RESUMO
OBJECTIVE: To describe the rationale and the methodology of a multicenter project to study the etiology of breast cancer in young Latin American women. MATERIALS AND METHODS: The International Agency for Research on Cancer has established an international collaborative population-based case-control study in four countries in Latin America: Chile, Colombia, Costa Rica, and Mexico (the PRECAMA study). Standardized methodologies were developed to collect information on reproductive variables, lifestyle, anthropometry, diet, clinical and pathological data, and biological specimens. The study will be extended to other countries in the region. CONCLUSIONS: PRECAMA is unique in its multidisciplinary approach that combines genetics, genomics, and metabolomics with lifestyle factors. Then data generated through this project will be instrumental to identify major risk factors for molecular subtypes of breast cancer in young women, which will be important for pre- vention and targeted screening programs in Latin America.
OBJETIVO: Describir la justificación y la metodología para el establecimiento de un proyecto multicéntrico sobre el cáncer de mama en mujeres jóvenes de América Latina. MATERIAL Y MÉTODOS: La Agencia Internacional para la Investigación del Cáncer (IARC) ha establecido un estudio colaborativo internacional de casos y controles con base poblacional en cuatro países de América Latina: Chile, Colombia, Costa Rica y México (el estudio PRECAMA). Se han desarrollado metodologías estandarizadas para recolectar información sobre variables reproductivas, estilos de vida, antropometría y dieta, datos clínicos y patológicos y muestras biológicas. CONCLUSIONES: PRECAMA es único en su enfoque multidisciplinario. Los datos generados a través de este proyecto serán fundamentales para identificar los principales factores de riesgo del cáncer de mama en mujeres jóvenes. Los hallazgos serán relevantes para la prevención y los programas de detección oportuna en América Latina, con beneficios clínicos inmediatos.
Assuntos
Neoplasias da Mama/etiologia , Adulto , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Chile , Colômbia , Costa Rica , Ingestão de Alimentos , Exercício Físico , Feminino , Humanos , Consentimento Livre e Esclarecido , América Latina , Estilo de Vida , México , Seleção de Pacientes , Fatores de Risco , Manejo de Espécimes/métodos , Adulto JovemRESUMO
Abstract: Objective: To describe the rationale and the methodology of a multicenter project to study the etiology of breast cancer in young Latin American women. Materials and methods: The International Agency for Research on Cancer has established an international collaborative population-based case-control study in four countries in Latin America: Chile, Colombia, Costa Rica, and Mexico (the PRECAMA study). Standardized methodologies were developed to collect information on reproductive variables, lifestyle, anthropometry, diet, clinical and pathological data, and biological specimens. The study will be extended to other countries in the region. Conclusion: PRECAMA is unique in its multidisciplinary approach that combines genetics, genomics, and metabolomics with lifestyle factors. The data generated through this project will be instrumental to identify major risk factors for molecular subtypes of breast cancer in young women, which will be important for prevention and targeted screening programs in Latin America.
Resumen: Objetivo: Describir la justificación y la metodología para el establecimiento de un proyecto multicéntrico sobre el cáncer de mama en mujeres jóvenes de América Latina. Material y métodos: La Agencia Internacional para la Investigación del Cáncer (IARC) ha establecido un estudio colaborativo internacional de casos y controles con base poblacional en cuatro países de América Latina: Chile, Colombia, Costa Rica y México (el estudio PRECAMA). Se han desarrollado metodologías estandarizadas para recolectar información sobre variables reproductivas, estilos de vida, antropometría y dieta, datos clínicos y patológicos y muestras biológicas. Conclusión: PRECAMA es único en su enfoque multidisciplinario. Los datos generados a través de este proyecto serán fundamentales para identificar los principales factores de riesgo del cáncer de mama en mujeres jóvenes. Los hallazgos serán relevantes para la prevención y los programas de detección oportuna en América Latina, con beneficios clínicos inmediatos.
Assuntos
Humanos , Feminino , Adulto , Adulto Jovem , Neoplasias da Mama/etiologia , Manejo de Espécimes/métodos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Exercício Físico , Estudos de Casos e Controles , Chile , Fatores de Risco , Colômbia , Seleção de Pacientes , Costa Rica , Ingestão de Alimentos , Consentimento Livre e Esclarecido , América Latina , Estilo de Vida , MéxicoRESUMO
Due to patterns of migration, selection, and population expansion, founder effects are common among humans. In Southern Brazil, a recurrent TP53 mutation, p.R337H, is detected in families with cancer predisposition. We have used whole locus resequencing and high-density single nucleotide polymorphism (SNP) genotyping to refine TP53 locus haplotype definitions. Haplotyping of 12 unrelated p.R337H carriers using a set of 29 tag SNPs, revealed that all subjects carried the same haplotype, and presence of the mutation on this haplotype was confirmed by allele-specific PCR. The probability that this haplotype occurs independently in all index cases was of 3.1x10(-9), demonstrating a founder effect. Analysis of the patterns of 103 tumors diagnosed in 12 families showed that the presence of p.R337H is associated with multiple cancers of the Li-Fraumeni Syndrome (LFS) spectrum, with relatively low penetrance before the age of 30 but a lifetime risk comparable to classical LFS. The p.R337H families are mostly distributed along a road axis historically known as the main route used by merchants of Portuguese origin in the XVIII and XIX century. This historical circumstance and the relatively low penetrance before the age of 30 may have contributed to the maintenance of this pathogenic mutation in a large, open population.
Assuntos
Substituição de Aminoácidos/genética , Efeito Fundador , Loci Gênicos/genética , Haplótipos/genética , Heterozigoto , Mutação/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Sequência de Bases , Brasil , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Genética Populacional , Humanos , Lactente , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Neoplasias/diagnóstico , Neoplasias/genética , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Adulto JovemRESUMO
Germline TP53 mutations predispose to a rare familial cancer syndrome, the Li-Fraumeni Syndrome (LFS), characterized by the early onset of multiple cancers including childhood adrenocortical carcinomas, sarcomas and brain tumors, and breast and colon cancer in young adults. An identical germline mutation at codon 337 in TP53 (R337H) has been shown to be causally related to an increased risk of multiple cancers in unrelated subjects with familial cancer risk in Southern Brazil. Here we have assessed the prevalence of R337H in 750 healthy women participating in a community-based breast cancer screening program in the area of Porto Alegre. The mutant was detected in two participants (0.3%) who were fourth-degree relatives and reported a familial history of cancer at multiple sites that did not match classical criteria for LFS and its variants. Testing in additional family members detected the mutation in three subjects, one of whom developed breast cancer at the age of 36. These findings indicate that R337H may be a low penetrance mutant which predisposes to multiple cancers and occurs in the population of Southern Brazil at a frequency 10-20 times higher than other TP53 mutants commonly associated with LFS.
Assuntos
Genes p53 , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias/genética , Adulto , Idoso , Brasil , Neoplasias da Mama/diagnóstico , Feminino , Testes Genéticos , Humanos , Síndrome de Li-Fraumeni/genética , Pessoa de Meia-Idade , LinhagemRESUMO
A TP53 germline mutation, R337H, has been previously described in children from southern Brazil with adrenocortical tumours but no documented familial history of other cancers. Here, we have screened for TP53 mutation 45 Brazilian unrelated individuals with family histories fulfilling the clinical definitions of Li-Fraumeni (LFS) or Li-Fraumeni-like (LFL) syndromes. Mutations were found in 13 patients (28.9%), including six (46.1%) R337H mutations, and four novel germline mutations (V173M, V197M, G244D and IVS6+1G>T). Families with the R337H mutation presented a wide spectrum of tumours, including breast cancers (30.4%), brain cancers (10.7%), soft tissue sarcomas (10.7%) and adrenocortical carcinomas (8.9%). Testing of 53 Brazilian subjects with no cancer history showed that R337H was not a common polymorphism in that population. Moreover, loss of heterozygocity with retention of the R337H allele was observed in a breast adenocarcinoma, supporting a role for this mutation in breast tumorigenesis. These results show that the TP53 R337H germline mutation predisposes to a larger spectrum of tumours, similar to the one reported for other TP53 mutations.
Assuntos
Mutação em Linhagem Germinativa , Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Sequência de Bases , Brasil , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença/genética , Humanos , Síndrome de Li-Fraumeni/patologia , Masculino , Mutação de Sentido Incorreto , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologiaRESUMO
Due to particular social and economical development, and to the impact of globalization of lifestyles, Latin America shows a superposition of cancers that are frequent in low resource countries (gastric, oesophageal squamous cell and cervical cancers) and high resource countries (cancers of breast, colon and rectum, lung and prostate). Latin America thus offers opportunities for investigating the impact on changing lifestyle patterns on the occurrence of cancer. At the molecular level, mutations in the tumor suppressor gene TP53 are common in many cancers and their distribution can be informative of the nature of the mutagenic mechanisms, thus giving clues to cancer etiology and molecular pathogenesis. However most of the data available are derived from studies in industrialized countries. In this review, we discuss current trends on cancer occurrence in Latin American countries, and we review the literature available on TP53 mutations and polymorphisms in patients from Latin America. Overall, a total of 285 mutations have been described in 1213 patients in 20 publications, representing 1.5% of the total number of mutations reported world-wide. Except for hematological cancers, TP53 mutation frequencies are similar to those reported in other regions of the world. The only tumor site presenting significant differences in mutation pattern as compared to other parts of the world is colon and rectum. However, this difference is based on a single study with 35 patients. Recently, a characteristic TP53 mutation at codon 337 (R337H) has been identified in the germline of children with adrenocortical carcinoma in Southern Brazil. Further and better focused analyses of TP53 mutation patterns in the context of epidemiological studies, should help to improve our understanding of cancer etiology in order to develop appropriate health policies and public health programs in Latin America.