[Correlation between mismatch-repair protein expression and clinicopathologic features in 658 colorectal cancers].

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.

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.

XRCC2 Polymorphisms and Environmental Factors Predict High Risk of Colorectal Cancer.

BACKGROUND This case-control study aimed to analyze the association of [i]XRCC2[/i] polymorphisms (rs3218408 and rs3218384) with colorectal cancer (CRC) risk. The interaction of [i]XRCC2[/i] polymorphisms with environmental factors was investigated as well. MATERIAL AND METHODS We enrolled 147 CRC patients and 114 healthy individuals into the study. Polymerase chain reaction (PCR)-sequencing method was performed to detect rs3218408 and rs3218384 polymorphisms. Hardy-Weinberg equilibrium (HWE) was checked in the control group. Odds ratio (OR) with 95% confidence interval (CI) represented the risk of CRC. Cross-table method was used in analyzing the interaction effects. RESULTS Compared to the control group, the frequency of smokers was much higher in the case group ([i]P[/i]<0.001). A similar result was observed in drinkers (55.8% [i]vs.[/i] 40.4%, [i]P[/i]=0.013). Dietary habits of all subjects were investigated as well, showing that CRC patients ate fewer vegetables than did healthy controls (P<0.001). In the analysis of polymorphisms, rs3218408 appeared to be an independent risk factor of CRC (GG: OR=2.048, 95%CI=1.032-4.061; G allele: OR=1.445, 95%CI=1.019-2.049). There were 68 (76.4%) C allele carriers (rs3218384) among smokers, which was higher than the number of G allele carriers ([i]P[/i]<0.001). A similar outcome was observed for alcohol drinkers ([i]P[/i]=0.048), which suggests a relationship of rs3218384 with smoking and drinking. Further analysis indicated that interaction of rs3218384 with smoking increased the risk of CRC (GG and smoking: OR=3.250, 95%CI=1.235-8.556; GC+CC and smoking: OR=2.167, 95%CI=1.175-3.996). CONCLUSIONS We found that rs3218408 was related with increased risk of CRC, and the interaction of rs3218384 with smoking increased the risk of CRC.

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.

An E-Learning Module to Improve Nongenetic Health Professionals' Assessment of Colorectal Cancer Genetic Risk: Feasibility Study.

BACKGROUND: Nongenetic health providers may lack the relevant knowledge, experience, and communication skills to adequately detect familial colorectal cancer (CRC), despite a positive attitude toward the assessment of history of cancer in a family. Specific training may enable them to more optimally refer patients to genetic counseling. OBJECTIVE: The aim of this study was to develop an e-learning module for gastroenterologists and surgeons (in training) aimed at improving attitudes, knowledge, and comprehension of communication skills, and to assess the feasibility of the e-learning module for continued medical education of these specialists. METHODS: A focus group helped to inform the development of a training framework. The e-learning module was then developed, followed by a feasibility test among a group of surgeons-in-training (3rd- and 4th-year residents) and then among gastroenterologists, using pre- and posttest questionnaires. RESULTS: A total of 124 surgeons-in-training and 14 gastroenterologists participated. The e-learning was positively received (7.5 on a scale of 1 to 10). Between pre- and posttest, attitude increased significantly on 6 out of the 10 items. Mean test score showed that knowledge and comprehension of communication skills improved significantly from 49% to 72% correct at pretest to 67% to 87% correct at posttest. CONCLUSIONS: This study shows the feasibility of a problem-based e-learning module to help surgeons-in-training and gastroenterologists in recognizing a hereditary predisposition in patients with CRC. The e-learning led to improvements in attitude toward the assessment of cancer family history, knowledge on criteria for referral to genetic counseling for CRC, and comprehension of communication skills.

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.

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...

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.

Improving survival after endometrial cancer: the big picture.

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.

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.

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.

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.

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.

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.

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...

Multiple primary carcinoma in Chinese hereditary nonpolyposis colorectal cancer patients in Northeast China / 中华普通外科杂志

Objective To investigate the familial incidence of multiple primary carcinoma in Chinese hereditary nonpolyposis colorectal cancer patients (HNPCC) in Northeast China.Methods By family line investigation,multiple primary carcinoma (MPC) spectrum' s characteristics of 509 patients in 85 families registered in strict conformity with the HNPCC Amsterdam criteria Ⅱ were analyzed retrospectively.Results Of the 85 HNPCC families,multiple primary carcinoma developed in 55 patients in 25 families,among them 45 patients had metachronous carcinoma in 17 families,16 patients had synchronous carcinoma occurred in 12 families,6 patients with both synchronous carcinoma and metachronous carcinoma in 4 families.Conclusions Multiple primary carcinoma developed in significantly high incidence in Northeast China in Chinese hereditary nonpolyposis colorectal cancer patients,the most common MPC are colorectal cancer and endometrial cancer.

Clinicalpathological characteristics of Lynch syndrome related epithelial ovarian cancer / 中华妇产科杂志

Objective To explore the clinicalpathological characteristics of Lynch syndrome associated ovarian cancer.Methods Totally 260 cases ovarian cancer patients were admitted to Tianjin Medical University General Hospital during Jan.2004 and Jan.2011,among which 10 patients( LS group) belonged to Lynch syndrome associated ovarian cancer according to Amsterdam Ⅱ criteria.One hundred ovarian cancer patients without any family cancer history were enrolled randomizely as control group (sporadic group).Results Lynch syndrome associated ovarian cancer accounted for 3.8％ ( 10/260),the incidence rate of ovarian cancer for female family members of Lynch syndrome was 8.7％ ( 10/115 ).Mean age at time of diagnosis in LS group was (46 ±7) years,significantly earlier than that in sporadic group [ (56 ±11 ) years,P ＜ 0.05 ].There was no statistical difference between two groups in histological type or International Federation of Gynecology and Obstetrics ( FIGO ) stage ( P ＞ 0.05 ).Most of the tissue differentiation in LS group were well or moderate differentiated,there was statistical difference between the two groups(9/10 vs.55％,P ＜0.05).The 3-year and 5-year survival rate in LS group were 87.5％ and 52.5％respectively,compared with 55.4％and 22.7％ in sporadic group(all P＜0.05).Conclusion Compared with sporadic ovarian cancer,Lynch syndrome associated ovarian cancer is more likely present as the clinicalpathological characteristics of early age of onset,serous adenocarcinoma,lower grade and better prognosis.

Clinicopathologic Characteristics of Left-Sided Colon Cancers with High Microsatellite Instability

BACKGROUND: High microsatellite instability (MSI-H) colorectal carcinomas (CRCs) with numerous mutations in the microsatellite sequence are characterized by a right-sided preponderance, frequent peritumoral and intratumoral lymphocytic infiltration, and frequent mucin production. However, no study has correlated anatomic site and type of genetic changes with clinicopathologic changes. METHODS: We analyzed the histopathologic features of 135 MSI-H CRCs and compared them to 140 microsatellite stable (MSS) CRCs. Histopathologic changes in MSI-H were further analyzed according to anatomic sites and genetic changes. RESULTS: MSI-H CRCs showed previously reported clinicopathologic findings; a right-sided preponderance, an increased number of mucinous carcinomas, and peritumoral lymphoid reactions (p<0.001 for each variable). Increased serum CEA levels showed an MSS CRC preponderance (p=0.013). We further analyzed the histologic differences between right- and left-sided MSI-H tumors. We found that MSI-H CRCs on both sides had similar clinicopathologic findings, except for higher tumor stage (p=0.048) and less frequent abnormal CEA levels in left-sided MSI-H tumors (p=0.027). We found that not all clinicopathologic features were different between hereditary nonpolyposis colorectal cancers (HNPCCs) and sporadic MSI-H CRCs. CONCLUSIONS: These findings indicate that MSI-H CRCs of the left colon have similar clinicopathologic characteristics as right-sided MSI-H CRCs. We did not find any significant clinicopathological difference between HNPCCs and sporadic MSI-H CRCs.

Síndrome de Lynch: Caracterización genético clínica. Caso clínico / Hereditary non-polyposis colorectal cancer: Report of four siblings

Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch Syndrome is an autosomic dominant syndrome involving 596-1096 of colorectal cancer patients. Mutations in MLH1 and MSH2 genes account for most cases. These two genes particípate in the DNA mismatch repair pathway. Therefore mutation carriers show microsatellite instability (MSI) in tumors. This syndrome is characterized by the early development of colorectal cancer (before 50 years) and an increased incidence of cancer in other organs. We report four siblings from a family diagnosed with HNPCC. All of them were subjected to colonic surgery for colorectal cancer Moreover, one patient developed an ampulloma after her colon surgery. The molecular-genetic analysis revealed three brothers with microsatellite instability in the tumor tissue, the absence of the MLH1 protein, and the presence of a germ Une mutation localized in introm 15 ofthe MLH1 gene.