using relative quantification of 5mdC by HPLC, and we compared methylation levels between cases and controls with nonparametric statistical tests. Since the Uruguayan population is admixed and both melanoma and breast cancer have very high incidences in Uruguay compared to other populations, we examined whether individual ancestry influences global leucocyte DNA methylation status. We carried out a correlation analysis between the percentage of African, European and Native American individual ancestries, determined using 59 ancestry informative markers, and global DNA methylation in all participants. RESULTS: We detected global DNA hypomethylation in leukocytes of melanoma and breast cancer patients compared with healthy controls (p < 0.001). Additionally, we found a negative correlation between African ancestry and global DNA methylation in cancer patients (p <0.005). CONCLUSIONS: These results support the potential use of global DNA methylation as a biomarker for cancer risk. In addition, our findings suggest that the ancestral genome structure generated by the admixture process influences DNA methylation patterns, and underscore the importance of considering genetic ancestry as a modifying factor in epigenetic association studies in admixed populations such as Latino ones.
Assuntos
Neoplasias da Mama/genética , Metilação de DNA/genética , Etnicidade/genética , Melanoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Feminino , Genética Populacional , Humanos , Leucócitos/metabolismo , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas , Melanoma Maligno CutâneoRESUMO
BACKGROUND: Uruguay exhibits one of the highest rates of breast cancer in Latin America, similar to those of developed nations, the reasons for which are not completely understood. In this study we investigated the effect that ancestral background has on breast cancer susceptibility among Uruguayan women. METHODS: We carried out a case-control study of 328 (164 cases, 164 controls) women enrolled in public hospitals and private clinics across the country. We estimated ancestral proportions using a panel of nuclear and mitochondrial ancestry informative markers (AIMs) and tested their association with breast cancer risk. RESULTS: Nuclear individual ancestry in cases was (mean ± SD) 9.8 ± 7.6% African, 13.2 ± 10.2% Native American and 77.1 ± 13.1% European, and in controls 9.1 ± 7.5% African, 14.7 ± 11.2% Native American and 76.2 ± 14.2% European. There was no evidence of a difference in nuclear or mitochondrial ancestry between cases and controls. However, European mitochondrial haplogroup H was associated with breast cancer (OR = 2.0; 95% CI 1.1, 3.5). CONCLUSIONS: We have not found evidence that overall genetic ancestry differs between breast cancer patients and controls in Uruguay but we detected an association of the disease with a European mitochondrial lineage, which warrants further investigation.
Assuntos
Indígena Americano ou Nativo do Alasca/genética , População Negra/genética , Neoplasias da Mama/genética , DNA Mitocondrial/análise , População Branca/genética , Adulto , Idoso , Neoplasias da Mama/etnologia , Estudos de Casos e Controles , DNA/análise , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Pessoa de Meia-Idade , UruguaiRESUMO
BACKGROUND: Multiple genetic studies have confirmed associations of 8q24 variants with susceptibility to prostate cancer (CaP). However, the magnitude of risk conferred in men living in West Africa is unknown. METHODS: Here we determine the prevalence of 8q24 risk alleles and test for association with CaP risk alleles in West African (WA) descent populations from rural Nigeria, Cameroon, and the Caribbean island of Jamaica. Ten 8q24 SNPs were genotyped in histologically confirmed CaP cases (n = 308) and clinically evaluated controls (n = 469). In addition, unrelated individuals from Sierra Leone (n = 380) were genotyped for comparison of allele frequency comparisons. RESULTS: SNPs rs6983561, rs7008482, and rs16901979 were significantly associated with CaP risk in WAs (P < 0.03). No associations with CaP were observed in our Caribbean samples. Risk alleles for rs6983267, rs7008482, and rs7000448 were highly prevalent (>84%) in West Africa. We also reveal that the A-risk allele for the 'African-specific' SNP bd11934905 was not observed in 1,886 chromosomes from three WA ethnic groups suggesting that this allele may not be common across West Africa, but is geographically restricted to specific ethnic group(s). CONCLUSIONS: We provide evidence of association of 8q24 SNPs with prostate cancer risk in men from Nigeria and Cameroon. Our study is the first to reveal genetic risk due to 8q24 variants (in particular, region 2) with CaP within two WA countries. Most importantly, in light of the disparate burden of CaP in African-Americans, our findings support the need for larger genetic studies in WA descent populations to validate and discern function of susceptibility loci in the 8q24 region.
Assuntos
Alelos , População Negra/genética , Cromossomos Humanos Par 8/genética , Etnicidade/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Idoso , Idoso de 80 Anos ou mais , População Negra/etnologia , Camarões/etnologia , Região do Caribe/etnologia , Estudos de Casos e Controles , Etnicidade/etnologia , Estudos de Associação Genética/métodos , Humanos , Jamaica/etnologia , Masculino , Pessoa de Meia-Idade , Nigéria/etnologia , Neoplasias da Próstata/etnologia , Fatores de RiscoRESUMO
Argentine population genetic structure was examined using a set of 78 ancestry informative markers (AIMs) to assess the contributions of European, Amerindian, and African ancestry in 94 individuals members of this population. Using the Bayesian clustering algorithm STRUCTURE, the mean European contribution was 78%, the Amerindian contribution was 19.4%, and the African contribution was 2.5%. Similar results were found using weighted least mean square method: European, 80.2%; Amerindian, 18.1%; and African, 1.7%. Consistent with previous studies the current results showed very few individuals (four of 94) with greater than 10% African admixture. Notably, when individual admixture was examined, the Amerindian and European admixture showed a very large variance and individual Amerindian contribution ranged from 1.5 to 84.5% in the 94 individual Argentine subjects. These results indicate that admixture must be considered when clinical epidemiology or case control genetic analyses are studied in this population. Moreover, the current study provides a set of informative SNPs that can be used to ascertain or control for this potentially hidden stratification. In addition, the large variance in admixture proportions in individual Argentine subjects shown by this study suggests that this population is appropriate for future admixture mapping studies.
Assuntos
Indígenas Sul-Americanos/genética , Povo Asiático/genética , Teorema de Bayes , População Negra/genética , Frequência do Gene , Marcadores Genéticos , Variação Genética , Genética Populacional , Humanos , Americanos Mexicanos/genética , População Branca/genéticaRESUMO
Ancestry informative markers (AIMs) are genetic loci showing alleles with large frequency differences between populations. AIMs can be used to estimate biogeographical ancestry at the level of the population, subgroup (e.g. cases and controls) and individual. Ancestry estimates at both the subgroup and individual level can be directly instructive regarding the genetics of the phenotypes that differ qualitatively or in frequency between populations. These estimates can provide a compelling foundation for the use of admixture mapping (AM) methods to identify the genes underlying these traits. We present details of a panel of 34 AIMs and demonstrate how such studies can proceed, by using skin pigmentation as a model phenotype. We have genotyped these markers in two population samples with primarily African ancestry, viz. African Americans from Washington D.C. and an African Caribbean sample from Britain, and in a sample of European Americans from Pennsylvania. In the two African population samples, we observed significant correlations between estimates of individual ancestry and skin pigmentation as measured by reflectometry (R(2)=0.21, P<0.0001 for the African-American sample and R(2)=0.16, P<0.0001 for the British African-Caribbean sample). These correlations confirm the validity of the ancestry estimates and also indicate the high level of population structure related to admixture, a level that characterizes these populations and that is detectable by using other tests to identify genetic structure. We have also applied two methods of admixture mapping to test for the effects of three candidate genes (TYR, OCA2, MC1R) on pigmentation. We show that TYR and OCA2 have measurable effects on skin pigmentation differences between the west African and west European parental populations. This work indicates that it is possible to estimate the individual ancestry of a person based on DNA analysis with a reasonable number of well-defined genetic markers. The implications and applications of ancestry estimates in biomedical research are discussed.