Lynch syndrome (LS), an autosomal dominantly inherited disease previously known as hereditary non-polyposis colorectal cancer (HNPCC), leads to a high risk of colorectal cancer (CRC) as well as malignancy at certain sites including endometrium, ovary, stomach, and small bowel (Hampel et al., 2008; Lynch et al., 2009). Clinically, LS is considered the most common hereditary CRC-predisposing syndrome, accounting for about 3% of all CRC cases (Popat et al., 2005). LS is associated with mutations of DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, PMS2, and EPCAM (Ligtenberg et al., 2009; Lynch et al., 2009), which can trigger a high frequency of replication errors in both microsatellite regions and repetitive sequences in the coding regions of various cancer-related genes. Immunohistochemistry (IHC) tests followed by genetic analysis of these mutations play a significant role in diagnosis, treatment determination, and therapeutic response prediction of LS (Lynch et al., 2009; Alex et al., 2017; Ryan et al., 2017). Here, we report substitution of one base-pair in exon 1 of MLH3 (c.1397C>A) and a frameshift mutation in exon 19 of MLH1 (c.2250_2251ins AA) in a 43-year-old Chinese male with an LS pedigree.
Adult ; Asian People/genetics* ; China ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics* ; Exons ; Female ; Frameshift Mutation ; Germ-Line Mutation ; Humans ; Male ; MutL Protein Homolog 1/genetics* ; MutL Proteins/genetics* ; Pedigree

INTRODUCTIONThe Singapore Polyposis Registry (SPR) was established in 1989 in Singapore General Hospital (SGH). The aims were to provide a central registry service to facilitate identification, surveillance and management of families and individuals at high risk of colorectal cancer.

MATERIALS AND METHODSThis is a review of published literature in the department.

RESULTSThe registry currently has 253 families with several genetic conditions-93 familial adenomatous polyposis (FAP) families, 138 Amsterdam-criteria positive presumed Lynch syndrome (LS) families, 12 families with Peutz Jeghers syndrome, 2 families with Cowden's syndrome, and 8 families with hereditary mixed polyposis syndrome (HMPS). There are also 169 families with a strong family history of colorectal cancer but no abnormal genes yet identified. In FAP, a diagnostic tool developed has allowed a 94% local APC germline detection rate in FAP families. Knowledge obtained studying the phenotype of FAP patients has allowed better choice of surgery between ileal pouch anal anastomosis (IPAA) against an ileal-rectal anastomosis (IRA). In LS, our review has noted a highly heterogenous mutational spectrum and novel variants made up 46.7% (28/60) of all variants identified in this cohort. This may suggest that our Southeast Asian ethnic groups have distinct mutational variants from Western populations. Pathogenic mutations were only confined to MLH1 and MSH2, and identified in 28.8% of families.

CONCLUSIONThe impact of predictive gene testing for hereditary cancer risk in clinical practice has allowed evolution of care. Risk-reducing surgery and aggressive surveillance allows reduction in morbidity and mortality of patients. The SPR will continue to grow and improve outcomes in hereditary colorectal cancer patients and families.

Adaptor Proteins, Signal Transducing ; genetics ; Colorectal Neoplasms ; diagnosis ; ethnology ; genetics ; surgery ; Disease Management ; Female ; Genetic Testing ; methods ; Humans ; Male ; MutL Protein Homolog 1 ; MutS Homolog 2 Protein ; genetics ; Mutation ; Neoplastic Syndromes, Hereditary ; classification ; diagnosis ; ethnology ; genetics ; surgery ; Nuclear Proteins ; genetics ; Registries ; statistics & numerical data ; Singapore ; epidemiology

OBJECTIVETo explore the relationship between DNA mismatch repair (MMR) and clinicopathologic features and prognosis in patients with stages II and III colon cancers.

METHODSThe clinical and pathological data of 440 patients with stage II/III colon cancer after radical resection were retrospectively reviewed and analyzed. Immunohistochemical staining was used to assess the expression of MMR proteins (MLH1, MSH2, MSH6 and PMS2), and the correlation between DNA MMR and clinicopathological features and prognosis of colon cancers was analyzed.

RESULTSOf the 440 tumor samples tested for DNA mismatch repair status, 90 (20.5%) demonstrated defective DNA mismatch repair and 350 (79.5%) had proficient DNA mismatch repair. Defective DNA mismatch repair (dMMR) was associated with young patients (≤ 60), proximal colon cancer, stage II, poorly differentiated adenocarcinoma and mucinous adenocarcinoma (P<0.05 for all). Among the 440 patients, 126 (28.6%) cases had recurrence or metastasis and 93 (21.1%) died during the median follow-up of 61.0 months. The five-year disease-free survival (DFS) rate was 82.2% among the patients with tumor exhibiting dMMR, significantly higher than that in patients with tumors exhibiting pMMR (68.9%, P=0.02). The univariate and mutlivariate analyses showed that the MMR status is an independent factor affecting 5-year disease-free survival and overall survival (OS) in colon cancer patients (P<0.05 for both).

CONCLUSIONSDefective DNA mismatch repair (dMMR) is associated with patients with proximal colon cancer, stage II and poorly defferentiated adenocarcinoma and mucinous adenocarcinoma. The prognosis for patients with dMMR is better than those with pMMR. dMMR may be a useful biomarker for the prognosis of colon cancer.

Adaptor Proteins, Signal Transducing ; metabolism ; Adenocarcinoma ; genetics ; metabolism ; mortality ; pathology ; Adenocarcinoma, Mucinous ; genetics ; metabolism ; mortality ; pathology ; Adenosine Triphosphatases ; metabolism ; Age Factors ; Analysis of Variance ; Colonic Neoplasms ; genetics ; metabolism ; mortality ; pathology ; DNA Mismatch Repair ; DNA Repair Enzymes ; metabolism ; DNA-Binding Proteins ; metabolism ; Disease-Free Survival ; Humans ; Mismatch Repair Endonuclease PMS2 ; MutL Protein Homolog 1 ; MutS Homolog 2 Protein ; metabolism ; Neoplasm Recurrence, Local ; Nuclear Proteins ; metabolism ; Prognosis ; Retrospective Studies ; Survival Rate

OBJECTIVETo evaluate the application of mismatch repair (MMR) genes proteins expression to screen for Lynch syndrome in colorectal cancer patients.

METHODSOne hundred consecutive colorectal cancers cases collected from 2012 to 2013 were tested immunohistochemically for the protein expression of MLH1, MSH2, MSH6 and PMS2, and also by the ARMS method for the mutation status of BRAF genes in those cases lacking protein expression for MLH1.

RESULTSThe result of MMR immunocytochemistry showed that nine of 100 cases lacked MMR protein expression, including three cases each that were MLH1-/PMS2- and MSH2-/MSH6- respectively, two cases were MLH6- and one case was PMS2-; overall, the majority of these cases lacked protein expression of MLH1 and MSH2. The BRAF genes mutation test showed one case of mutation, indicating that the patient might have MLH1 gene methylation as a result of the mutation of BRAF genes, and that was a sporadic case. The age of onset for patients lacking MMR protein expression was lower than patients with sporadic colorectal cancer (P = 0.011). Colorectal cancers associated with the lack of MMR protein expression mostly occurred in the right colon (P = 0.001), and histomorphologically were often accompanied by mucinous adenocarcinoma (P = 0.010) and tumor lymphocytic infiltration.

CONCLUSIONImmunohistochemical staining for MMR proteins in patients with colorectal cancer, accompanied by testing for BRAF genes mutation, may be an effective approach to screen for Lynch syndrome.

Adaptor Proteins, Signal Transducing ; genetics ; metabolism ; Colorectal Neoplasms, Hereditary Nonpolyposis ; diagnosis ; genetics ; DNA Mismatch Repair ; Humans ; Immunohistochemistry ; MutL Protein Homolog 1 ; Mutation ; Nuclear Proteins ; genetics ; metabolism ; Proto-Oncogene Proteins B-raf ; genetics ; metabolism

OBJECTIVETo analyze immunophenotypes and gene mutations of colorectal precancerous lesions and adenocarcinoma, and to compare the difference of carcinogenetic mechanisms between the two precancerous lesions.

METHODSFifty-three cases of colorectal serrated lesions including 30 hyperplastic polyps, 20 sessile serrated adenomas (SSA) and 3 mixed polyps were collected from January 2006 to June 2012.Forty-five cases of traditional adenomas and 50 cases of colorectal adenocarcinomas were also recruited. Thirty hyperplastic polyps, 20 cases of SSA, 3 mixed polyps and 45 traditional adenomas were investigated by immunohistochemistry for the expression of DNA mismatch repair (MMR) proteins (MLH1, MSH2 and MSH6) and DNA methyltransferase MGMT. Mutations of KRAS, BRAF and PIK3CA genes in 10 cases of SSAs, 10 traditional adenomas, 1 mixed polyps and 50 colorectal adenocarcinomas were analyzed by PCR followed by direct Sanger sequencing.

RESULTS(1) Only 3 cases of hyperplastic polyps lost MLH1 expression, and none of SSAs or traditional adenomas showed loss of MLH1. The negative expression rates of MSH2, MSH6 and MGMT in hyperplastic polyps and SSA were significantly higher than those of traditional adenomas. (2) KRAS mutation was found in 5/10 cases of SSAs, 5/10 traditional adenomas and 1/1 mixed polyps. (3) Colorectal adenocarcinomas harbored the mutations of KRAS (48%, 24/50), BRAF (6%, 3/50) and PIK3CA (4%, 2/50).

CONCLUSIONSImmunophenotypic and gene mutation profiles are different between colorectal serrated lesion and traditional adenoma. Alterations of MMR and MGMT expression play important roles in the pathogenesis of "serrated neoplasm". KRAS mutation is a significant genetic change in the early phase of colorectal carcinogenesis.

Adaptor Proteins, Signal Transducing ; metabolism ; Adenocarcinoma ; genetics ; metabolism ; Adenoma ; genetics ; metabolism ; Aged ; Class I Phosphatidylinositol 3-Kinases ; Colonic Polyps ; genetics ; metabolism ; Colorectal Neoplasms ; genetics ; metabolism ; DNA Mismatch Repair ; DNA Modification Methylases ; metabolism ; DNA Repair Enzymes ; metabolism ; DNA, Neoplasm ; metabolism ; DNA-Binding Proteins ; metabolism ; Female ; Humans ; Hyperplasia ; Immunophenotyping ; Male ; Middle Aged ; MutL Protein Homolog 1 ; MutS Homolog 2 Protein ; metabolism ; Nuclear Proteins ; metabolism ; Phosphatidylinositol 3-Kinases ; genetics ; Point Mutation ; Precancerous Conditions ; genetics ; metabolism ; Proto-Oncogene Proteins ; genetics ; Proto-Oncogene Proteins B-raf ; genetics ; Proto-Oncogene Proteins p21(ras) ; Sequence Analysis, DNA ; Tumor Suppressor Proteins ; metabolism ; ras Proteins ; genetics

Adaptor Proteins, Signal Transducing ; genetics ; metabolism ; Adenosine Triphosphatases ; genetics ; metabolism ; DNA Mismatch Repair ; DNA Repair Enzymes ; genetics ; metabolism ; DNA-Binding Proteins ; genetics ; metabolism ; Endometrial Neoplasms ; etiology ; genetics ; metabolism ; pathology ; Female ; Genetic Predisposition to Disease ; Humans ; Lynch Syndrome II ; complications ; genetics ; metabolism ; pathology ; Mismatch Repair Endonuclease PMS2 ; MutL Protein Homolog 1 ; MutS Homolog 2 Protein ; genetics ; metabolism ; Mutation ; Nuclear Proteins ; genetics ; metabolism

OBJECTIVETo investigate the aberrant promoter methylation of hMLH1 gene promoter and its clinical significance in papillary thyroid cancer (PTC).

METHODSmethylation of hMLH1 gene promoter in the cancer tissue and matched tumor-adjacent normal tissue of 152 PTC patients were detected by real-time methylation specific PCR (qMSP). The relationship between the methylation of hMLH1 gene promoter and clinicopathological features was analyzed.

RESULTSThe methylation rate of hMLH1 gene promoter in cancer tissues was 37.5% (57/152), of which 33 cases were totally methylated and 24 cases were partially methylated. The methylation rate of adjacent normal tissues was 5.3% (8/152)(all were partially methylated). The methylation rate of PTC tissues was significantly higher than that in the tumor-adjacent normal tissue (P < 0.01). The promoter methylation of hMLH1 gene in PTC was significantly correlated with age, size and number of the primary lesion, local invasion, T stage and lymph node metastasis (P < 0.05) , but not correlated with gender and clinical stage (P > 0.05).

CONCLUSIONPromoter methylation of hMLH1 gene is a common molecular event in PTC tissue, and it is significantly correlated with the progression of PTC.

Adaptor Proteins, Signal Transducing ; genetics ; metabolism ; Adolescent ; Adult ; Age Factors ; Aged ; Carcinoma ; genetics ; metabolism ; pathology ; Carcinoma, Papillary ; DNA Methylation ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Lymphatic Metastasis ; Male ; Middle Aged ; MutL Protein Homolog 1 ; Neoplasm Invasiveness ; Neoplasm Staging ; Nuclear Proteins ; genetics ; metabolism ; Promoter Regions, Genetic ; genetics ; Thyroid Neoplasms ; genetics ; metabolism ; pathology ; Tumor Burden ; Young Adult

OBJECTIVETo explore whether the abnormality of hMLH1 gene may be an early event of carcinogenesis in rectal carcinoma, and to evaluate the diagnostic value in differentiation between intraepithelial neoplasm and early stage of colorectal carcinoma.

METHODSThe expression of hMLH1 protein in 28 cases with early invasive rectal carcinoma(EIRC), 36 cases with rectal intraepithelial neoplasm(RIEN), and 30 cases with normal rectal mucosa(NRM) which were collected through surgical operations were detected by PV-9000 immunohistochemical method.

RESULTSThe positive expression rates of hMLH1 protein were 100%(30/30), 77.8%(28/36), and 39.3%(11/28) in NRM, RIEN, and EIRC respectively. The difference was statistically significant between RIEN and EIRC(P=0.002), and the difference was also statistically significant between RIEN and NRM(P=0.006). The positive expression of hMLH1 was not related to age, gender, tumor maximum diameter, dysplasia, tumor types, and distance from the anal verge in RIEV group(P>0.05). In EIRC group, hMLH1 was associated with tumor differentiation(P<0.05).

CONCLUSIONhMLH1 gene deletion may be an early event during carcinogenesis of rectal carcinoma, which may be useful in differentiation of intraepithelial neoplasm from early rectal carcinoma.

Adaptor Proteins, Signal Transducing ; genetics ; metabolism ; Adult ; Aged ; Aged, 80 and over ; Carcinoma in Situ ; diagnosis ; metabolism ; Early Detection of Cancer ; Female ; Humans ; Male ; Middle Aged ; MutL Protein Homolog 1 ; Nuclear Proteins ; genetics ; metabolism ; Rectal Neoplasms ; diagnosis ; metabolism

OBJECTIVETo investigate the expression of DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) in endometrial adenocarcinoma (EC) of patients under 50 years and to explore the relationship between MMR expression and clinicopathological features including body mass index (BMI), histological grade and pathological stage of EC.

METHODSMMR gene expression was investigated by immunohistochemical S-P method in endometrial adenocarcinomas of patients under age of 50. The control groups included complexity atypical hyperplasia endometrium (CAHE), simple hyperplasia endometrium (SHE), normal endometrium (NE) of patients under age of 50 and EC of patients older than 65 years.

RESULTSTwenty seven of 40 EC (67.5%) lost at least one MMR protein expression. Loss of at least one MMR protein expression was seen in 5/15 cases of CAHE, 1/13 SHE and 1/11 NE, respectively (P < 0.01). The rates of loss of expression of MLH1, MSH2, MSH and PMS2 proteins in EC were 52.5%, 12.5%, 35.0%, and 30.0%, respectively. The difference between MLH1 and MSH6 expression among the four groups were significant (P < 0.05), but the expression of MSH2 showed no significant difference among the groups (P = 0.295). The expression of MMR protein had no relationship with histological grade and pathological stage, although loss of MSH6 was more frequently seen in patients of higher BMI.

CONCLUSIONSAbnormal expression of MMR proteins is correlated with the development of EC from complex atypical hyperplasia. With the exception of the correlation of MSH6 expression with higher BMI, the expression of MMR proteins in EC has no significant relationship with histological grade and pathological stage.

Adaptor Proteins, Signal Transducing ; metabolism ; Adenocarcinoma ; genetics ; metabolism ; pathology ; Adenosine Triphosphatases ; metabolism ; Adult ; Body Mass Index ; DNA Mismatch Repair ; DNA Repair Enzymes ; metabolism ; DNA-Binding Proteins ; metabolism ; Endometrial Neoplasms ; genetics ; metabolism ; pathology ; Female ; Humans ; Immunohistochemistry ; Middle Aged ; Mismatch Repair Endonuclease PMS2 ; MutL Protein Homolog 1 ; MutS Homolog 2 Protein ; metabolism ; Neoplasm Grading ; Neoplasm Staging ; Nuclear Proteins ; metabolism

Adaptor Proteins, Signal Transducing ; metabolism ; Adenocarcinoma, Clear Cell ; genetics ; metabolism ; pathology ; surgery ; Adenosine Triphosphatases ; metabolism ; Age Factors ; Carcinoma, Endometrioid ; genetics ; metabolism ; pathology ; surgery ; Colorectal Neoplasms, Hereditary Nonpolyposis ; genetics ; metabolism ; pathology ; surgery ; Cystadenocarcinoma, Serous ; genetics ; metabolism ; pathology ; surgery ; DNA Mismatch Repair ; DNA Repair Enzymes ; metabolism ; DNA-Binding Proteins ; metabolism ; Endometrial Neoplasms ; genetics ; metabolism ; pathology ; surgery ; Female ; Humans ; Mismatch Repair Endonuclease PMS2 ; MutL Protein Homolog 1 ; MutS Homolog 2 Protein ; metabolism ; Neoplasms, Multiple Primary ; genetics ; metabolism ; pathology ; surgery ; Nuclear Proteins ; metabolism