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京都大学 / 新制・課程博士 / 博士(医学) / 甲第25497号 / 医博第5097号 / 新制||医||1073(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 羽賀 博典, 教授 中島 貴子, 教授 武藤 学 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Aims: The purpose of the research was to investigate the benefits of a hereditary colorectal cancer registry in the management of patients and families with Lynch syndrome. In study one, a systematic review was performed to quantify the impact of registration and screening on colorectal cancer (CRC) incidence and mortality, with comparison between familial adenomatous polyposis (FAP) and Lynch syndrome (LS). In study two, a regional Lynch syndrome registry was utilised to evaluate the uptake of predictive testing and colorectal screening among first-degree relatives (FDRs) and investigate novel methods for engaging at-risk relatives, including an enhanced role for the general practitioner (GP). In study three, the registry was used to investigate proposed associations between Lynch syndrome and prostate and bladder cancer. In study four, mismatch repair-deficient (dMMR) CRCs from Lynch syndrome patients and randomised-controlled trials (RCTs) were used to evaluate a novel prognostic biomarker, beta-2 microglobulin (B2M). Methods: An electronic database search was conducted to identify studies describing CRC incidence and/or mortality in FAP or LS, with comparison of either: 1) screened and unscreened patients or 2) patients ‘before and after’ establishment of the registry. Using the Manchester regional Lynch syndrome registry database, the uptake of predictive testing and colorectal screening among FDRs was assessed with Kaplan-Meier analysis. Novel strategies for improving engagement were explored via a patient advisory group discussion and a regional primary care questionnaire. Cases of prostate and bladder cancer in male mutation carriers and their male FDRs were identified, and cumulative and relative risks were calculated, using expected rates from cancer registry data. DNA from 350 dMMR CRC specimens from Lynch syndrome patients and RCTs were tested for B2M mutations using Sanger sequencing, and correlated with clinical outcome. Results: 43 studies were included in the systematic review (33 FAP; 10 Lynch). Registry-based screening was associated with a significant reduction in CRC incidence and in Lynch syndrome, CRC-related mortality was negligible in those undergoing surveillance. 242 Lynch syndrome families were recorded on the Manchester Lynch syndrome registry. 329 of 591 (55.7%) eligible FDRs had undergone predictive testing. Uptake was significantly lower in males and younger age groups (<25 yrs). Compliance with colorectal screening was excellent following a mutation positive predictive test but poor in untested individuals (97.3% vs 35.0%). Eight prostate cancers were identified in 821 male LS mutation carriers and male FDRs. MSH2 mutation carriers had a ten-fold increased risk of prostate cancer (RR 10.41; 95%CI 2.80, 26.65) but no association with bladder cancer was identified. 69/286 (24.1%) of dMMR CRCs contained significant B2M mutations. B2M mutations were associated with complete absence of recurrence (0/39) during follow-up in the QUASAR trial (stage II), compared with 14/77 (18.2%) in wild-type B2M (p=0.005). Conclusion: Studies consistently report that registration and screening result in a reduction of CRC incidence and mortality in FAP and LS (Level 2a evidence, Grade B recommendation). Funding and managerial support for registries should be made available. Uptake of predictive testing and colorectal screening in Lynch syndrome could be substantially improved, particularly among males and younger age groups, but this requires advances in communication with at-risk relatives. It is unlikely that GPs will actively participate without considerable support from genetics services. A trial of PSA screening in MSH2 mutation carriers from 50 years would be appropriate. B2M mutation status has potential clinical utility as a prognostic biomarker in stage II dMMR CRC.

Orientador: Carmen Silvia Bertuzzo / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T16:42:29Z (GMT). No. of bitstreams: 1 Viana_DaniloVilela_D.pdf: 5689445 bytes, checksum: ecee0316f70f957068dbfd39107b9161 (MD5) Previous issue date: 2013 / Resumo: Há muito tempo reconhece-se a importância de fatores hereditários na oncogênese. Dentre os genes associados ao câncer, um importante grupo é formado por aqueles direta ou indiretamente relacionados ao reparo do DNA, entre os quais está um grupo de genes pertencentes ao sistema de reparo de erros de pareamento de bases do DNA (mismatch repair - MMR), do qual fazem parte hMLH1, hMSH2, hMSH6 e hPMS2. Quando mutações monoalélicas nesses genes são herdadas, elas são responsáveis pela síndrome de Lynch, que cursa com predisposição ao câncer de cólon e endométrio, entre outros, geralmente na terceira ou quarta década de vida. A ocorrência de câncer na infância ou de tumores hematológicos não é comum na síndrome de Lynch. Nos últimos anos, entretanto, foram relatados diversos casos de pacientes que, na primeira ou segunda década de vida, apresentam tumores de sistema nervoso central, gastrintestinais, hematológicos, alguns deles com manifestações cutâneas semelhantes à neurofibromatose tipo 1. Nesses pacientes, foram identificadas mutações bialélicas nos genes do sistema MMR. O presente estudo propôs-se a analisar os tecidos tumorais de uma série retrospectiva de pacientes de zero a 35 anos de idade (inclusive), com diagnóstico de câncer de sistema nervoso central, visando a identificação de pacientes com mutações bialélicas nos genes do sistema MMR e a caracterização de seu quadro clínico. Teve por objetivos específicos: identificar os casos com instabilidade de microssatélites (MSI); determinar a proporção de tumores instáveis e o genótipo para os genes do sistema MMR nos casos que foram instáveis; correlacionar as mutações encontradas com o fenótipo e história familial. Um total de 79 pacientes foram incluídos no estudo. O diagnóstico era de glioma em 42 e meduloblastoma em 37. Inicialmente foi realizada a pesquisa de MSI nos tumores de todos os pacientes, seguido de avaliação clínica e coleta de sangue para pesquisa de mutações deletérias nos genes do sistema MMR, naqueles que apresentavam instabilidade. Foi encontrada baixa MSI (MSI-L) em sete casos de glioma e oito casos de meduloblastoma. Esses pacientes foram convocados para avaliação quanto à história clínica, exame físico e história familial. Seis pacientes atenderam ao convite, foram avaliados e tiveram sequenciamento e pesquisa de deleções por meio da técnica de MLPA realizados para os genes hMLH1, hMSH2, hMSH6. Não foram encontradas mutações deletérias em nenhum desses indivíduos. Procedeu-se, ainda, a determinação do intervalo de variação quase monomórfico para a população estudada, após o qual, cinco dos pacientes com diagnóstico de meduloblastoma, originalmente classificados como MSI-L, foram reclassificados como sendo estáveis (MSS). No presente estudo demonstrou-se que 8,3% dos pacientes com diagnóstico de meduloblastoma e 17,5% daqueles com gliomas possuíam MSI-L. A correlação do genótipo com o fenótipo e história familial não pôde ser realizada, visto não terem sido encontradas mutações deletérias. Sugere-se que sejam realizados estudos adicionais, preferencialmente prospectivos, para estabelecer a frequência de mutações nos genes do sistema MMR em pacientes pediátricos e adultos jovens com tumores de sistema nervoso central e instabilidade de microssatélites, uma questão importante para o aconselhamento genético, e, possivelmente, para implantação de uma rotina de rastreamento com pesquisa de MSI nessa população de pacientes / Abstract: Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition disorder characterized by early onset of cancer (mean age, approximately 40-45 years), especially edometrium and/or colorectal cancer in the absence of gastrointestinal polyposis, and which, in addition, shows increased frequency of carcinomas of the ovary, small intestine, ureter, renal pelvis, stomach, among others. Its molecular hallmark is a type of genetic instability known as miscrosattelite instability (MSI) that affects short sequences of DNA repeats (miscrosattelites) found throughout the genome, leading to accumulation of genetic alterations. In LS, Cancer predisposition is due almost exclusively to heterozygous germline mutations in one of the DNA MMR genes (hMSH2, hMLH1, hPMS1, hPMS2, and hMSH6). Childhood cancers and hematological neoplasia generally do not belong to the Lynch tumour spectrum. However, over the past few years there have been reports of children that have presented with the constellation of early onset gastrointestinal cancers, along with features of neurofibromatosis type-1 and/or hematologic malignancies, and/or neurological tumors due to homozygous mutations in the mismatch repair genes. The present study analyzed a retrospective series of central nervous system tissue from patients with 0 to 35 years of age, with the aim to identify biallelic mutations in MMR genes and characterization of its clinical tumor spectrum. The aims of this study were to analyze: the frequency of microsattelite instability in tumors; the genotype and the frequency of germline mutations in MMR genes in patients who had MSI; its correlation to the phenotype and family history. A total of 42 gliomas and 37 medulloblastomas were analyzed. Initially, they were screened for microsatellite instability (MSI), followed by clinical evaluation, family history taking and sequence analysis of DNA obtained from blood lymphocytes. Low MSI (MSI-L) was found in seven gliomas and eight meduloblastomas. These patients were invited for clinical examination, family history taking and blood drawing. Six attended the clinical evaluation and had their sequence analysis done for hMLH1, hMSH2, hMSH6. No deleterious mutations were found among these patients. In adition, the quasi-monomorphic variation range was determined for this population, a important step previously not investigated in Brazilian population, that showed that with the proper values for the target population, 5 from the original MSI-L medulloblastomas were reclassified as stable (MSS). In clonclusion, the present study showed that 8,3% of the medulloblastomas and 17,5% of gliomas had MSI-L. The correlation of the genotype with clinical characteristics and family history could not be done, as no deleterious mutations were found. It was suggestd that new prospective studies are necessary to properly address the issue of the frequency of biallelic mutations in pediatric and young adults patients with MSI-L tumors of the CNS / Doutorado / Genetica Medica / Doutor em Ciências Médicas

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