RESUMO
Allele frequencies and forensic parameters for 21 STR autosomal markers (CSF1PO, D10S1248, D12S391, D13S317,D16S539, D18S51, D19S433, D1S1656,D21S11, D22S1045, D2S1338, D2S441, D3S1358, D5S818, D7S820, D8S1179, FGA, SE33, TH01, TPOX and vWA) were reported in 289 unrelated individuals from Mexico City, Mexico. In addition, an interpopulation analysis was performed including other world populations. In brief, the established population database of 21 autosomal STR markers in the present work is adequate for human identification purposes.
Assuntos
Genética Populacional , Repetições de Microssatélites , Humanos , México , Repetições de Microssatélites/genética , Impressões Digitais de DNA , Frequência do GeneRESUMO
The median age of cervical cancer (CC) presentation coincides with the mean age of menopause presentation (49 years) in Mexico. Here, we investigated the association between different HPV16 variants and early (≤ 49 years) or delayed (≥ 50 years) CC presentation. We conducted a case-case study that included 462 CCs, 386 squamous cell carcinomas (SCC), 63 adenocarcinomas (ACC), and 13 additional cell types. Variants were identified by PCR and DNA sequencing. The risk conferred by each variant for developing CC earlier than 50 years was analyzed using a univariate logistic regression model considering old-aged patients (≥ 50 years) and non-HPV16 cases as the reference variables. Overall, the frequency of HPV16 was 50.9%, and the only identified variants were the European A1/2 (31.2%) and the Asian-American D2 (10.8%), and D3 (8.9%). D2 was mainly associated with ≤ 49-year-old patients (15.9%); A1/2 was uniformly distributed between the two age groups (~31%), whereas D3 increased with age to a frequency of 11.8% in the older group. Only the D2 variant conferred a 3.3-fold increase in the risk of developing CC before 50 years of age (OR = 3.3, 95% CI = 1.7-6.6, p < 0.001) in relation with non-HPV16 cases. Remarkably, this risk was higher for ACC (OR = 6.0, 95% CI = 1.1-33, p < 0.05) than for SCC (OR = 2.8, 95% CI = 1.3-5.9, p < 0.01). Interestingly, when analyzing only the HPV16-positive CC, D2 increases (OR = 2.5, 95% CI = 1.2-5, p < 0.05) and D3 decreases (OR = 0.45, 95% CI 0.2-0.9, p < 0.05) the risk to develop CC before 50 years old in relation with A1/2 variant. These results indicated that D2 variant is associated with early and D3 with delayed CC presentation, whereas A1/2 variant was uniformly distributed between the two age groups.
Assuntos
Adenocarcinoma/virologia , Carcinoma de Células Escamosas/virologia , Papillomavirus Humano 16/isolamento & purificação , Infecções por Papillomavirus/epidemiologia , Displasia do Colo do Útero/virologia , Neoplasias do Colo do Útero/virologia , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , DNA Viral/genética , Feminino , Variação Genética , Papillomavirus Humano 16/classificação , Papillomavirus Humano 16/genética , Humanos , México/epidemiologia , Pessoa de Meia-Idade , Infecções por Papillomavirus/virologia , Fatores de Risco , Análise de Sequência de DNA , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologia , Adulto Jovem , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/patologiaRESUMO
PURPOSE: Cervical cancer is one of the most common causes of cancer mortality for women living in poverty, causing more than 28,000 deaths annually in Latin America and 266,000 worldwide. To better understand the molecular basis of the disease, we ascertained blood and tumor samples from Guatemala and Venezuela and performed genomic characterization. EXPERIMENTAL DESIGN: We performed human papillomavirus (HPV) typing and identified somatically mutated genes using exome and ultra-deep targeted sequencing with confirmation in samples from Mexico. Copy number changes were also assessed in the exome sequence. RESULTS: Cervical cancer cases in Guatemala and Venezuela have an average age of diagnosis of 50 years and 5.6 children. Analysis of 675 tumors revealed activation of PIK3CA and other PI3K/AKT pathway genes in 31% of squamous carcinomas and 24% of adeno- and adenosquamous tumors, predominantly at two sites (E542K, E545K) in the helical domain of the PIK3CA gene. This distribution of PIK3CA mutations is distinct from most other cancer types and does not result in the in vitro phosphorylation of AKT. Somatic mutations were more frequent in squamous carcinomas diagnosed after the age of 50 years. Frequent gain of chromosome 3q was found, and low PIK3CA mutation fractions in many tumors suggest that PI3K mutation can be a late event in tumor progression. CONCLUSIONS: PI3K pathway mutation is important to cervical carcinogenesis in Latin America. Therapeutic agents that directly target PI3K could play a role in the therapy of this common malignancy.
Assuntos
Genoma Humano , Genômica , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/etiologia , Adulto , Idoso , Alphapapillomavirus/classificação , Alphapapillomavirus/genética , Biomarcadores Tumorais , Mapeamento Cromossômico , Classe I de Fosfatidilinositol 3-Quinases , Variações do Número de Cópias de DNA , Exoma , Feminino , Expressão Gênica , Guatemala/epidemiologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , México/epidemiologia , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Risco , Transdução de Sinais , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Venezuela/epidemiologiaRESUMO
Although human papillomavirus (HPV) infection is the main causal factor for cervical cancer (CC), there are data suggesting that genetic factors could modulate the risk for CC. Sibling studies suggest that maternally inherited factors could be involved in CC. To assess whether mitochondrial DNA (mtDNA) polymorphisms are associated to CC, HPV infection and HPV types, a case-control study was performed in the Mexican population. Polymorphism of mtDNA D-loop was investigated in 187 CC patients and 270 healthy controls. HPV was detected and typed in cervical scrapes. The expression of 29 mitochondrial genes was analyzed in a subset of 45 tumor biopsies using the expression microarray ST1.0. The Amerindian haplogroup B2 increased the risk for CC (odds ratio (OR)=1.6; 95% confidence interval (CI): 1.05-2.58) and enhanced 36% (OR=208; 95% CI: 25.2-1735.5) the risk conferred by the HPV alone (OR=152.9; 95% CI: 65.4-357.5). In cases, the distribution of HPV types was similar in all haplogroups but one (D1), in which is remarkable the absence of HPV18, a very low frequency of HPV16 and high frequencies of HPV45, HPV31 and other HPV types. Two mtDNA genes (mitochondrial aspartic acid tRNA (MT-TD), mitochondrial lysine tRNA (MT-TK)) could be involved in the increased risk conferred by the haplogroup B2, as they were upregulated exclusively in B2 tumors (P<0.01, t-test). Although the association of mtDNA with CC and HPV infection is clear, other studies with higher sample size will be needed to elucidate the role of mtDNA in cervical carcinogenesis.
Assuntos
DNA Mitocondrial/genética , Haplótipos , Indígenas Norte-Americanos/genética , Neoplasias do Colo do Útero/genética , Adulto , Alelos , Estudos de Casos e Controles , DNA Viral/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Genes Mitocondriais , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/patogenicidade , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/patogenicidade , Papillomavirus Humano 31/genética , Papillomavirus Humano 31/patogenicidade , Humanos , Pessoa de Meia-Idade , Mitocôndrias/genética , Fatores de Risco , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/virologia , Adulto JovemRESUMO
There are limited data on mitochondrial DNA (mtDNA) variation in the Mexican mestizo population. To examine the genetic diversity and matrilineal ancestry, the full mtDNA hypervariable regions I and II were sequenced in 270 unrelated mestizos from different regions of Mexico. A total of 202 different haplotypes were identified and the haplotype diversity was 0.9945. Amerindian haplotypes predominated in the sample with a proportion of 93.3%, followed by European (6.0%) and African haplotypes (0.7%). The frequency of the Amerindian haplogroups A2, B2, C1 and D1 was 51.1, 17.8, 18.5 and 5.9%, respectively. The frequency of Amerindian haplogroups was higher in the central region than in Mexico City, whereas it was the contrary for European haplogroups. This difference was accounted principally by the high frequency of B2 haplotypes in the central region. The minimum spanning network, the mismatch distribution and Tajima's D neutrality test suggest a population expansion for each Amerindian haplogroup, which could be initiated more recently for haplogroups A2 and D1. The present knowledge combined with other nuclear genetic markers will be essential in future association studies to correct for genetic substructure in mestizo populations.