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MLH1 hypermethylation

Pritha Bhattacharjee, Tamalika Sanyal, Sandip Bhattacharjee, Pritha Bhattacharjee
INTRODUCTION: Arsenic exposure and its adverse health outcome, including the association with cancer risk are well established from several studies across the globe. The present study aims to analyze the epigenetic regulation of key mismatch repair (MMR) genes in the arsenic-exposed population. METHOD: A case-control study was conducted involving two hundred twenty four (N=224) arsenic exposed [with skin lesion (WSL=110) and without skin lesion (WOSL=114)] and one hundred and two (N=102) unexposed individuals...
February 27, 2018: Environmental Research
Minoru Koi, Stephanie S Tseng-Rogenski, John M Carethers
Microsatellite alterations within genomic DNA frameshift as a result of defective DNA mismatch repair (MMR). About 15% of sporadic colorectal cancers (CRCs) manifest hypermethylation of the DNA MMR gene MLH1, resulting in mono- and di-nucleotide frameshifts to classify it as microsatellite instability-high (MSI-H) and hypermutated, and due to frameshifts at coding microsatellites generating neo-antigens, produce a robust protective immune response that can be enhanced with immune checkpoint blockade. More commonly, approximately 50% of sporadic non-MSI-H CRCs demonstrate frameshifts at di- and tetra-nucleotide microsatellites to classify it as MSI-low/elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) as a result of functional somatic inactivation of the DNA MMR protein MSH3 via a nuclear-to-cytosolic displacement...
January 15, 2018: World Journal of Gastrointestinal Oncology
Diana Pinto, Carla Pinto, Joana Guerra, Manuela Pinheiro, Rui Santos, Hege Marie Vedeld, Zeremariam Yohannes, Ana Peixoto, Catarina Santos, Pedro Pinto, Paula Lopes, Ragnhild Lothe, Guro Elisabeth Lind, Rui Henrique, Manuel R Teixeira
Constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, has been identified as an alternative mechanism that predisposes to the development of Lynch syndrome. In the present work, we aimed to investigate the prevalence of MLH1 constitutional methylation in colorectal cancer (CRC) patients with abnormal expression of the MLH1 protein in their tumors. In a series of 38 patients who met clinical criteria for Lynch syndrome genetic testing, with loss of MLH1 expression in the tumor and with no germline mutations in the MLH1 gene (35/38) or with tumors presenting the BRAF p...
January 17, 2018: Cancer Medicine
Lochlan J Fennell, Saara Jamieson, Diane McKeone, Tracie Corish, Megan Rohdmann, Tori Furner, Mark Bettington, Cheng Liu, Futoshi Kawamata, Catherine Bond, Jolieke Van De Pols, Barbara Leggett, Vicki Whitehall
BACKGROUND: Sessile serrated adenomas with BRAF mutation progress rapidly to cancer following the development of dysplasia (SSAD). Approximately 75% of SSADs methylate the mismatch repair gene MLH1, develop mismatch repair deficiency and the resultant cancers have a good prognosis. The remaining SSADs and BRAF mutant traditional serrated adenomas (TSA) develop into microsatellite stable cancers with a poor prognosis. The reason for this dichotomy is unknown. In this study, we assessed the genotypic frequency of the MLH1-93 polymorphism rs1800734 in SSADs and TSAs to determine if the uncommon variant A allele predisposes to MLH1 promoter hypermethylation...
January 5, 2018: BMC Cancer
Jasmine Lee, Yin-Yi Xiao, Yan Yu Sun, Jasminka Balderacchi, Bradley Clark, Jatin Desani, Vivek Kumar, Angela Saverimuthu, Khin Than Win, Yiwu Huang, Yiqing Xu
BACKGROUND: The prevalence of Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is 2 to 5% in the Caucasian population. HNPCC is caused by genomic mutations in DNA mismatch repair genes (MMR), namely MLH1, MSH2, MSH6, PMS2, and EPCAM. A non-hereditary, acquired process of hypermethylation of the MLH1 promoter can also lead to silencing of MLH1 protein expression. Diagnosis of HNPCC in patients with colorectal and other related cancers is important in the clinical treatment and surveillance of related cancers...
December 13, 2017: BMC Cancer
Haochang Hu, Xiaoying Chen, Cong Zhou, Bin Li, Yong Yang, Xiuru Ying, Yiyi Mao, Yihan Zhang, Jie Zhong, Jie Dai, Hang Yu, Boyi Wu, Xiaodong Li, Tiangong Wang, Shiwei Duan
BACKGROUND: Non-small cell lung cancer (NSCLC) is a common malignant tumor. DNA hypermethylation in the promoter region has been served as a potential molecular marker for several tumors. The goal of the current study was to assess the diagnostic ability of mutL homolog 1 (MLH1) promoter methylation in NSCLC. METHODS: A total of 111 NSCLC patients' paired tissue samples were obtained to explore the association between MLH1 promoter methylation and NSCLC by methylation-specific polymerase chain reaction (MSP) method...
December 5, 2017: Journal of Clinical Laboratory Analysis
Stijn Crobach, Anne M L Jansen, Marjolein J L Ligtenberg, Marije Koopmans, Maartje Nielsen, Frederik J Hes, Juul T Wijnen, Winand N M Dinjens, Tom van Wezel, Hans Morreau
Patients synchronously or metachronously presenting with ovarian and colon cancer can pose diagnostic challenges. A primary colon carcinoma can metastasize to one or both ovaries, two independent primary tumors can arise or an ovarian carcinoma can metastasize to the colon. Clinical and immunohistochemical characterization can aid the diagnosis. Recently, we reported that in difficult cases finding pathogenic APC variants supports a colonic origin.In this case report we describe the clinical history of a female patient suspected for Lynch syndrome...
November 9, 2017: Familial Cancer
Jessica L Dillon, Jorge L Gonzalez, Leslie DeMars, Katarzyna J Bloch, Laura J Tafe
Lynch syndrome (LS) is an inherited clinical syndrome characterized by a high risk of colorectal, endometrial (lifetime risk of up to 60%), ovarian, and urinary tract cancers. The diagnosis is confirmed by identification of germline mutations in the DNA mismatch repair genes MLH1, PMS2, MSH2, MSH6, or EPCAM. In 2015, our institution implemented universal screening of endometrial cancer (EC) hysterectomy specimens by mismatch repair immunohistochemistry (IHC) with reflex MLH1 promoter hypermethylation analysis for tumors with loss of MLH1/PMS2 expression...
December 2017: Human Pathology
R Cohen, O Buhard, P Cervera, E Hain, S Dumont, A Bardier, J-B Bachet, J-M Gornet, D Lopez-Trabada, S Dumont, R Kaci, P Bertheau, F Renaud, F Bibeau, Y Parc, D Vernerey, A Duval, M Svrcek, Thierry André
BACKGROUND: Patients treated with chemotherapy for microsatellite unstable (MSI) and/or mismatch repair deficient (dMMR) cancer metastatic colorectal cancer (mCRC) exhibit poor prognosis. We aimed to evaluate the relevance of distinguishing sporadic from Lynch syndrome (LS)-like mCRCs. PATIENTS AND METHODS: MSI/dMMR mCRC patients were retrospectively identified in six French hospitals. Tumour samples were screened for MSI, dMMR, RAS/RAF mutations and MLH1 methylation...
November 2017: European Journal of Cancer
S Gunes, A Agarwal, R Henkel, A M Mahmutoglu, R Sharma, S C Esteves, A Aljowair, D Emirzeoglu, A Alkhani, L Pelegrini, A Joumah, E Sabanegh
MLH1 and MSH2 are important genes for DNA mismatch repair and crossing over during meiosis and are implicated in male infertility. Therefore, the methylation patterns of the DNA mismatch repair genes MLH1 and MSH2 in oligozoospermic males were investigated. Ten oligozoospermic patients and 29 normozoospermic donors were analysed. Methylation profiles of the MLH1 and MSH2 promotors were analysed. In addition, sperm motility and seminal reactive oxygen species (ROS) were recorded. Receiver operating characteristic (ROC) analysis was conducted to determine the accuracy of the DNA methylation status of MLH1 and MSH2 to distinguish between oligozoospermic and normozoospermic men...
October 6, 2017: Andrologia
Kayoko Nakano, Hidetaka Yamamoto, Minako Fujiwara, Yutaka Koga, Shinichi Tsuruta, Eikichi Ihara, Eiji Oki, Masafumi Nakamura, Yoshihiro Ogawa, Yoshinao Oda
Synchronous colorectal carcinoma (CRC) is a unique disease associated with a high prevalence (∼35%) of microsatellite instability and occasionally with Lynch syndrome. The clinicopathologic and molecular features of synchronous CRC are poorly understood, particularly in Japanese patients. We examined 118 Japanese patients (236 tumors) with synchronous CRC and 117 Japanese patients (117 tumors) with solitary CRC with immunohistochemical staining for TP53 and mismatch repair (MMR) protein (MLH1, MSH2, PMS2, and MSH6) and mutation analyses of KRAS and BRAF genes...
February 2018: American Journal of Surgical Pathology
Bogdan V Micu, Octavian Andercou, Stefan C Vesa, Carmen M Micu, Tudor R Pop, Nicolae Constantea
BACKGROUND: Data from the literature regarding the prognostic role of DNA mismatch repair system (MMR) in colorectal cancer are still controversial. AIM: The aim of the study was to identify the prognostic role of different phenotypic, clinical and pathological characteristics in microsatellite unstable vs. microsatellite stable colorectal cancer in terms of survival and disease free interval. METHODS: We conducted a retrospective study that included a total of 103 patients who underwent curative surgery for colorectal cancer...
2017: Annali Italiani di Chirurgia
Stine Dam Henriksen, Poul Henning Madsen, Anders Christian Larsen, Martin Berg Johansen, Inge Søkilde Pedersen, Henrik Krarup, Ole Thorlacius-Ussing
Correct staging of pancreatic cancer is paramount, as treatment is stage specific. However, minimally invasive tools to facilitate staging are lacking. DNA promoter hypermethylation is a hallmark of cancer. The aim of this study is to evaluate promoter hypermethylation in cell-free DNA as a prognostic marker for stage classification of pancreatic adenocarcinoma. Consecutive patients with pancreatic adenocarcinoma were prospectively included. Plasma samples were obtained before diagnostic work-up and treatment...
December 15, 2017: International Journal of Cancer. Journal International du Cancer
Tao Wang, Zsofia K Stadler, Liying Zhang, Martin R Weiser, Olca Basturk, Jaclyn F Hechtman, Efsevia Vakiani, Lenard B Saltz, David S Klimstra, Jinru Shia
Microsatellite instability, a well-established driver pathway in colorectal carcinogenesis, can develop in both sporadic and hereditary conditions via different molecular alterations in the DNA mismatch repair (MMR) genes. MMR protein immunohistochemistry (IHC) is currently widely used for the detection of MMR deficiency in solid tumors. The IHC test, however, can show varied staining patterns, posing challenges in the interpretation of the staining results in some cases. Here we report a case of an 80-year-old female with a colonic adenocarcinoma that exhibited an unusual "null" IHC staining pattern with complete loss of all four MMR proteins (MLH1, MSH2, MSH6, and PMS2)...
August 17, 2017: Familial Cancer
Priyanjali Bhattacharya, Trupti N Patel
OBJECTIVE: The objective of our review is to highlight the significance of microsatellite hypervariation in diagnostics of hematologic malignancies. METHODS: For the past few decades, extensive experiments in cancer research have explored all the possible pathways and a number of deleterious mutations that either make the tumor suppressor genes (TSGs) dysfunctional or cause the proto-oncogenes to behave abnormally by changing the cellular phenotype hence rendering disease...
July 20, 2017: Hematology (Amsterdam, Netherlands)
E Ryan, K Sheahan, B Creavin, H M Mohan, D C Winter
Colorectal Cancer (CRC) is the third most prevalent cancer in men and women. Up to 15% of CRCs display microsatellite instability (MSI). MSI is reflective of a deficient mismatch repair (MMR) system and is most commonly caused by hypermethylation of the MLH1 promoter. However, it may also be due to autosomal dominant constitutional mutations in DNA MMR, termed Lynch Syndrome. MSI may be diagnosed via polymerase chain reaction (PCR) or alternatively, immunohistochemistry (IHC) can identify MMR deficiency (dMMR)...
August 2017: Critical Reviews in Oncology/hematology
Fedaa Najdawi, Ashley Crook, Jayne Maidens, Christopher McEvoy, Andrew Fellowes, Justine Pickett, Musei Ho, David Nevell, Kirsten McIlroy, Amy Sheen, Loretta Sioson, Mahsa Ahadi, John Turchini, Adele Clarkson, Russell Hogg, Sue Valmadre, Greg Gard, Susan J Dooley, Rodney J Scott, Stephen B Fox, Michael Field, Anthony J Gill
Despite a trend towards universal testing, best practice to screen patients presenting with gynaecological malignancy for Lynch syndrome (LS) is uncertain. We report our institutional experience of a co-ordinated gynaecological LS screening program. All patients with endometrial carcinoma or carcinosarcoma, or gynaecological endometrioid or clear cell carcinomas undergo reflex four panel immunohistochemistry (IHC) for MLH1, PMS2, MSH2 and MSH6 followed by cascade somatic hypermethylation analysis of the MLH1 promoter locus for dual MLH1/PMS2 negative tumours...
August 2017: Pathology
Alain G Zeimet, Harald Mori, Edgar Petru, Stephan Polterauer, Alexander Reinthaller, Christian Schauer, Tonja Scholl-Firon, Christian Singer, Katharina Wimmer, Johannes Zschocke, Christian Marth
PURPOSE: This manuscript reports the consensus recommendations on screening and diagnosis of Lynch syndrome (LS) in patients with endometrial or ovarian cancer as well as on possible preventive measures in effectively LS-diagnosed women. The recommendations are issued by the Austrian Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO) of the Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe (OEGGG) after consultation of the most recent and relevant literature and following deliberation by the Genetic Task-Force convoked May, 2015 by the AGO Council...
July 2017: Archives of Gynecology and Obstetrics
Mafalda Trippel, Sara Imboden, Andrea Papadia, Michael D Mueller, Nando Mertineit, Kirsi Härmä, Alina Nicolae, Erik Vassella, Tilman T Rau
BACKGROUND: Intestinal differentiation of primary mucinous adenocarcinoma of the uterine corpus is exceedingly rare in comparison to the approximately 25% rate in endocervical and ovarian mucinous carcinoma. Additionally, little is known about the related genetic and epigenetic alterations, even though large-scale molecular characterisation of the different types of endometrial cancer took place in the TCGA project along the entities defined by the recent WHO classification. CASE PRESENTATION: We present a 62-year-old patient harbouring a primary mucinous carcinoma of the uterine corpus with a morphological resemblance to mucinous colorectal adenocarcinoma...
May 12, 2017: Diagnostic Pathology
Ileana Carnevali, Laura Libera, Annamaria Chiaravalli, Nora Sahnane, Daniela Furlan, Alessandra Viel, Giulia Cini, Laura Cimetti, Thomas Rossi, Giorgio Formenti, Fabio Ghezzi, Cristina Riva, Fausto Sessa, Maria Grazia Tibiletti
OBJECTIVE: Recent data from the literature indicate gynecological cancers (GCs) as sentinel cancers for a diagnosis of Lynch syndrome (LS). Clinical approaches to identifying LS have low sensitivity, whereas somatic tests on GCs may be a more sensitive and cost-effective strategy. METHODS: A series of 78 GCs belonging to 74 patients sent to the Genetic Counselling Service were investigated using microsatellite instability, immunohistochemical expression of mismatch repair (MMR) genes, and MLH1 promoter methylation...
September 2017: International Journal of Gynecological Cancer
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