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MLH1 hypermethylation

E Stelloo, A M L Jansen, E M Osse, R A Nout, C L Creutzberg, D Ruano, D N Church, H Morreau, V T H B M Smit, T van Wezel, T Bosse
BACKGROUND: Mismatch repair (MMR)-deficiency analysis is increasingly recommended for all endometrial cancers, as it identifies Lynch syndrome-patients, and is emerging as a prognostic classifier to guide adjuvant treatment. The aim of this study was to define the optimal approach for MMR-deficiency testing and to clarify discrepancies between microsatellite instability (MSI) analysis and immunohistochemical (IHC) analysis of MMR protein expression. PATIENTS AND METHODS: 696 endometrial cancers were analyzed for MSI (pentaplex panel) and MMR protein expression (IHC)...
October 13, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
T Rau
The pathogenesis of precursor lesions of gastrointestinal tumors is manifested in many ways. In the esophagus an aberrant genetic expression of intestinal transcription factors, such as CDX2 is initiated by local environment factors. During the subsequent dysplasia to carcinoma sequence, chromosomal gain and loss of genes occurs. A 4-color fluorescence in situ hybridization (FISH) assay can be applied in dysplasia as well as in Barrett's adenocarcinoma to define prognostic marker combinations. In the gastric carcinogenesis sequence the gene expression of CDX1 is regulatively dependent on an interplay between inflammation and promotor methylation...
September 14, 2016: Der Pathologe
Fernanda Viviane Mariano, Erika Said Egal, Dimitrius Pramio, Felipe Fidalgo, Érica Sara, Ana Flávia Costa, Rogério de Oliveira Gondak, Ricardo Della Coletta, Oslei Paes de Almeida, Luiz Paulo Kowalski, Ana Cristina Victorino Krepischi, Albina Altemani
OBJECTIVE: The progression of pleomorphic adenoma (PA) to carcinoma ex-pleomorphic adenoma (CXPA) encompasses several genomic alterations involving complex pathways. Tumor suppressor genes seem to play important roles in the tumorigenesis of both tumors. The aim of this study was to evaluate copy number and methylation of tumor suppressor genes' status in PA and CXPA samples. STUDY DESIGN: Eight cases of PA, 2 cases of residual PA in CXPA, and 5 cases of CXPA were studied; the latter were classified according to invasiveness and histopathological subtype...
September 2016: Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Emily A Sloan, Christopher A Moskaluk, Anne M Mills
Defects in the DNA mismatch-repair system are identified in ∼25%-30% of endometrial carcinomas (ECs). Whereas some ECs are due to germline Lynch syndrome (LS)-associated mutations, the majority demonstrate sporadic MLH1 promoter hypermethylation (MLH1hm). MLH1hm characterizes a unique subset of colorectal cancers with a relatively poor prognosis; however, the morphology and behavior of sporadically methylated ECs (SMECs) are less well understood. We herein review the clinicopathologic features of 34 SMECs diagnosed at The University of Virginia and compare them with LS-associated and Lynch-like endometrial cancers...
August 10, 2016: International Journal of Gynecological Pathology
Lama Farchoukh, Shih-Fan Kuan, Beth Dudley, Randall Brand, Marina Nikiforova, Reetesh K Pai
Between 10% and 15% of colorectal carcinomas demonstrate sporadic DNA mismatch-repair protein deficiency as a result of MLH1 promoter methylation and are thought to arise from sessile serrated adenomas, termed the serrated neoplasia pathway. Although the presence of the BRAF V600E mutation is indicative of a sporadic cancer, up to 30% to 50% of colorectal carcinomas with MLH1 promoter hypermethylation will lack a BRAF mutation. We report the clinicopathologic and molecular features of MLH1-deficient colorectal carcinoma with wild-type BRAF and MLH1 promoter hypermethylation (referred to as MLH1-hypermethylated BRAF wild-type colorectal carcinoma, n=36) in comparison with MLH1-deficient BRAF-mutated colorectal carcinoma (n=113) and Lynch syndrome-associated colorectal carcinoma (n=36)...
October 2016: American Journal of Surgical Pathology
Virginia E Duncan, Shuko Harada, Todd M Stevens
We report a case of a 53-year-old woman who presented with rectal bleeding and a 9.5 cm hemicircumferential ascending colon mass. Histology revealed adenosquamous carcinoma (ASC), a rare subtype comprised of malignant squamous and glandular elements. Immunohistochemistry revealed loss of MLH1/PMS2 expression and retained MSH2/MSH6 expression in squamous and glandular components, indicative of microsatellite instability (MSI). MSI is caused by loss-of-function defects in DNA mismatch repair genes, leading to increased susceptibility to a variety of neoplasms; the role of MSI in colorectal ASC is unknown...
October 2016: International Journal of Surgical Pathology
Jung Ho Kim, Hye Eun Park, Nam-Yun Cho, Hye Seung Lee, Gyeong Hoon Kang
BACKGROUND: The aim of this study was to reveal the clinicopathological and molecular characteristics of microsatellite instability-high (MSI-H) colorectal cancers (CRCs) showing programmed death ligand-1 (PD-L1) positivity, which are good candidates for anti-PD-1/PD-L1 immunotherapy. METHODS: The PD-L1 expression status of 208 MSI-H CRCs was retrospectively analysed using immunohistochemistry. PD-L1 positivity in tumour cells (PD-L1+(T)) and PD-L1 positivity in immune cells (PD-L1+(I)) were separately evaluated...
August 9, 2016: British Journal of Cancer
Marco Scarpa, Melania Scarpa, Ignazio Castagliuolo, Francesca Erroi, Silvia Basato, Paola Brun, Imerio Angriman, Carlo Castoro
BACKGROUND: The lack of positive costimulatory molecules represents one of the mechanisms by which tumor cells evade immune surveillance. Promoter hypermethylation plays a major role in cancer development through transcriptional silencing of critical genes. The aim of this study was to examine the expression of the costimulatory molecule CD80 in relationship with genomic methylation in non-inflammatory colon carcinogenesis. METHODS: Colonic mucosal samples were collected from healthy subjects (n = 30) and from dysplastic adenoma (n = 14), and colon adenocarcinoma (n = 10)...
2016: BMC Cancer
Stacey A Cohen, Emily H Turner, Mallory B Beightol, Angela Jacobson, Ted A Gooley, Stephen J Salipante, Sigurdis Haraldsdottir, Christina Smith, Sheena Scroggins, Jonathan F Tait, William M Grady, Edward H Lin, David E Cohn, Paul J Goodfellow, Mark W Arnold, Albert de la Chapelle, Rachel Pearlman, Heather Hampel, Colin C Pritchard
BACKGROUND & AIMS: Some colorectal and endometrial tumors with microsatellite instability not attributable to MLH1 hypermethylation or germline mutations contain 2 or more somatic mutations in genes encoding mismatch repair (MMR) proteins. We sought to define the molecular phenotype of this newly recognized tumor subtype. METHODS: From 2 prospective studies of the efficacy of screening for Lynch syndrome, we identified patients with colorectal and endometrial tumors who had 2 or more somatic (but not germline) mutations in genes encoding MMR proteins (double somatic)...
September 2016: Gastroenterology
Anne M L Jansen, Marije A Geilenkirchen, Tom van Wezel, Shantie C Jagmohan-Changur, Dina Ruano, Heleen M van der Klift, Brendy E W M van den Akker, Jeroen F J Laros, Michiel van Galen, Anja Wagner, Tom G W Letteboer, Encarna B Gómez-García, Carli M J Tops, Hans F Vasen, Peter Devilee, Frederik J Hes, Hans Morreau, Juul T Wijnen
BACKGROUND AND AIMS: Lynch Syndrome (LS) is caused by pathogenic germline variants in one of the mismatch repair (MMR) genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS) because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history...
2016: PloS One
Fabio Coppedè, Pierpaola Tannorella, Andrea Stoccoro, Lucia Chico, Gabriele Siciliano, Ubaldo Bonuccelli, Lucia Migliorea
There is substantial evidence of impaired DNA repair activities in Alzheimer's disease (AD) neurons and peripheral tissues, inducing some investigators to speculate that this could partially result from promoter hypermethylation of DNA repair genes, resulting in gene silencing in those tissues. In the present study a screening cohort composed by late-onset AD (LOAD) patients and healthy matched controls was evaluated with a commercially available DNA methylation array for the assessment of the methylation levels of a panel of 22 genes involved in major DNA repair pathways in blood DNA...
April 11, 2016: Mechanisms of Ageing and Development
David Tougeron, Karline Guilloteau, Lucie Karayan-Tapon
BACKGROUND: Colorectal cancers (CRCs) with deficient DNA mismatch repair system (dMMR) represents approximately 12% of all CRCs. Sporadic dMMR CRCs are due to hypermethylation MLH1 gene promoter and associated with the CpG island methylator phenotype (CIMP). Isocitrate dehydrogenase (IDH) mutant tumors are associated with DNA hypermethylation in various cancers. AIMS: Look if dMMR CRC are associated with IDH mutations. METHODS: All consecutive dMMR CRCs between 2005 and 2014 were included in this study...
June 2016: Digestive and Liver Disease
Celine H M Leenen, Anne Goverde, Esther W de Bekker-Grob, Anja Wagner, Margot G F van Lier, Manon C W Spaander, Marco J Bruno, Carli M Tops, Ans M W van den Ouweland, Hendrikus J Dubbink, Ernst J Kuipers, Winand N M Dinjens, Monique E van Leerdam, Ewout W Steyerberg
PURPOSE: To assess the cost-effectiveness of routine Lynch syndrome (LS) screening among colorectal cancer (CRC) patients ≤70 years of age. METHODS: A population-based series of CRC patients ≤70 years of age was routinely screened for LS. We calculated life years gained (LYG) and incremental cost-effectiveness ratios (ICERs) for different age cutoffs and comparing age-targeted screening with the revised Bethesda guidelines. RESULTS: Screening 1,117 CRC patients identified 23 LS patients, of whom 7 were ≤50 years of age, 7 were 51-60, and 9 were 61-70...
October 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Iris H Liu, James M Ford, Pamela L Kunz
BACKGROUND: The role of DNA repair in pathogenesis and response to treatment is not well understood in pancreatic neuroendocrine tumors (pNETs). However, the existing literature reveals important preliminary trends and targets in the genetic landscape of pNETs. Notably, pNETs have been shown to harbor defects in the direct reversal MGMT gene and the DNA mismatch repair genes, suggesting that these genes may be strong candidates for further prospective studies. METHODS: PubMed searches were conducted for original studies assessing the DNA repair genes MGMT and MMR in pNETs, as well as for PTEN and MEN1, which are not directly DNA repair genes but are involved in DNA repair pathways...
March 2016: Cancer Treatment Reviews
Andrea J Savio, Darshana Daftary, Elizabeth Dicks, Daniel D Buchanan, Patrick S Parfrey, Joanne P Young, Daniel Weisenberger, Roger C Green, Steven Gallinger, John R McLaughlin, Julia A Knight, Bharati Bapat
BACKGROUND: Aberrant Wnt signaling activation occurs commonly in colorectal carcinogenesis, leading to upregulation of many target genes. APC (adenomatous polyposis coli) is an important component of the β-catenin destruction complex, which regulates Wnt signaling, and is often mutated in colorectal cancer (CRC). In addition to mutational events, epigenetic changes arise frequently in CRC, specifically, promoter hypermethylation which silences tumor suppressor genes. APC and the Wnt signaling target gene ITF2 (immunoglobulin transcription factor 2) incur hypermethylation in various cancers, however, methylation-dependent regulation of these genes in CRC has not been studied in large, well-characterized patient cohorts...
2016: BMC Cancer
Jonathan C Dudley, Ming-Tseh Lin, Dung T Le, James R Eshleman
Initial results by Le and colleagues, which were published in the June 25, 2015 issue of the New England Journal of Medicine, report significant responses of cancers with microsatellite instability (MSI) to anti-PD-1 inhibitors in patients who failed conventional therapy. This finding fits into a broader body of research associating somatic hypermutation and neoepitope formation with response to immunotherapy, with the added benefit of relying on a simple, widely used diagnostic test. This review surveys the pathogenesis and prognostic value of MSI, diagnostic guidelines for detecting it, and the frequency of MSI across tumors, with the goal of providing a reference for its use as a biomarker for PD-1 blockade...
February 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Zoran Gatalica, Semir Vranic, Joanne Xiu, Jeffrey Swensen, Sandeep Reddy
Approximately 15 % of colorectal carcinomas (CRC) display high level microsatellite instability (MSI-H) due to either a germline mutation in one of the genes responsible for DNA mismatch repair (Lynch syndrome, 3 %) or somatic inactivation of the same pathway, most commonly through hypermethylation of the MLH1 gene (sporadic MSI-H, 12 %). Although heterogeneous, MSI-H colorectal carcinomas as a group show some distinct biologic characteristics when compared to CRC with stable or low level microsatellite instability...
July 2016: Familial Cancer
Sigurdis Haraldsdottir, Heather Hampel, Christina Wu, Daniel Y Weng, Peter G Shields, Wendy L Frankel, Xueliang Pan, Albert de la Chapelle, Richard M Goldberg, Tanios Bekaii-Saab
PURPOSE: Mismatch repair-deficient (dMMR) colorectal cancer (CRC) is caused by Lynch syndrome (LS) in 3% and sporadic inactivation of MLH1 by hypermethylation (MLH1-hm) in 12% of cases. It is not clear whether outcomes between LS-associated and MLH1-hm CRC differ. The objective of this study was to explore differences in clinical factors and outcomes in these two groups. METHODS: Patients with dMMR CRC identified by immunohistochemistry staining and treated at a single institution from 1998 to 2012 were included...
September 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Marco Scarpa, Melania Scarpa, Ignazio Castagliuolo, Francesca Erroi, Andromachi Kotsafti, Silvia Basato, Paola Brun, Renata D'Incà, Massimo Rugge, Imerio Angriman, Carlo Castoro
UNLABELLED: BACKGROUND PROMOTER: hypermethylation plays a major role in cancer through transcriptional silencing of critical genes. The aim of our study is to evaluate the methylation status of these genes in the colonic mucosa without dysplasia or adenocarcinoma at the different steps of sporadic and UC-related carcinogenesis and to investigate the possible role of genomic methylation as a marker of CRC. RESULTS: The expression of Dnmts 1 and 3A was significantly increased in UC-related carcinogenesis compared to non inflammatory colorectal carcinogenesis...
March 1, 2016: Oncotarget
Aya Kato, Naoki Sato, Tae Sugawara, Kazue Takahashi, Masahiko Kito, Kenichi Makino, Toshiharu Sato, Dai Shimizu, Hiromistu Shirasawa, Hiroshi Miura, Wataru Sato, Yukiyo Kumazawa, Akira Sato, Jin Kumagai, Yukihiro Terada
Lynch syndrome (LS) is an autosomal-dominant inherited disorder mainly caused by a germline mutation in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and is associated with increased risk for various cancers, particularly colorectal cancer and endometrial cancer (EC). Women with LS account for 2% to 6% of EC patients; it is clinically important to identify LS in such individuals for predicting and/or preventing additional LS-associated cancers. PMS2 germline mutation (PMS2-LS) is the rarest contribution to LS etiology among the 4 LS-associated MMR germline mutations, and its detection is complicated...
June 2016: American Journal of Surgical Pathology
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