Síndrome de Lynch: aspectos genéticos, clínicos y diagnósticos / Lynch syndrome: genetic, clinical and diagnostic aspects

Esta revisión tiene como objetivo dar a conocer los aspectos genéticos, clínicos y diagnósticos del síndrome de Lynch, además de brindar la información más relevante acerca de la asesoría genética en estos pacientes y las recomendaciones actuales para su seguimiento.

This review aims to present the genetic, clinical and diagnostic aspects of Lynch syndrome, as well as providing the most relevant information about genetic counseling in these patients and the current recommendations for their surveillance.

Correlation between mismatch-repair protein expression and clinicopathologic features in 658 colorectal cancers / 中华病理学杂志

Objective@#To investigate the expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2) in colorectal cancers and to explore the relationship between MMR expression and clinicopathologic features.@*Methods@#Six hundred and fifty-eight colon cancers were collected from January 2016 to January 2017 at Shengjing Hospital of China Medical University. Of the 658 patients there were 409 male and 249 female. The patients were 20 to 92 years old, with average age of (63±5) years old. Expression of MLH1, MSH2, MSH6 and PMS2 protein was detected by immunohistochemical method. Immunohistochemistry for BRAF V600E was performed in colorectal cancers with loss of MLH1 protein expression. Relationship between MMR protein expression and clinicopathologic features was analyzed statistically. @*Results@#Forty-four cases of 658 cases (6.7%) lost at least one MMR protein expression. Expression deficiency rates of MLH1, MSH2, MSH6 and PMS2 were 4.1%(27/658), 2.3%(15/658), 2.4% (16/658), and 4.3% (28/658), respectively. MMR expression deficiency mainly consisted of combined loss of MLH1/PMS2 (61.4%, 27/44) and MSH2/MSH6 (34.1%, 15/44). Two unique mutations were identified including one MSH6-deficient(2.3%, 1/44) and PMS2-deficient(2.3%, 1/44). Seven cases (25.9%, 7/27) had positive BRAF V600E expression, suggesting BRAF gene mutation related sporadic colorectal cancers. No correlation was observed between the expression of MMR and depth of tumor infiltration, lymph node metastasis, vascular tumor emboli, clinical stage or hematogenous metastasis (P>0.05). MMR status was associated with tumor cell differentiation, histological type and tumor location (P<0.01). Tumors with combined MLH1 and PMS2 loss were associated with mucinous differentiation (P=0.049, P=0.013) and located in the right hemi-colon (P=0.006, P=0.002). Combined MSH2 and PMS2 loss was related to gender, while loss of MSH2 protein was observed more frequently in female patients (P=0.048) and loss of PMS2 protein was seen more frequently in male patients (P=0.031). @*Conclusions@#Patients with MMR protein deficiency have a younger onset age and poorly differentiated tumors. Most tumors are located in the right hemi-colon and have mucinous differentiation.

Cáncer colorrectal hereditario no asociado a poliposis o síndrome de Lynch / Hereditary colorectal cancer not associated with polyposis or Lynch syndrome

El cáncer colorrectal hereditario no asociado a poliposis, también llamado síndrome de Lynch, es reconocido como un síndrome hereditario de patrón autosómico dominante de penetrancia incompleta, en el cual hay mutación en los genes reparadores del ADN. De 2 a 3 % de todos los tumores colorrectales se originan por este síndrome hereditario que predispone a su desarrollo. El síndrome Lynch, el más frecuente de los síndromes genéticos, incrementa, además del riesgo de desarrollar cáncer de colon, el de cáncer metacrónico y otros tipos de cáncer no colorrectal como los de endometrio, de intestino delgado, de uréter o de la pelvis renal. Por lo tanto, es indispensable reconocerlo e identificar a los individuos en riesgo de presentarlo para prevenir, diagnosticar y tratar de manera precoz la aparición de estas neoplasias, y poder disminuir las tasas de morbilidad y mortalidad asociadas

Hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome is recognized as an autosomal dominant hereditary syndrome of incomplete penetrance characterized by mutations in DNA repair genes. It is the most frequent of all the hereditary syndromes, and increases the likelihood of developing colorectal cancer, thus representing 2-3% of all colorectal cancers (CRC). This syndrome predisposes to metachronous (CRC) and other extracolonic cancers, as endometrium, small bowel, ureter and renal pelvis, among others. Therefore, it is necessary to recognize this syndrome and identify individuals with HNPCRC to prevent, diagnose and provide, if possible, early treatment in an effort to decrease its morbidity and mortality

Case Report of Menopausal Woman Diagnosed with Endometrial Cancer after Colon Cancer with Germline Mutation in MSH6 in Korea

We present a case of an endometrial cancer patient with germline mutation in MutS homolog 6 (MSH6), associated with Lynch syndrome. A 60-year-old Korean woman had a personal history of colon cancer 23 years ago. She also had a family history of endometrial cancer and colon cancer of her sisters and brothers. Immunohistochemistry was negative for MutL homolog 1 (MLH1) and positive for MutS homolog 2 (MSH2). Based on these findings, she underwent genetic counseling and testing that revealed a frameshift germline mutation at MSH6 (c. 3261dupC).

Hereditary Nonpolyposis Colorectal Cancer / 이화의대지

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary colorectal cancer syndrome and accounts for about 5% of colorectal cancer. It is inherited as autosomal dominant type and is caused by germline mutations in mismatch repair genes such as MLH1, MSH2, MSH6, and PMS2. Patients with HNPCC are characterized by a high level of microsatellite instability. They commonly develop colorectal cancer at young age and increase risk of extra-colic malignancies, especially endometrial cancer. They also show better oncologic outcomes compared to sporadic colorectal cancer. Several tools are used in diagnosis of HNPCC, including history taking, microsatellite instability test, immunohistochemistry for mismatch repair protein, and gene test. Affected patients and their families should get genetic counseling and regular surveillance for cancers, which can improve their survival rate.

Molecular diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome) / Diagnóstico molecular del cáncer colorrectal no polipósico hereditario (síndrome de Lynch)

Abstract Lynch syndrome is the most common cause of inherited colorectal cancer, totaling 5 to 8% of all the cases with high susceptibility to this type of cancer and extracolonic cancer. It is related to germinal mutations taking place at mismatch repair genes. The diagnosis of Lynch syndrome is essential for both monitoring patients with this disease and detecting asymptomatic carriers, in order to establish appropriate clinical monitoring, preventive management and genetic counseling. Although clinical criteria have been standardized by implementing Amsterdam I and II, as well as Bethesda guidelines, the detection rate of mutations in these genes only varies between 20% and 60%. The objective of this research was to review the state of the art regarding molecular diagnosis of Lynch syndrome; thus, a review of the literature published from 1995 to 2015 in PubMed database was performed by using the criteria "lynch syndrome molecular screening". 19 articles were selected and reviewed, and the relevant bibliography related to such articles was also reviewed. This paper presents different approaches proposed by several researchers on molecular algorithms to improve the efficiency of Lynch syndrome diagnosis.

Resumen El síndrome de Lynch es la causa más frecuente de cáncer colorectal (CCR) hereditario y representa el 5-8% de los casos con alta susceptibilidad a CCR y cánceres extracolónicos. Este síndrome se relaciona con mutaciones germinales en genes de reparación de malos apareamientos (MMR); su diagnóstico es fundamental, tanto para el seguimiento de los afectados como para la detección de portadores asintomáticos, y tiene el propósito de instaurar un adecuado seguimiento, un manejo preventivo y un asesoramiento genético. Si bien los criterios clínicos han sido estandarizados con la implementación de las guías de Amsterdam I y II y Bethesda, la tasa de detección de mutaciones en estos genes solo varía entre 20% y 60%. El objetivo de esta investigación fue revisar el estado del arte con relación al diagnóstico molecular del síndrome de Lynch, para lo cual se realizó una revisión de la literatura publicada entre 1995 y 2015 en la base de datos PubMed usando como criterio de revisión: "Lynch syndrome molecular screening". Se escogieron y revisaron 19 artículos y además se revisó y escogió la bibliografía pertinente de los artículos. Se presentan propuestas de varios autores sobre los algoritmos moleculares para mejorar la eficiencia del diagnóstico del síndrome de Lynch.

A influência da instabilidade de microssatélites e outros biomarcadores nos desfechos clínicos de pacientes com câncer colorretal metastático: um estudo caso-controle / The influence of microsatellite instability and other biomarkers on the clinical outcomes of patients with metastatic colorectal cancer: a case-control study

O câncer colorretal metastático (CCRm) é uma doença clinicamente e molecularmente heterogênea. Os pacientes apresentam diferentes prognósticos e respostas variáveis às terapias direcionadas contra o tumor. Alterações na função do sistema de reparo do DNA (deficiency mismatch repair - dMMR) estão associadas com o fenótipo de instabilidade de microssatélites e bom prognóstico em tumores de estádio inicial. No entanto, dMMR é raro no CCRm e pouco se sabe sobre sua influência na taxa de resposta (TR) ao tratamento. Nosso objetivo primário foi comparar a TR, de acordo com o status dMMR, nos pacientes com CCRm. Os desfechos secundários foram TR, conforme RAS e BRAF mutados, e a sobrevida global (SG), de acordo com dMMR. MÉTODOS: Estudo retrospectivo com grupo controle que comparou a TR por RECIST 1.1 em pacientes com CCRm, tratados com quimioterapia (QT) sistêmica, de acordo com o status dMMR. Os dados clínicos foram coletados, retrospectivamente, dos prontuários médicos. Todas as imagens foram digitais e recuperadas para avaliação de resposta por um único radiologista, cego quanto ao status dMMR. dMMR foi definido como a perda de expressão imuno-histoquímica em pelo menos um dos genes MMR (MLH1, MSH2, MSH6 e PMS2). Mutações em RAS e BRAF foram investigadas por meio de sequenciamento gênico. Os casos foram os pacientes com dMMR, e os controles, com MMR proficiente (pMMR), selecionados de forma consecutiva, em proporção de 1:2. Com base em características clínicas e moleculares, os indivíduos dMMR foram classificados como provável Lynch ou dMMR esporádico. Estatística descritiva foi usada para resumir os resultados. A associação entre dMMR e os resultados específicos de cada grupo foram analisados pelo teste do qui-quadrado, e para a avaliação de SG mediana, curvas de Kaplan-Meier e teste log-rank foram utilizados. Valores bicaudados de p < 0.05 foram considerados significativos. RESULTADOS: Entre janeiro de 2009 e janeiro de 2013, de...

Metastatic colorectal cancer (mCRC) is a clinically and molecularly heterogeneous disease, where patients present different prognosis and variable responses to cancer-directed therapies. Alterations in the function of DNA deficiency mismatch repair (dMMR) genes are associated with microsatellite instability and good prognosis in early stage tumors. However dMMR dysfunction is rare in mCRC and little is known about its influence on treatment response rate (RR). Our primary endpoint was to compare the RR of mCRC patients according to dMMR status and to explore differences between patients with likely sporadic versus likely Lynch-related tumors. Secondary endpoints were RR according to RAS and BRAF mutation status, and survival times as per dMMR status. METHODS: Retrospective study with control group that compared the RR by RECIST 1.1 in patients with mCRC treated with systemic chemotherapy according to dMMR status. Clinical data were collected retrospectively from medical charts. All images were digital and were retrieved for response evaluation by a single radiologist blinded to dMMR results. dMMR status was defined as loss of immunohistochemistry expression in at least one of the MMR genes (MLH1, MSH2, MSH6 e PMS2). RAS and BRAF mutations were investigated through next generation sequencing. Cases were defined as dMMR and controls, as proficient MMR (pMMR) patients, in a 1:2 fashion. Based on clinical and molecular features, dMMR patients were classified as likely Lynch or sporadic. Descriptive statistics was used to summarize the results. The association between dMMR and outcomes of each group were analyzed by chi-square test; estimates of median overall survival were done by the Kaplan-Meier method and comparisons, by the log-rank test. Two-tailed p values < 0.05 were considered significant. RESULTS: From January 2009 to January 2013, out of 1270 patients, 762 were eligible and screened for dMMR: N = 27 (3.5%) had dMMR and N = 735 (96.5%) had...

Validation of Prediction Models for Mismatch Repair Gene Mutations in Koreans / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Lynch syndrome, the commonest hereditary colorectal cancer syndrome, is caused by germline mutations in mismatch repair (MMR) genes. Three recently developed prediction models for MMR gene mutations based on family history and clinical features (MMRPredict, PREMM1,2,6, and MMRPro) have been validated only in Western countries. In this study, we propose validating these prediction models in the Korean population. MATERIALS AND METHODS: We collected MMR gene analysis data from 188 individuals in the Korean Hereditary Tumor Registry. The probability of gene mutation was calculated using three prediction models, and the overall diagnostic value of each model compared using receiver operator characteristic (ROC) curves and area under the ROC curve (AUC). Quantitative test characteristics were calculated at sensitivities of 90%, 95%, and 98%. RESULTS: Of the individuals analyzed, 101 satisfied Amsterdam criteria II, and 87 were suspected hereditary nonpolyposis colorectal cancer. MMR mutations were identified in 62 of the 188 subjects (33.0%). All three prediction models showed a poor predictive value of AUC (MMRPredict, 0.683; PREMM1,2,6, 0.709; MMRPro, 0.590). Within the range of acceptable sensitivity (> 90%), PREMM1,2,6 demonstrated higher specificity than the other models. CONCLUSION: In the Korean population, overall predictive values of the three models (MMRPredict, PREMM1,2,6, MMRPro) for MMR gene mutations are poor, compared with their performance in Western populations. A new prediction model is therefore required for the Korean population to detect MMR mutation carriers, reflecting ethnic differences in genotype-phenotype associations.

Clinicopathological Features and Type of Surgery for Lynch Syndrome: Changes during the Past Two Decades / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The Korean Hereditary Tumor Registry, the first and one of the largest registries of hereditary tumors in Korea, has registered about 500 families with hereditary cancer syndromes. This study evaluates the temporal changes in clinicopathologic features and surgical patterns of Lynch syndrome (LS) patients. MATERIALS AND METHODS: Data on 182 unrelated LS patients were collected retrospectively. The patients were divided into the period 1 group (registered in 1990-2004) and 2 (registered in 2005-2014). The clinical characteristics of the two groups were compared to identify changes over time. RESULTS: The period 1 group included 76 patients; the period 2 group, 106 patients. The mean ages at diagnosis were 45.1 years (range, 13 to 85 years) for group 1 and 49.7 years (range, 20 to 84 years) for group 2 (p=0.015). The TNM stage at diagnosis did not differ significantly-period 1 group: stage 0-I (n=18, 23.7%), II (n=37, 48.7%), III (n=19, 25.0%), and IV (n=2, 2.6%); period 2 group: stage 0-I (n=30, 28.3%), II (n=35, 33.0%), III (n=37, 34.9%), and IV (n=4, 3.8%). Extended resection was more frequently performed (55/76, 72.4%) in the period 1 group than period 2 (49/106, 46.2%) (p=0.001). CONCLUSION: Colorectal cancer in patients with LS registered at the Korean Hereditary Tumor Registry is still diagnosed at an advanced stage, more than two decades after registry's establishment. Segmental resection was more frequently performed in the past decade. A prompt nationwide effort to raise public awareness of hereditary colorectal cancer and to support hereditary cancer registries is required in Korea.

Adherence to colonoscopy recommendations for first-degree relatives of young patients diagnosed with colorectal cancer

OBJECTIVES:Colorectal cancer is the third leading cause of cancer death in the United States. The American College of Gastroenterology recommends screening for first-degree relatives of patients diagnosed with colorectal cancer before the age of 50. A colonoscopy is one of the most commonly recommended exams due to its specificity and the possibility to resect pre-malignant lesions. Nevertheless, the rate of physician adherence to this recommendation is unknown.METHODS:This transversal study was performed at a major cancer center in Brazil with 62 patients, aged 18 to 50, who completed a questionnaire on information received from their physicians regarding screening their first-degree relatives. We used the answers from patients who provided explicit consent.RESULTS:Two hundred and three patients were eligible to participate and 93 (45.8%) agreed to complete the questionnaire. Twenty-three questionnaires (24.73%) were returned and 39 were completed by telephone. Of the patients who answered the questionnaire, 39 (62.9%) had received a colonoscopy recommendation for their first-degree relatives and 23 (37.1%) were not informed of the recommendation. Among the patients who received the recommendations, 20.51% affirmed that all relatives completed the exam and 51.28% stated that no relatives completed the exam.DISCUSSION:The adherence rate of our physicians to the ACG guideline recommendations was 62.9%. Considering that our study was performed at a leading center for cancer treatment in Latin America, we had expected better adherence. The results show that adherence to the colorectal cancer screening recommendations for high-risk patients must be improved.

Syndrome in question

AbstractMuir-Torre syndrome is a rare genodermatosis characterized by the occurrence of at least one sebaceous tumor associated with visceral neoplasia, but with no predisposing factors. The sebaceous neoplasm may appear before, during or after the diagnosis of colorectal cancer. As it is regarded as a subtype of nonpolyposis hereditary colorectal cancer, it is important to evaluate the patient's first-degree relatives. The clinical course of the neoplasm is usually more indolent and the syndrome has a good prognosis. We report the case of a patient who, after a ten-year diagnosis of colorectal cancer, presented with multiple sebaceous neoplasms.

Characteristics of hereditary nonpolyposis colorectal cancer patients with double primary cancers in endometrium and colorectum

OBJECTIVE: The hereditary nonpolyposis colorectal cancer is inherited syndrome characterized by the development of cancers in various organ system; these includes colorectum, endometrium, and less frequently, small bowel, stomach, urinary tract, ovaries, and brain. We aimed to investigate the clinicopathologic characteristics of hereditary nonpolyposis colorectal cancer patients who had both endometrial and colorectal cancers. METHODS: Between January 2004 and December 2013, 12 women diagnosed with endometrial and colorectal cancers in a single institution were included in this analysis. For these patients, clinical and molecular findings were analyzed retrospectively. RESULTS: All 12 women undertook microsatellite instability analysis, and 9 (75%) were confirmed of having microsatellite instability-high. Among 9 cases with immunohistochemical staining for MLH1 and MSH2, 6 were positive for the loss of mismatch repair protein. Mutational analyses for MLH1 and MSH2 were performed in 3 out of 12 patients; all of them showed germline mutation. CONCLUSION: This study suggests that there is a genetic background in patients with double primary malignancies in their endometrium and colorectum when analyzed with microsatellite instability studies, immunohistochemistry staining, and mutation studies. This finding supports the necessity of re-defining the high-risk groups in endometrial cancers clinically. This will also help diagnose malignancies in such patients in early stages, as well as counsel other family members.

Improving survival after endometrial cancer: the big picture / 부인종양

To improve survival in women with endometrial cancer, we need to look at the "big picture" beyond initial treatment. Although the majority of women will be diagnosed with early stage disease and are cured with surgery alone, there is a subgroup of women with advanced and high-risk early stage disease whose life expectancy may be prolonged with the addition of chemotherapy. Immunohistochemistry will help to identify those women with Lynch syndrome who will benefit from more frequent colorectal cancer surveillance and genetic counseling. If they happen to be diagnosed with colorectal cancer, this information has an important therapeutic implication. And finally, because the majority of women will survive their diagnosis of endometrial cancer, they remain at risk for breast and colorectal cancer, so these women should be counselled about screening for these cancers. These three interventions will contribute to improving the overall survival of women with endometrial cancer.

The research progress of Lynch syndrome-associated endometrial cancers / 中国医师杂志

Lynch syndrome.(LS) is an autosomal dominant condition caused by a mutation in the mismatch repair genes (MMR).Endometrial cancer (EC) is the most common extra-colonic cancers of LS Ⅱ type.Among the female members of LS family with the MMR gene mutation,EC has an overall lifetime risk more than 35％.LS-associated EC is more likely present as the clinical pathological characteristics of early age of onset,endometrioid adenocarcinoma,lower grade,lower uterine segment involvement,and better prognosis.LS patients with family history and early age of onset should be performed with a combined screening and genetic testing,while high-risk patients should be taken clinical monitoring methods as endometrial biopsy.Oral contraceptives mav be reasonable chemopreventive agents in the patients with LS.Although prophylactic hysterectomy with bilateral salpingo-oophorectomy is an effective strategy to prevent EC in women with LS,preoperative counseling should address the trade-offs between the reduction in the risk of cancer,and the risks and side effects of surgery.The patients need hormone replacement therapy after surgery.

Constitutional mismatch repair deficiency syndrome: Do we know it.

Constitutional mismatch repair deficiency syndrome is a rare autosomal recessive syndrome caused by homozygous mutations in mismatch repair genes. This is characterized by the childhood onset of brain tumors, colorectal cancers, cutaneous manifestations of neurofibromatosis‑1 like café au lait spots, hematological malignancies, and occasionally other rare malignancies. Here, we would like to present a family in which the sibling had glioblastoma, and the present case had acute lymphoblastic lymphoma and colorectal cancer. We would like to present this case because of its rarity and would add to literature.

Síndromes hereditarios de predisposición al cáncer colorrectal identificados en el Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Perú / Inherited colorectal cancer predisposition syndromes identified in the Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Peru

Introducción: El cáncer colorrectal (CCR) es la cuarta neoplasia más frecuente en el mundo y según el origen de las alteraciones en el genoma de las células, el CCR se clasifica en esporádico (~70%) y genético (~30%), éste último involucra a los síndromes hereditarios de predisposición al CCR. Objetivo: Describir los síndromes hereditarios de predisposición al CCR, polipósicos y no polipósicos, identificados en el consultorio de Oncogenética del INEN. Material y métodos: Estudio descriptivo observacional a partir del registro de atenciones en el consultorio de Oncogenética del INEN durante el periodo 2009 al 2013. Se incluyeron a los pacientes con antecedentes personales o familiares de CCR y/o con poliposis colónica que fueron referidos para la evaluación clínica genética al consultorio de Oncogenética del INEN. Resultados: El 59,3% fueron mujeres, 40,7% varones, 69,8% fueron menores de 50 años, 60,5% presentó un CCR único, 23,2% más de un CCR o un CCR asociado a otra neoplasia extracolónica y el 32,6% poseían antecedentes familiares de cáncer con patrón de herencia autosómico dominante. Según el diagnóstico clínico genético, el 93,1% de los casos incluidos correspondieron a síndromes hereditarios de predisposición al CCR, siendo el 33,8% síndromes de poliposis colónica, 23,3% síndromes de CCR hereditario no polipósico (CCRHNP) y el 36,0% casos probables de síndrome CCRHNP. Conclusiones: La evaluación clínica genética de los pacientes con antecedentes personales o familiares de CCR y/o con poliposis colónica permite identificar a los síndromes hereditarios de predisposición al CCR y brindar una adecuada asesoría genética al paciente y familiares en riesgo, estableciendo medidas de seguimiento y estrategias de prevención a fin de evitar la morbimortalidad por cáncer.

Background: Colorectal cancer (CRC) is the fourth most common cancer in the world and is classified according to their origin in sporadic CRC (~ 70%) and genetic CRC (~ 30%), this latter involves cases of familial aggregation and inherited syndromes that predispose to CRC. Objective: To describe inherited CRC predisposition syndromes, polyposic and non-polyposic, identified in the Oncogenetics Unit at National Institute of Cancer Disease (INEN). Material and methods: A descriptive observational record from the attentions of the Oncogenetics Unit at INEN during 2009 to 2013. We included patients with personal or familiar history of CRC and/or colonic polyposis who were referred for clinical assessment to the Oncogenetics Unit at INEN. Results: 59.3 % were female, 40.7 % male, 69.8% under 50 years old, 60.5% had a single CRC, 23.2% had more than one CRC or CRC associated with other extracolonic neoplasia and 32.6% had a familiar history of cancer with autosomal dominant inheritance. According to the clinical genetic diagnosis, 93.1% of the included cases were inherited syndromes that predispose to CRC, with 33.8% of colonic polyposis syndromes, 23.3% of hereditary nonpolyposis CRC syndromes (HNPCC) and 36.0% of CCRHNP probable cases. Conclusions: Clinical genetic evaluation of patients with personal or familiar history of CRC and/or colonic polyposis can identify inherited colorectal cancer predisposition syndromes and provide an appropriate genetic counseling to patients and relatives at risk, establishing guidelines to follow-up and prevention strategies to prevent morbidity and mortality by cancer.

Expression of hMLH1 and hMSH2 in suspected hereditary non-polyposis colorectal cancer / 实用医学杂志

Objective To analyse the suspected hereditary non-polyposis colorectal cancer (HNPCC) in mismatch repair protein (MMR) expression of hMLH1 and hMSH2. Methods Immunohistochemical staining method was used for the detection of hMLH1 and hMSH2 protein expression in 193 cases suspected HNPCC patients, the deletion of MMR proteins was identified as highly suspected HNPCC cases. Results Of the 193 patients with suspected HNPCC hMLH1/hMSH2 abnormal expression rate was 29.02%; ≤30 years old was 40%, 31 ~ 40 years old was 28.05%, 41 ~ 50 years old was 28.71%,3 suspected HNPCC showed the deletion of hMLH1/hMSH2 protein expression at the same time ,; In the right colon , the left half colon and rectal anomaly detection rates were 40.74%, 32.65%and 18.89%; hMLH1/hMSH2 deletion was 46.15%with family history. Conclusions The deletion of MMR protein is closely related to age,site and family history in suspected HNPCC, and the deletion of hMLH1 is an important factor to induce early-set colorectal cancer. The deletion of hMLH1/hMSH2 at the same time indicates that hMLH1/hMSH2 genes may play important role in the incidence of HNPCC.

Caracterização imuno-histoquímica e molecular dos pacientes com suspeita clínica de Síndrome de Lynch / Immunohistochemical and molecular characterization of patients with clinical suspicion of Lynch Syndrome

Suspeita-se da Síndrome de Lynch (SL) a partir da história pessoal e familial do indivíduo. Posteriormente, os dados histopatológicos, imuno-histoquímicos e moleculares podem ser utilizados para aprimorar o diagnóstico da doença. Entretanto, um grande desafio no diagnóstico da Síndrome de Lynch é a baixa acurácia dos critérios clínicos utilizados. OBJETIVOS: Avaliar a frequência de SL em pacientes submetidos a tratamento cirúrgico por câncer colorretal e com história familial de câncer. Avaliar quais dos critérios clínicos e/ou moleculares seriam mais informativos no diagnóstico desta Síndrome na população brasileira. PACIENTES E MÉTODOS: Estudaram-se 458 casos de câncer colorretal (CCR), do Serviço de Coloproctologia do Departamento de Gastroenterologia do Hospital das Clínicas - FMUSP, de janeiro de 2005 a dezembro de 2008. História familial (HF) positiva para CCR ocorreu em 118 pacientes. Promoveu-se a revisão das lâminas para critérios histopatológicos de MSI (diretrizes de Bethesda), avaliação imuno-histoquímica (IHC) para as proteínas MLH1, MSH2, MSH6, PMS2, através do complexo avidina-biotina-peroxidase e instabilidade de microssatélites (MSI) (BAT-25, BAT-26, NR-21, NR-24 e MONO-27). Realizada a análise da mutação somática para o BRAF em todos os casos com MSI positiva. RESULTADOS: Dos 118 pacientes com HF, 61 (51,69%) preencheram pelo menos um dos critérios de Bethesda revisados. 36 eram do sexo feminino (59%), média de idade de 53,2 anos. Nove (14,7%) pacientes apresentaram todos os critérios de Amsterdam I. Cinquenta e dois tumores localizaram-se no cólon esquerdo. Os componentes histopatológicos de MSI incluíram: linfócitos intratumoral (47,5%), característica expansiva do tumor (29,5%) e o componente mucinoso (27,8%) (componentes histopatológicos de MSI instável) em 44 (72%). A IHC estava alterada em oito (13%) e a MSI em 12 pacientes (20%). Houve associação entre os critérios de Amsterdam I e MSI e na IHC com MLH1 e PMS2. Houve associação entre...

Lynch Syndrome is suspected due to the personal and familial history of the individual. Subsequently, histopathological, immunohistochemical and molecular data can be used to improve diagnosis of the disease. However, a major challenge in the diagnosis of Lynch Syndrome is the low accuracy of clinical criteria. OBJECTIVES: To assess the frequency of Lynch Syndrome in patients with familial cancer history submitted to colorectal cancer resection. To assess what clinical and / or molecular criteria would be the most informative in the diagnosis of this syndrome in Brazilian population. PATIENTS AND METHODS: 458 colorectal cancer (CRC) cases were studied, from the Coloproctology Unit of the Department of Gastroenterology, Hospital das Clinicas - USP, from January 2005 to December 2008. Positive family history (FH) for CRC occurred in 118 patients. The pathologic slides were reviewed for histological criteria for MSI (Bethesda guidelines), immunohistochemical analysis (IHC) for MLH1, MSH2, MSH6, PMS2 proteins, through the avidin-biotin-peroxidase complex, and microsatellite instability (MSI) (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). BRAF somatic mutation was analyzed in all cases with positive MSI. RESULTS: Of the 118 patients with HF, 61 (51.69%) met at least one of the revised Bethesda criteria. Thirty-six were female (59%), and the mean age was 53.2 years. Nine (14.7%) patients presented all Amsterdam criteria I. Fifty-two tumors were located in the left colon. MSI histopathological components included: intratumoral lymphocytes (47.5%), expansive characteristics of the tumor (29.5%) and mucinous component (27.8%) (Histological unstable components of MSI) in 44 (72%). IHC was abnormal in eight (13%) and MSI in 12 patients (20%). There was an association between the Amsterdam criteria I and MSI; and between IHC with MLH1 and PMS2. There was an association with the revised Bethesda criteria with: sex, mucinous histology and Crohn's like...

Muir-Torre Syndrome: case report and molecular characterization / Sindrome de Muir-Torre: relato de caso e caracterizacao molecular

CONTEXT: Muir-Torre syndrome is a rare autosomal dominant genodermatosis caused by mutations in the mismatch repair genes. It is characterized by the presence of sebaceous skin tumors and internal malignancies, affecting mainly the colon, rectum and urogenital tract. Awareness of this syndrome among physicians can lead to early diagnosis of these malignancies and a better prognosis. CASE REPORT: We report the case of a Chilean patient who, over the course of several years, had multiple skin lesions, endometrial cancer and colon cancer. The syndrome was diagnosed using molecular techniques such as microsatellite instability analysis, immunohistochemistry and DNA sequencing, which allowed us to find the causative mutation. CONCLUSION: Molecular diagnostics is a highly useful tool, since it allows clinicians to confirm the presence of mutations causing Muir-Torre syndrome. It is complementary to the analysis of the clinical data, such as dermatological presentation, presence of visceral malignancies and family history of colorectal tumors, and it provides important knowledge to help physicians and patients choose between treatment options. .

CONTEXTO: A síndrome de Muir-Torre é uma genodermatose autossômica dominante rara causada por mutações nos genes de reparo de incorreções. Caracteriza-se pela presença de tumores sebáceos da pele e doenças malignas internas, afetando principalmente cólon, reto e trato urogenital. A consciência desta síndrome pelos médicos pode levar ao diagnóstico precoce dessas doenças malignas e a um melhor prognóstico. RELATO DE CASO: Relatamos o caso de uma paciente chilena que, ao longo de vários anos, teve lesões cutâneas múltiplas, câncer de endométrio e câncer de cólon. A síndrome foi diagnosticada com técnicas moleculares, como a análise de instabilidade de microssatélites, imunoistoquímica e sequenciamento de DNA, o que nos permitiu encontrar a mutação causadora. CONCLUSÃO: Diagnóstico molecular é uma ferramenta muito útil, uma vez que permite que os clínicos confirmem a presença de mutações causadoras de síndrome de Muir-Torre. É complementar para a análise dos dados clínicos, tais como a apresentação dermatológica, a presença de doenças malignas viscerais e história familiar de tumores colorrectais, e fornece conhecimentos importantes para ajudar os médicos e os pacientes a escolher entre opções de tratamento. .

Investigação de mutações nos genes MLH1 e MSH2 em portadores de câncer colorretal hereditário sem polipose (HNPCC) / Investigation of mutations in MLH1 and MSH2 genes in carriers with Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

O câncer colorretal tem importância elevada frente a sua incidência e morbidade. Dentre os casos hereditários, o câncer colorretal hereditário sem polipose (HNPCC), ou Síndrome de Lynch, é responsável por cerca de 5% do total de casos. No HNPCC, a alteração genética herdada é a inativação de um dos alelos dos genes envolvidos em reparo do DNA, sendo os principais os genes hMLH1 e hMSH2. O objetivo deste trabalho foi investigar, em indivíduos com diagnóstico clínico de HNPCC, a presença de mutações nos genes MLH1 e MSH2, associar as variáveis clínicas com o gene mutado e investigar os familiares de portadores de HNPCC aos quais tivemos acesso, com relação a mutações germinativas. A investigação das mutações foi realizada por meio de sequenciamento direto dos éxons, região promotora e regiões de junção. Foram analisados 65 indivíduos divididos em três grupos, sendo (I) 46 pacientes portadores de câncer colorretal inclusos nos Critérios de Amsterdã, (II) dois familiares portadores de câncer colorretal e (III) 17 familiares sem câncer, todos da região metropolitana de Campinas, atendidos no Hospital de Clínicas da UNICAMP. Em 21 (45,65%) dos pacientes foram encontradas mutações deletérias. As mutações deletérias nos genes MLH1 e MSH2 estavam na proporção de 34,78% (16 pacientes) e 10,86% (5 pacientes), respectivamente. As mutações não deletérias nos genes MLH1 e MSH2 estavam na proporção de 65,22% dos pacientes (30 alterações) e 50% dos pacientes (23 alterações), respectivamente...

Colorectal cancer has high importance because of its incidence and morbidity. Among the hereditary cases, the hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, accounts for about 5% of cases. In HNPCC, the genetic alteration inherited is the inactivation of one of the alleles of genes involved in the DNA repair, being hMSH2 and hMLH1 the main genes. The objective of this study is to investigate the presence of mutations in MLH1 and MSH2 in patients with clinical diagnosis of HNPCC, correlate clinical variables with the mutated gene, and investigate the relatives of patients with HNPCC who we had access to, in relation to germline mutations. Investigation of the mutations was performed by éxons direct sequencing, the promoter and junction regions. Sixty-five individuals, divided into three groups, were studied: (I) 46 patients with colorectal cancer included in the Amsterdam Criteria, (II) two family members of colorectal cancer patients and (III) 17 relatives without cancer, all of them treated at Hospital das Clínicas at UNICAMP and living in the Campinas metropolitan area. Deleterious mutations were found in 21 patients (45.65%). The ratio of deleterious mutations in MLH1 and MSH2 was 34.78% (16 patients) and 10.86% (5 patients) respectively. The ratio of non deleterious mutations in genes MLH1 and MSH2 was 65.22% of patients (30 alterations) and 50% of patients (23 alterations) respectively. Among patients with HNPCC, 23 potentially deleterious mutations were identified, via sequences of MLH1 and MSH2 with a 50% detection rate. It doesn't seem to appear variations in the clinical characteristics of the tumor when a germline mutation occurs in MLH1 or MSH2, with the exception of the relationship between the presence of mutation in the MLH1 gene and age of disease onset. As it occurs throughout the world, the disease present a his molecular extremely heterogeneoty, where only two mutations were repeated in two patients...