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https://www.readbyqxmd.com/read/28635682/relationship-between-human-mutl-homolog-1-hmlh1-hypermethylation-and-colorectal-cancer-a-meta-analysis
#1
Hui-Feng Zhang, You-Wang Lu, Zhen-Rong Xie, Kun-Hua Wang
BACKGROUND Hypermethylation of CpG islands in gene promoter regions is an important mechanism of gene inactivation in cancers. Promoter hypermethylation of human mutL homolog 1 (hMLH1) has been implicated in a subset of colorectal cancers that show microsatellite instability (MSI), while the connection of the epigenetic inactivation of hMLH1 in colorectal cancers remains unknown. The aim of this study was to evaluate the relationship between the promoter hypermethylation of hMLH1 and colorectal cancers by performing a meta-analysis...
June 21, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28635639/immune-checkpoints-as-a-target-for-colorectal-cancer-treatment
#2
REVIEW
Alessandro Passardi, Matteo Canale, Martina Valgiusti, Paola Ulivi
Anti-tumor immunity is a new line of research for the treatment of patients with solid tumors. In this field, negative regulators of the immune system called immune checkpoints play a key role in limiting antitumor immunologic responses. For this reason, immune checkpoint-inhibiting agents, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 receptor (PD1) and its ligand PD-L1, have been developed as antitumor drugs, producing interesting results in preclinical and clinical studies...
June 21, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28628639/small-molecule-inhibitors-uncover-synthetic-genetic-interactions-of-human-flap-endonuclease-1-fen1-with-dna-damage-response-genes
#3
Thomas A Ward, Peter J McHugh, Stephen T Durant
Flap endonuclease 1 (FEN1) is a structure selective endonuclease required for proficient DNA replication and the repair of DNA damage. Cellularly active inhibitors of this enzyme have previously been shown to induce a DNA damage response and, ultimately, cell death. High-throughput screens of human cancer cell-lines identify colorectal and gastric cell-lines with microsatellite instability (MSI) as enriched for cellular sensitivity to N-hydroxyurea series inhibitors of FEN1, but not the PARP inhibitor olaparib or other inhibitors of the DNA damage response...
2017: PloS One
https://www.readbyqxmd.com/read/28623901/biomarker-correlation-network-in-colorectal-carcinoma-by-tumor-anatomic-location
#4
Reiko Nishihara, Kimberly Glass, Kosuke Mima, Tsuyoshi Hamada, Jonathan A Nowak, Zhi Rong Qian, Peter Kraft, Edward L Giovannucci, Charles S Fuchs, Andrew T Chan, John Quackenbush, Shuji Ogino, Jukka-Pekka Onnela
BACKGROUND: Colorectal carcinoma evolves through a multitude of molecular events including somatic mutations, epigenetic alterations, and aberrant protein expression, influenced by host immune reactions. One way to interrogate the complex carcinogenic process and interactions between aberrant events is to model a biomarker correlation network. Such a network analysis integrates multidimensional tumor biomarker data to identify key molecular events and pathways that are central to an underlying biological process...
June 17, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28621832/break-induced-replication-links-microsatellite-expansion-to-complex-genome-rearrangements
#5
REVIEW
Michael Leffak
The instability of microsatellite DNA repeats is responsible for at least 40 neurodegenerative diseases. Recently, Mirkin and co-workers presented a novel mechanism for microsatellite expansions based on break-induced replication (BIR) at sites of microsatellite-induced replication stalling and fork collapse. The BIR model aims to explain single-step, large expansions of CAG/CTG trinucleotide repeats in dividing cells. BIR has been characterized extensively in Saccharomyces cerevisiae as a mechanism to repair broken DNA replication forks (single-ended DSBs) and degraded telomeric DNA...
June 16, 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28621686/pseudoprogression-in-microsatellite-instability-high-colorectal-cancer-during-treatment-with-combination-t-cell-mediated-immunotherapy-a-case-report-and-literature-review
#6
Young Kwang Chae, Si Wang, Halla Nimeiri, Aparna Kalyan, Francis J Giles
Evading tumor-mediated immunosuppression through antibodies to immune checkpoints has shown clinical benefit in patients with select solid tumors. There is a heterogeneity of responses in patients receiving immunotherapy, including pseudoprogression in which the tumor burden increases initially before decreasing to reach disease control. The characteristics and basis of pseudoprogression, however, remains poorly understood. We hereby report a case of microsatellite instability (MSI)-high metastatic colorectal cancer treated with combination of OX40 agonist and programmed death ligand-1 (PD-L1) antagonist that demonstrated pseudoprogression reaching 163% increase from baseline tumor burden...
June 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28619747/successful-immune-checkpoint-blockade-in-a-patient-with-advanced-stage-microsatellite-unstable-biliary-tract-cancer
#7
Elena Czink, Matthias Kloor, Benjamin Goeppert, Stefan Froehling, Sebastian Uhrig, Tim F Weber, Joern Meinel, Christian Sutter, Karl Heinz Weiss, Peter Schirmacher, Magnus von Knebel Doeberitz, Dirk Jaeger, Christoph Springfeld
Cancers acquire multiple somatic mutations that can lead to the generation of immunogenic mutation-induced neoantigens. These neoantigens can be recognized by the host's immune system. However, continuous stimulation of immune cells against tumor antigens can lead to immune cell exhaustion, which allows uncontrolled outgrowth of tumor cells. Recently, immune checkpoint inhibitors have emerged as a novel approach to overcome immune cell exhaustion and re-activate anti-tumor immune responses. In particular, antibodies blocking the exhaustion-mediating programmed death receptor (PD-1)/PD-L1 pathway have shown clinical efficacy...
June 15, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28617917/genomic-profiling-of-small-bowel-adenocarcinoma
#8
Alexa B Schrock, Craig E Devoe, Robert McWilliams, James Sun, Thomas Aparicio, Philip J Stephens, Jeffrey S Ross, Richard Wilson, Vincent A Miller, Siraj M Ali, Michael J Overman
Importance: Small-bowel adenocarcinomas (SBAs) are rare cancers with a significantly lower incidence, later stage at diagnosis, and worse overall survival than other intestinal-derived cancers. To date, comprehensive genomic analysis of SBA is lacking. Objective: To perform in-depth genomic characterization of a large series of SBAs and other gastrointestinal tumors to draw comparisons and identify potentially clinically actionable alterations. Design, Setting, and Participants: Prospective analysis was performed of clinical samples from patients with SBA (n = 317), colorectal cancer (n = 6353), and gastric carcinoma (n = 889) collected between August 24, 2012, and February 3, 2016, using hybrid-capture-based genomic profiling, at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions...
June 15, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28617623/timing-of-aspirin-and-other-nonsteroidal-anti-inflammatory-drug-use-among-patients-with-colorectal-cancer-in-relation-to-tumor-markers-and-survival
#9
Xinwei Hua, Amanda I Phipps, Andrea N Burnett-Hartman, Scott V Adams, Sheetal Hardikar, Stacey A Cohen, Jonathan M Kocarnik, Dennis J Ahnen, Noralane M Lindor, John A Baron, Polly A Newcomb
Purpose Regular use of aspirin is associated with improved survival for patients with colorectal cancer (CRC). However, the timing of and the subtype of CRC that would benefit the most from using aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in relation to survival is unclear. Patients and Methods In all, 2,419 patients age 18 to 74 years with incident invasive CRC who were diagnosed from 1997 to 2008 were identified from population-based cancer registries in the United States, Canada, and Australia...
June 15, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28614814/tumor-heterogeneity-in-endometrial-carcinoma-practical-consequences
#10
Sònia Gatius, Dolors Cuevas, Carlos Fernández, Berta Roman-Canal, Virginia Adamoli, Josep Maria Piulats, Núria Eritja, Mireia Martin-Satue, Gema Moreno-Bueno, Xavier Matias-Guiu
Endometrial carcinoma (EC) shows intertumor heterogeneity, with several different histologic types differing in their morphologic and molecular features. There is also intratumoral morphologic heterogeneity, with different neoplastic cell components within the same tumor, with different morphologic and molecular features. In this article, we discuss the consequences of tumor heterogeneity in EC at the morphologic and molecular levels, by describing some illustrative examples produced by the research team. They are (1) morphologic heterogeneity in conventional EC and mixed tumors, (2) EC with microsatellite instability, (3) branched evolution as shown by exome sequencing analysis, (4) morphologic, molecular, and metabolomic differences between the tumor surface and myometrial invasion front, (5) tumor heterogeneity at the microenviromental level, (6) the sensitivity of endometrial aspirates to detect tumor heterogeneity in EC, and (7) sampling strategies to detect tumor heterogeneity in hysterectomy specimens...
June 15, 2017: Pathobiology: Journal of Immunopathology, Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28611049/comprehensive-evaluation-of-protein-coding-mononucleotide-microsatellites-in-microsatellite-unstable-colorectal-cancer
#11
Johanna Kondelin, Alexandra E Gylfe, Sofie Lundgren, Tomas Tanskanen, Jiri Hamberg, Mervi Aavikko, Kimmo Palin, Heikki Ristolainen, Riku Katainen, Eevi Kaasinen, Minna Taipale, Jussi Taipale, Laura Renkonen-Sinisalo, Heikki Järvinen, Jan Böhm, Jukka-Pekka Mecklin, Pia Vahteristo, Sari Tuupanen, Lauri A Aaltonen, Esa Pitkänen
<span style="background-color: white;">Approximately 15% of colorectal cancers (CRC) exhibit microsatellite instability (MSI), which leads to accumulation of a large numbers of small insertions and deletions (indels). Genes that provide growth advantage to cells via loss-of-function mutations in microsatellites are called MSI target genes. Several criteria to define these genes have been suggested, one of them being simple mutation frequency. Microsatellite mutation rate, however, depends on the length and nucleotide context of the microsatellite...
June 13, 2017: Cancer Research
https://www.readbyqxmd.com/read/28608265/constitutional-mismatch-repair-deficiency-and-lynch-syndrome-among-consecutive-arab-bedouins-with-colorectal-cancer-in-israel
#12
Naim Abu Freha, Yaara Leibovici Weissman, Alexander Fich, Inbal Barnes Kedar, Marisa Halpern, Ignacio Sztarkier, Doron M Behar, Orly Arbib Sneh, Alex Vilkin, Hagit N Baris, Rachel Gingold, Flavio Lejbkowicz, Yaron Niv, Yael Goldberg, Zohar Levi
We assessed the molecular characteristics and the frequency of mutations in mismatch-repair genes among Bedouin patients with colorectal cancer (CRC) in Israel. Bedouin patients with a diagnosis of CRC at a major hospital in the southern part of Israel were deemed eligible for this study. The primary screening method was immunohistochemical staining for mismatch-repair proteins (MLH1, MSH2, MSH6, and PMS2). For subjects with abnormal immunohistochemical staining, we performed microsatellite instability (MSI) analyses, and for tumors with a loss of MLH1 expression we also performed BRAF testing...
June 12, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28607805/simplified-microsatellite-instability-detection-protocol-provides-equivalent-sensitivity-to-robust-detection-strategies-in-lynch-syndrome-patients
#13
Hadi Babaei, Mehrdad Zeinalian, Mohammad Hassan Emami, Mortaza Hashemzadeh, Najmeh Farahani, Rasoul Salehi
OBJECTIVE: : Germline mutations in mismatch repair (MMR) genes cause Lynch syndrome (LS). LS is an inherited disease, and an important consequence of MMR deficiency is microsatellite instability (MSI) phenotype. MSI phenotype influences the efficacy of 5 fluorouracil (5-FU) chemotherapy. Reproducible, cost effective, and easy to perform laboratory tests are required to include MSI detection in routine laboratory practice. Evaluation of CAT25 as monomorphic short tandem repeat sequence enables CAT25 to be an efficient screening tool among hereditary nonpolyposis colorectal cancer (HNPCC) patients compared with other methods used currently...
May 2017: Cancer Biology & Medicine
https://www.readbyqxmd.com/read/28601671/ebv-infection-and-msi-status-significantly-influence-the-clinical-outcomes-of-gastric-cancer-patients
#14
Hua Shen, Meizuo Zhong, Weili Wang, Ping Liao, Xianli Yin, Daniel Rotroff, Todd C Knepper, Howard L Mcleod, Chengfang Zhou, Shangchen Xie, Wei Li, Biaobo Xu, Yijing He
BACKGROUND: Epstein-Barr virus (EBV) and microsatellite instability (MSI) are associated with the carcinogenesis of many kinds of tumors, including gastric cancer (GC). However, the impact of EBV and MSI status on the prognosis of stage II and III GC is still unclear. The aim of this study was to find out the prognostic value of EBV and MSI status in a population of GC patients from Southern China. METHODS: Patients were genotyped for EBV infection based on the detection of EBV DNA from the formalin-fixed paraffin-embedded (FFPE) specimens...
June 7, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28597080/intratumoral-fusobacterium-nucleatum-abundance-correlates-with-macrophage-infiltration-and-cdkn2a-methylation-in-microsatellite-unstable-colorectal-carcinoma
#15
Hye Eun Park, Jung Ho Kim, Nam-Yun Cho, Hye Seung Lee, Gyeong Hoon Kang
Fusobacterium nucleatum (Fn), a specific species of gut microbiota, has been suggested to be enriched in the microsatellite instability-high (MSI-H) molecular subtype of colorectal carcinomas (CRCs). However, the clinicopathologic and molecular factors that interact with Fn in MSI-H CRCs are poorly understood. In this study, 16S ribosomal RNA gene DNA sequence of Fn was quantitatively measured by real-time polymerase chain reaction in tumor DNA samples from a total of 160 surgically resected MSI-H CRC tissues...
June 8, 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/28595259/molecular-profiling-of-signet-ring-cell-colorectal-cancer-provides-a-strong-rationale-for-genomic-targeted-and-immune-checkpoint-inhibitor-therapies
#16
Muhammad A Alvi, Maurice B Loughrey, Philip Dunne, Stephen McQuaid, Richard Turkington, Marc-Aurel Fuchs, Claire McGready, Victoria Bingham, Brendan Pang, Wendy Moore, Perry Maxwell, Mark Lawler, Jacqueline A James, Graeme I Murray, Richard H Wilson, Manuel Salto-Tellez
BACKGROUND: Signet ring cell colorectal cancer (SRCCa) has a bleak prognosis. Employing molecular pathology techniques we investigated the potential of precision medicine in this disease. METHODS: Using test (n=26) and validation (n=18) cohorts, analysis of mutations, DNA methylation and transcriptome was carried out. Microsatellite instability (MSI) status was established and immunohistochemistry (IHC) was used to test for adaptive immunity (CD3) and the immune checkpoint PDL1...
June 8, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28591715/brca2-egfr-and-ntrk-mutations-in-mismatch-repair-deficient-colorectal-cancers-with-msh2-or-mlh1-mutations
#17
Safoora Deihimi, Avital Lev, Michael Slifker, Elena Shagisultanova, Qifang Xu, Kyungsuk Jung, Namrata Vijayvergia, Eric A Ross, Joanne Xiu, Jeffrey Swensen, Zoran Gatalica, Mark Andrake, Roland L Dunbrack, Wafik S El-Deiry
Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs profiled at Caris Life Sciences. Caris-profiled MSI-H CRCs had high mutation rates (50% vs 14% in non-MSI-H, P < 0.0001) in BRCA2. Of 1104 profiled CRCs from a second cohort (COSMIC), MSH2/MLH1-mutant CRCs showed higher mutation rates in BRCA2 compared to non-MSH2/MLH1-mutant tumors (38% vs 6%, P < 0...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28585616/-role-of-immunotherapy-in-the-management-of-colorectal-cancer
#18
György Bodoky
Immunotherapy proved to be effective in various forms of cancer but it is in its infancy in colorectal cancer, although the Immunoscore was developed to classify this tumor immunologically. Various forms of immunotherapy were tested in early clinical trials but anti-PD-1 antibodies seem the most promising so far. These studies also revealed that one particular molecular subgroup of colorectal cancer, the microsatellite instable variant, is extremely sensitive for such modality.
June 6, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28585546/a-molecular-portrait-of-microsatellite-instability-across-multiple-cancers
#19
Isidro Cortes-Ciriano, Sejoon Lee, Woong-Yang Park, Tae-Min Kim, Peter J Park
Microsatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair. Although MSI has been studied for decades, large amounts of sequencing data now available allows us to examine the molecular fingerprints of MSI in greater detail. Here, we analyse ∼8,000 exomes and ∼1,000 whole genomes of cancer patients across 23 cancer types. Our analysis reveals that the frequency of MSI events is highly variable within and across tumour types...
June 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28585041/clinical-impact-of-mismatch-repair-protein-testing-on-outcome-of-early-staged-colorectal-carcinomas
#20
Jatin Sundersham Gandhi, Malini Goswami, Anila Sharma, Parul Tanwar, Gurudutt Gupta, Nikhil Gupta, Sunil Pasricha, Anurag Mehta, Shivender Singh, Mohit Agarwal, Nitin Gupta
INTRODUCTION: Colorectal cancer is the third most common cancer in men and second most common in women globally. In the present study, we aimed to analyse the proportion of patients with loss of immunostaining for mismatch repair (MMR) proteins in all newly diagnosed stage II cases of colorectal cancer for the purpose of prognostication, for determination of further chemotherapeutic strategy and for familial screening. METHOD: From January 2014 to December 2015, 62 consecutive newly diagnosed cases of stage II colorectal cancer were included in the study...
June 5, 2017: Journal of Gastrointestinal Cancer
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