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
PURPOSE: Lynch syndrome is the most common inherited syndrome of colorectal cancer, caused principally by germline mutations in MLH1 and MSH2. We report our experience with genetic screening in the diagnosis of Lynch syndrome in Chile, a country previously underserved in the capacity to diagnose hereditary colorectal cancer. METHODS: Families from our Familial Colorectal Cancer Registry were selected for this study if they fulfilled either Amsterdam I/II or Bethesda criteria for classification of Lynch syndrome. Analysis of colorectal tumors from probands included a microsatellite instability study and immunohistochemical evaluation for MLH1 and MSH2. Screening of germline mutations was performed by single-strand conformation polymorphism analysis and DNA sequencing. RESULTS: A total of 21 families were evaluated, 14 meeting Amsterdam criteria and 7 meeting Bethesda criteria. Tumors in 20 families (95%) showed microsatellite instability (19 high and 1 low) and 9 of these 20 families (45%) harbored a germline mutation (7 of 13 Amsterdam and 2 of 7 Bethesda families). Of the 9 mutations identified, 6 were in MLH1 and 3 in MSH2. Two of the mutations were novel, 3 were previously found in 1 to 2 European populations, and 4 were previously found in various ethnic populations worldwide. Only 2 mutations were previously found in another Latin American population (Colombia). In our probands, colorectal cancer was located mainly (57%) in the right or transverse colon. Pedigree information from 104 family affected members of 21 studied families showed endometrial cancer to be the most frequent primary extracolonic tumor, accounting for 15.1% of total cases, followed by stomach (13.2%) and breast cancer (11.3%). Analysis of mitochondrial DNA haplotypes showed a strong Amerindian genetic component in 15 (71.4%) of the 21 families analyzed. CONCLUSION: The study of Lynch syndrome in families of different ethnic origins contributes to the definition of genetic and clinical differences among populations. Wide distribution in other ethnic populations strongly suggests varying origins of 4 the mutations found. Although cancer phenotype was consistent with those from other Latin American populations, only 2 of 9 mutations were shared with other South American populations and 2 novel mutations were found. The Chilean population is considered to be an admixture of Amerindian and European-mainly Spanish-populations, producing an ethnic group with significant genetic differences from populations previously studied.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Idoso , Sequência de Bases , Chile , Feminino , Predisposição Genética para Doença , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Técnicas Imunoenzimáticas , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Fenótipo , Polimorfismo Conformacional de Fita Simples/genética , Sistema de Registros , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Hereditary gastrointestinal polyposis syndromes are rare, accounting for approximately 1% of all colorectal cancers. They are important, however, because of the insight they provide on the genetic mechanisms underlying colorectal carcinogenesis, and because of their devastating effect on the families affected by them. They are best categorized according to the histology of the polyps. This review will summarize current knowledge of the hereditary gastrointestinal polyposes, and will provide recommendations for treatment and surveillance. The Syndromes: The adenomatous polyposes include familial adenomatous polyposis, the most familiar, commonest, and most well known of the polyposes, and MYH-associated polyposis, the most recently described. Familial adenomatous polyposis is caused by a dominantly inherited germline mutation in APC, a key tumor suppressor gene.Treatment is by prophylactic colectomy or proctocolectomy, and lifelong surveillance of the rest of the gastrointestinal tract is necessary. Cancers and benign tumors may occur in bones, skin, brain, thyroid, adrenals, liver, and duodenum. MYH-associated polyposis is due to recessive inheritance of a mutation in MYH, a gene involved in base excision repair. Conclusion: multiple colorectal polyps are a clue to the possible presence of an inherited syndrome predisposing patients to colorectal cancer. Diagnosis is based on biopsy of a representative number of polyps, documentation of likely extracolonic manifestations, a careful search of the family, and genetic testing for a germline mutation. Treatment depends on the organs affected, the severity of the polyposis and the nature and severity of symptoms. Lifelong surveillance of all affected family members is recommended.