RESUMO
After decades of unawareness about Lynch syndrome, the medical community in South America is increasingly interested and informed. The visits and support of mentors like H. T. Lynch had been crucial to this awakening. Several countries have at least one registry with skilled personnel in genetic counseling and research. However, this only represents a very restricted resource for the region. According to the GETH, there are 27 hereditary cancer care centers in South America (21 in Brazil, 3 in Argentina, 1 in Uruguay, 1 in Chile and 1 in Peru). These registries differ in fundamental aspects of function, capabilities and funding, but are able to conduct high quality clinical, research and educational activities due to the dedication and personal effort of their members, and organizational support. More support from the governments as well as the participation of the community would boost the initiatives of people leading these groups. Meantime, the collaboration among the South American registries and the involvement of registries and leaders from developed countries will allow to maximize the efficiency in caring for affected patients and their families. The aim of this article is to describe how the knowledge of LS began to be spread in South America, how the first registries were organized and to summarize the current state of progress. In addition, we will provide an update of the clinical and molecular findings in the region.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Aconselhamento Genético/estatística & dados numéricos , Aconselhamento Genético/tendências , Predisposição Genética para Doença , Testes Genéticos , Sistema de Registros/estatística & dados numéricos , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Mutação em Linhagem Germinativa , América do Sul/epidemiologiaRESUMO
Germline mutations in the human DNA mismatch repair (MMR) genes MSH2 and MLH1 are associated with the inherited cancer disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer or HNPCC. A proportion of MSH2 and MLH1 mutations found in suspected LS patients give rise to single amino acid substitutions. The functional consequences in regard to pathogenicity of many of these variants are unclear. We have examined the functionality of a panel of MLH1 missense mutations found in LS families, by testing the variant proteins in functional assays, addressing subcellular localization, and protein-protein interaction with the dimer partner PMS2 and the MMR-associated exonuclease 1. We show that a significant proportion of examined variant proteins have functional defects in either subcellular localization or protein-protein interactions, which is suspected to lead to the cancer phenotype observed in patients. Moreover, the obtained results correlate well with reported MMR activity and with in silico analysis for a majority of the variants.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Mutação de Sentido Incorreto , Proteínas Nucleares/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenosina Trifosfatases/química , Animais , Enzimas Reparadoras do DNA/química , Proteínas de Ligação a DNA/química , Proteínas de Escherichia coli/química , Células HeLa , Humanos , Camundongos , Endonuclease PMS2 de Reparo de Erro de Pareamento , Modelos Moleculares , Proteína 1 Homóloga a MutL , Proteínas MutL , Mutagênese Sítio-Dirigida , Células NIH 3T3 , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Estrutura Terciária de Proteína , Transporte Proteico , Homologia Estrutural de ProteínaRESUMO
Introdução - A Síndrome de Lynch (SL) tem padrão de herança autossômico dominante com alta penetrância (aproximadamente 70%- 80%). Predispõe ao desenvolvimento precoce de câncer colorretal (CCR), endométrio, ovário, intestino delgado, estômago e trato urinário. Os antecedentes familiares de câncer podem identificar indivíduos e famílias sob risco. Os principais critérios clínicos utilizados para a suspeita diagnóstica são os de Amsterdam e de Bethesda. Os genes de reparo de DNA, MSH2 e MLH1 são responsáveis por mais de 85% das mutações germinativas conhecidas em pacientes portadores de SL. Objetivos - O objetivo geral deste trabalho foi a pesquisa de mutações germinativas nos genes MLH1 e MSH2 em indivíduos com suspeita clinica de SL. Casuística e Métodos Foram estudados 99 pacientes não relacionados, portadores de CCR com os principais critérios clínicos para suspeita de SL. Os DNAs dos pacientes foram obtidos a partir de sangue periférico e submetidos a PCR para análise de todos os exons e regiões intron-exons dos genes. Foram então submetidos a sequenciamento direto em ambos os sentidos. Resultados Foram encontradas 32 (30%) mutações patogênicas nos genes MLH1 ou MSH2, sendo 21/41 (51,2%) dos pacientes com critérios de Amsterdam e 9/58 (15,5%) dos pacientes com critérios de Bethesda. Foram descritas pela primeira vez 13 mutações patogênicas nos genes MLH1 ou MSH2. Conclusão Nossos resultados foram concordantes com os encontrados na literatura tanto na porcentagem de mutações encontradas, como na proporção em cada um dos genes de reparo estudados. Além disso, observamos maior especificidade dos critérios de Amsterdam na detecção de indivíduos portadores da mutação germinativa. O sequenciamento automático é uma metodologia eficaz na detecção de alterações pontuais e de pequenas deleções, inserções e duplicações.
Introduction Lynch syndrome (LS) presents an autosomal dominant inheritance pattern with a high penetrance (approximately 70% - 80%). LS predisposes to early development of colorectal cancer (CRC), endometrium, ovary, small intestine, stomach and urinary tract. Family history of cancer could identify individuals and families at risk. The main clinical criteria for diagnosis are Amsterdam and Bethesda Criteria. The mismatch repair genes, MSH2 and MLH1 are responsible for more than 85% of known germline mutations in patients with SL. Objectives To study germline mutations in MLH1 and MSH2 genes in patients with clinically suspected SL. Material and Methods Here, described 99 unrelated patients suffering of CRC with the major clinical criteria for suspicion of SL. The DNAs of the patients were obtained from peripheral blood and subjected to PCR for analysis of all exons and intron-exon regions of genes. Then, they were directed sequenced in both directions. Results - We found 32 (30.4%) pathogenic mutations in MLH1 or MSH2 genes, and among them, 21/41 (51.27%) of patients with Amsterdam criteria and 9/58 (15.5%) of patients with Bethesda criteria. We described, for the first time, 13 pathogenic mutations in MLH1 or MSH2 genes. Conclusions - Our results were consistent with literature in the percentage of mutations found, as well as in the proportion of each mismatch repair genes studied. Moreover, we observed a higher specificity of the Amsterdam criteria for the detection of individuals carrying the germline mutation. The automated sequencing is an effective methodology for detection of substitutions, small deletions, insertions and duplications.
