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Lynch syndrome

Juana Martín-López, Pierluigi Gasparini, Kevin Coombes, Carlo M Croce, Gregory P Boivin, Richard Fishel
Non-steroidal anti-inflammatory drugs (NSAIDs) exhibit anti-neoplastic (chemoprevention) activity for sporadic cancers and the hereditary cancer predisposition Lynch syndrome (LS/HNPCC). However, the mechanism of NSAID tumor suppression has remained enigmatic. Defects in the core mismatch repair (MMR) genes MSH2 and MLH1 are the principal drivers of LS/HNPCC. Previous work has demonstrated that the villin - Cre+/- Msh2flox/flox (VpC-Msh2) mouse is a reliable model for LS/HNPCC intestinal tumorigenesis, which is significantly suppressed by treatment with the NSAID aspirin (ASA) similar to human chemoprevention...
February 27, 2018: Oncotarget
Anne Mills, Sara Zadeh, Emily Sloan, Zachary Chinn, Susan C Modesitt, Kari L Ring
Mismatch repair-deficient endometrial carcinomas are optimal candidates for immunotherapy given their high neoantigen loads, robust lymphoid infiltrates, and frequent PD-L1 expression. However, co-opting the PD-1/PD-L1 pathway is just one mechanism that tumors can utilize to evade host immunity. Another immune modulatory molecule that has been demonstrated in endometrial carcinoma is indoleamine 2,3-dioxygenase (IDO). We herein evaluate IDO expression in 60 endometrial carcinomas and assess results in relation to PD-L1 and mismatch repair status...
March 20, 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Elmire Hartmans, Jolien J J Tjalma, Matthijs D Linssen, Pilar Beatriz Garcia Allende, Marjory Koller, Annelies Jorritsma-Smit, Mariana E Silva de Oliveira Nery, Sjoerd G Elias, Arend Karrenbeld, Elisabeth G E de Vries, Jan H Kleibeuker, Gooitzen M van Dam, Dominic J Robinson, Vasilis Ntziachristos, Wouter B Nagengast
Adenoma miss rates in colonoscopy are unacceptably high, especially for sessile serrated adenomas / polyps (SSA/Ps) and in high-risk populations, such as patients with Lynch syndrome. Detection rates may be improved by fluorescence molecular endoscopy (FME), which allows morphological visualization of lesions with high-definition white-light imaging as well as fluorescence-guided identification of lesions with a specific molecular marker. In a clinical proof-of-principal study, we investigated FME for colorectal adenoma detection, using a fluorescently labelled antibody (bevacizumab-800CW) against vascular endothelial growth factor A (VEGFA), which is highly upregulated in colorectal adenomas...
2018: Theranostics
Chia Wei Teoh, Kathleen Mary Gorman, Bryan Lynch, Timothy H J Goodship, Niamh Marie Dolan, Mary Waldron, Michael Riordan, Atif Awan
Atypical hemolytic uremic syndrome (aHUS) is caused by dysregulation of the complement system. A humanised anti-C5 monoclonal antibody (eculizumab) is available for the treatment of aHUS. We present the first description of atypical HUS in a child with a coexistent diagnosis of a POL-III leukodystrophy. On standard eculizumab dosing regime, there was evidence of ongoing C5 cleavage and clinical relapses when immunologically challenged. Eculizumab is an effective therapy for aHUS, but the recommended doses may not be adequate for all patients, highlighting the need for ongoing efforts to develop a strategy for monitoring of treatment efficacy and potential individualisation of therapy...
2018: Case Reports in Nephrology
Morgan Anyla, Jérémie H Lefevre, Ben Creavin, Chrystelle Colas, Magali Svrcek, Olivier Lascols, Clotilde Debove, Najim Chafai, Emmanuel Tiret, Yann Parc
PURPOSE: Regular follow-up for patients with Lynch syndrome (LS) is vital due to the increased risk of colorectal (50-80%), endometrial (40-60%), and other cancers. However, there is an ongoing debate concerning the best interval between colonoscopies. Currently, no specific endoscopic follow-up has been decided for LS patients who already have an index colorectal cancer (CRC). The aim of this study was to evaluate the risk of metachronous cancers (MC) after primary CRC in a LS population and to determinate if endoscopic surveillance should be more intensive...
March 12, 2018: International Journal of Colorectal Disease
Mehrdad Zeinalian, Morteza Hashemzadeh-Chaleshtori, Rasoul Salehi, Mohammad Hassan Emami
Microsatellite instability (MSI) is a molecular hallmark for some colorectal cancers (CRCs) in which short tandem repeats are prone to mutations along with DNA sequences. It is due to DNA-mismatch-repair system deficiency because of a germline/somatic mutation in mismatch-repair (MMR) genes. The germline mutations lead to Lynch syndrome (LS) while epigenetic gene silencing results in sporadic CRC tumors. We discuss in our paper the most important clinical aspects of MSI testing in CRCs. We reviewed the most reliable relevant studies and clinical trials according to their high-quality methods, particularly within two recent decades...
2018: Advanced Biomedical Research
Veronica L Cox, Anas A Saeed Bamashmos, Wai Chin Foo, Shiva Gupta, Sireesha Yedururi, Naveen Garg, Hyunseon Christine Kang
Lynch syndrome is the most common hereditary cancer syndrome, the most common cause of heritable colorectal cancer, and the only known heritable cause of endometrial cancer. Other cancers associated with Lynch syndrome include cancers of the ovary, stomach, urothelial tract, and small bowel, and less frequently, cancers of the brain, biliary tract, pancreas, and prostate. The oncogenic tendency of Lynch syndrome stems from a set of genomic alterations of mismatch repair proteins. Defunct mismatch repair proteins cause unusually high instability of regions of the genome called microsatellites...
March 2018: Radiographics: a Review Publication of the Radiological Society of North America, Inc
Rita Vale Rodrigues, Isabel Claro, Pedro Lage, Isadora Rosa, Sara Ferreira, João Pereira da Silva, António Dias Pereira
PURPOSE: Lynch syndrome (LS) is associated with a high risk of colorectal cancer (CRC). The aim of this study was to assess the cumulative risk for the development of colorectal adenomas or carcinomas in a LS CRC surveillance program and to audit the quality of the endoscopic procedures. METHODS: We evaluated 147 asymptomatic LS mutation carriers, without previous CRC, in a surveillance program with colonoscopy every 12-18 months, between 2005 and 2016. Data was obtained by retrospective review of colonoscopy reports and hospital clinical files...
March 9, 2018: International Journal of Colorectal Disease
Nicole Köger, Lea Paulsen, Francisco López-Kostner, Adriana Della Valle, Carlos Alberto Vaccaro, Edenir Inêz Palmero, Karin Alvarez, Carlos Sarroca, Florencia Neffa, Pablo German Kalfayan, Maria Laura Gonzalez, Benedito Mauro Rossi, Rui Manuel Reis, Angela Brieger, Stefan Zeuzem, Inga Hinrichsen, Mev Dominguez-Valentin, Guido Plotz
Inactivating mutations in the MLH1 gene cause the cancer predisposition Lynch syndrome, but for small coding genetic variants it is mostly unclear if they are inactivating or not. Nine such MLH1 variants have been identified in South American colorectal cancer (CRC) patients (p.Tyr97Asp, p.His112Gln, p.Pro141Ala, p.Arg265Pro, p.Asn338Ser, p.Ile501del, p.Arg575Lys, p.Lys618del, p.Leu676Pro), and evidence of pathogenicity or neutrality was not available for the majority of these variants. We therefore performed biochemical laboratory testing of the variant proteins and compared the results to protein in-silico predictions on structure and conservation...
March 9, 2018: Genes, Chromosomes & Cancer
Christy L Rhine, Kamil J Cygan, Rachel Soemedi, Samantha Maguire, Michael F Murray, Sean F Monaghan, William G Fairbrother
Substitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations mapping to the canonical 5' and 3' splice sites. However, splicing mutations present in exons and deeper intronic positions are vastly underreported. A recent re-analysis of coding mutations in exon 10 of the Lynch Syndrome gene, MLH1, revealed an extremely high rate (77%) of mutations that lead to defective splicing. This finding is confirmed by extending the sampling to five other exons in the MLH1 gene...
March 5, 2018: PLoS Genetics
Tomasy Sarosiek, Małgorzata Stelmaszuk
Small intestine tumors are rarely diagnosed as they constitute only 0.6% of all malignant tumors, including about 1-3% of malignant neoplasms of the gastrointestinal tract. They also advocate for 0.2% of deaths caused by malignant tumors. Factors that increase the risk of disease include Crohn's disease, familial adenomatous polyposis (FAP), Lynch syndrome (HNPCC - hereditary non-polyposis colorectal cancer), Peuz-Jeghers syndrome, celiac disease and acquired immunodeficiency syndrome (AIDS). Diagnosis of small intestinal tumors is difficult because the symptoms reported by patients are not characteristic...
February 23, 2018: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
Heather Hampel
Colorectal cancer can be caused by hereditary cancer syndromes such as Lynch syndrome and the polyposis syndromes. Tumor screening for Lynch syndrome has been recommended by several professional organizations. In addition, it has been shown that patients with microsatellite unstable colorectal cancer can benefit from immunotherapy. Unfortunately, universal tumor screening for Lynch syndrome has not been implemented at all hospitals yet. More recent studies have found that the prevalence of all hereditary cancer syndromes is around 10%, and for those diagnosed under age 50, it is closer to 16%...
April 2018: Surgical Oncology Clinics of North America
Haibo Qiu, Zhiwei Zhou
The National Comprehensive Cancer Network (NCCN) issued the clinical practice guidelines for gastric cancer 2017 edition version 5, which has been fully updated for the treatment of gastric cancer, including systematic treatment, surgery and radiotherapy. This article review and summarize the updated NCCN clinical practice guidelines for gastric cancer in 2017 and try to interpret it. (1)Biomarkers: mismatch repair defect (dMMR) or high microsatellite instability (MSI-H), programmed death ligand 1 (PD-L1) and tumor Epstein Barr virus (EBV) status should be considered for patients with gastric cancer...
February 25, 2018: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
David W Brammer, Patrick J Gillespie, Mei Tian, Daniel Young, Muthuswamy Raveendran, Lawrence E Williams, Mihai Gagea, Fernando J Benavides, Carlos J Perez, Russell R Broaddus, Bruce J Bernacky, Kirstin F Barnhart, Mian M Alauddin, Manoop S Bhutani, Richard A Gibbs, Richard L Sidman, Renata Pasqualini, Wadih Arap, Jeffrey Rogers, Christian R Abee, Juri G Gelovani
Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus macaques ( Macaca mulatta ) at the nonhuman primate colony of the Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center. The distinctive feature in these cases, based on PET/computed tomography (CT) imaging, was the presence of two or three tumor lesions in different locations, including proximal to the ileocecal juncture, proximal to the hepatic flexure, and/or in the sigmoid colon...
February 28, 2018: Proceedings of the National Academy of Sciences of the United States of America
Yun Yang, Y Nancy You
Lynch syndrome (LS) arises from germline mutations that lead to defective functioning of the DNA mismatch repair (MMR) system. It is the most common cause of inherited colorectal cancer (CRC), and predisposes individuals to significantly elevated risks for extracolonic cancers. A sensitive and accurate diagnostic approach will enable proactive management of the proband and at-risk relatives in order to minimize their cancer burden. Comprehensive clinical genetics care should include personalized and tailored multidisciplinary oncologic care, with consideration for the extent of surgical resection, the choice of systemic agents, and the use of radiation...
February 2018: Chinese Clinical Oncology
Patrick M Boland, Matthew B Yurgelun, C Richard Boland
The current understanding of familial colorectal cancer was limited to descriptions of affected pedigrees until the early 1990s. A series of landscape-altering discoveries revealed that there were distinct forms of familial cancer, and most were related to genes previously not known to be involved in human disease. This review largely focuses on advances in our understanding of Lynch syndrome because of the unique relationship of this disease to defective DNA mismatch repair and the clinical implications this has for diagnostics, prevention, and therapy...
February 27, 2018: CA: a Cancer Journal for Clinicians
Serena Wong, Elena Ratner, Natalia Buza
AIMS: Prophylactic total hysterectomy (TH) and bilateral salpingo-oophorectomy (BSO) have become routine procedures in women at genetic risk for gynecologic malignancies. Intraoperative pathology diagnosis of an occult malignancy provides the opportunity for immediate surgical staging and helps avoiding a second surgery. However, no standard guidelines exist for optimal intraoperative evaluation (IOE) of these specimens. We performed a retrospective analysis of prophylactic TH and BSO cases to assess the presence of gross findings, frozen and permanent section sampling practices, frozen section diagnoses and diagnostic discrepancies...
February 26, 2018: Histopathology
D Gareth Evans, Emma Woodward, Elaine F Harkness, Anthony Howell, Inga Plaskocinska, Eamonn R Maher, Marc D Tischkowitz, Fiona Lalloo
PURPOSE: The identification of BRCA1 , BRCA2 or mismatch repair (MMR) pathogenic gene variants in familial breast/ovarian/colorectal cancer families facilitates predictive genetic testing of at-risk relatives. However, controversy still exists regarding overall lifetime risks of cancer in individuals testing positive. METHODS: We assessed the penetrance of BRCA1 , BRCA2, MLH1 and MSH2 mutations in men and women using Bayesian calculations based on ratios of positive to negative presymptomatic testing by 10-year age cohorts...
February 26, 2018: Journal of Medical Genetics
Monika Morak, Ayseguel Ibisler, Gisela Keller, Ellen Jessen, Andreas Laner, Daniela Gonzales-Fassrainer, Melanie Locher, Trisari Massdorf, Anke M Nissen, Anna Benet-Pagès, Elke Holinski-Feder
BACKGROUND: Germline defects in MLH1 , MSH2 , MSH6 and PMS2 predisposing for Lynch syndrome (LS) are mainly based on sequence changes, whereas a constitutional epimutation of MLH1 (CEM) is exceptionally rare. This abnormal MLH1 promoter methylation is not hereditary when arising de novo, whereas a stably heritable and variant-induced CEM was described for one single allele. We searched for MLH1 promoter variants causing a germline or somatic methylation induction or transcriptional repression...
February 22, 2018: Journal of Medical Genetics
Susanti Susanti, Wakkas Fadhil, Henry Okuchukwu Ebili, Abutaleb Asiri, Ausrine Nestarenkaite, Efthymios Hadjimichael, Hersh A Ham-Karim, Joanne Field, Katherine Stafford, Balwir Matharoo-Ball, James C Hassall, Abid Sharif, Anca Oniscu, Mohammad Ilyas
AIMS: We sought to use PCR followed by high-resolution melting analysis to develop a single closed-tube screening panel to screen for Lynch syndrome. This comprises tests for microsatellite instability (MSI), MLH1 methylation promoter and BRAF mutation. METHODS: For MSI testing, five mononucleotide markers (BAT25, BAT26, BCAT25, MYB , EWSR1 ) were developed. In addition, primers were designed to interrogate Region C of the MLH1 promoter for methylation (using bisulphite-modified DNA) and to test for mutations in codon 600 of BRAF...
February 22, 2018: Journal of Clinical Pathology
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