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Lynch syndrome

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https://www.readbyqxmd.com/read/28548127/mismatch-repair-deficiency-commonly-precedes-adenoma-formation-in-lynch-syndrome-associated-colorectal-tumorigenesis
#1
Shigeki Sekine, Taisuke Mori, Reiko Ogawa, Masahiro Tanaka, Hiroshi Yoshida, Hirokazu Taniguchi, Takeshi Nakajima, Kokichi Sugano, Teruhiko Yoshida, Mamoru Kato, Eisaku Furukawa, Atsushi Ochiai, Nobuyoshi Hiraoka
Lynch syndrome is a cancer predisposition syndrome caused by germline mutations in mismatch repair (MMR) genes. MMR deficiency is a ubiquitous feature of Lynch syndrome-associated colorectal adenocarcinomas; however, it remains unclear when the MMR-deficient phenotype is acquired during tumorigenesis. To probe this issue, the present study examined genetic alterations and MMR statuses in Lynch syndrome-associated colorectal adenomas and adenocarcinomas, in comparison with sporadic adenomas. Among the Lynch syndrome-associated colorectal tumors, 68 of 86 adenomas (79%) and all adenocarcinomas were MMR-deficient, whereas all the sporadic adenomas were MMR-proficient, as determined by microsatellite instability testing and immunohistochemistry for MMR proteins...
May 26, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28544821/predictive-model-for-high-frequency-microsatellite-instability-in-colorectal-cancer-patients-over-50%C3%A2-years-of-age
#2
Kenji Fujiyoshi, Tatsuro Yamaguchi, Miho Kakuta, Akemi Takahashi, Yoshiko Arai, Mina Yamada, Gou Yamamoto, Sachiko Ohde, Misato Takao, Shin-Ichiro Horiguchi, Soichiro Natsume, Shinsuke Kazama, Yusuke Nishizawa, Yoji Nishimura, Yoshito Akagi, Hirohiko Sakamoto, Kiwamu Akagi
Microsatellite instability (MSI) is an important biomarker for screening for Lynch syndrome, and also of response to immune checkpoint inhibitors. The aim of this study is to create a predictive model to determine which elderly patients with colorectal cancer (CRC) should undergo MSI and/or immunohistochemistry testing on the basis of clinicopathological data. We analyzed a test cohort of CRC patients aged ≥50 years (n = 2219) by multivariate logistic regression analyses to identify predictors of high-frequency MSI (MSI-H)...
May 23, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28534081/power-of-pedigree-likelihood-analysis-in-extended-pedigrees-to-classify-rare-variants-of-uncertain-significance-in-cancer-risk-genes
#3
Elisabeth A Rosenthal, John Michael O Ranola, Brian H Shirts
Rare and private variants of uncertain significance (VUS) are routinely identified in clinical panel, exome, and genome sequencing. We investigated the power of single family co-segregation analysis to aid classification of VUS. We simulated thousands of pedigrees using demographics in China and the United States, segregating benign and pathogenic variants. Genotypes and phenotypes were simulated using penetrance models for Lynch syndrome and breast/ovarian cancer. We calculated LOD scores adjusted for proband ascertainment (LODadj), to determine power to yield quantitative evidence for, or against, pathogenicity of the VUS...
May 22, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28531214/suspected-lynch-syndrome-associated-msh6-variants-a-functional-assay-to-determine-their-pathogenicity
#4
Hellen Houlleberghs, Anne Goverde, Jarnick Lusseveld, Marleen Dekker, Marco J Bruno, Fred H Menko, Arjen R Mensenkamp, Manon C W Spaander, Anja Wagner, Robert M W Hofstra, Hein Te Riele
Lynch syndrome (LS) is a hereditary cancer predisposition caused by inactivating mutations in DNA mismatch repair (MMR) genes. Mutations in the MSH6 DNA MMR gene account for approximately 18% of LS cases. Many LS-associated sequence variants are nonsense and frameshift mutations that clearly abrogate MMR activity. However, missense mutations whose functional implications are unclear are also frequently seen in suspected-LS patients. To conclusively diagnose LS and enroll patients in appropriate surveillance programs to reduce morbidity as well as mortality, the functional consequences of these variants of uncertain clinical significance (VUS) must be defined...
May 22, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28529751/comparison-of-lifestyle-hormonal-and-medical-factors-in-women-with-sporadic-and-lynch-syndrome-associated-endometrial-cancer-a-retrospective-case-case-study
#5
Mari H Aaltonen, Synnöve Staff, Jukka-Pekka Mecklin, Kirsi Pylvänäinen, Johanna U Mäenpää
Data available on lifestyle-associated hormonal and medical factors among endometrial cancer (EC)-affected women who carry the Lynch Syndrome (LS) mutation is limited. The aim of the present retrospective case study was to compare the reproductive and medical history, as well as lifestyle-associated factors, among patients with LS and sporadic EC. The study population consisted of 50 verified germline mismatch repair (MMR) gene mutation carriers diagnosed with EC, and 110 sporadic EC patients. Data were collected using postal questionnaires...
May 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28528517/loss-of-msh2-and-msh6-due-to-heterozygous-germline-defects-in-msh3-and-msh6
#6
Monika Morak, Sarah Käsbauer, Martina Kerscher, Andreas Laner, Anke M Nissen, Anna Benet-Pagès, Hans K Schackert, Gisela Keller, Trisari Massdorf, Elke Holinski-Feder
Lynch Syndrome (LS) is the most common dominantly inherited colorectal cancer (CRC) predisposition and is caused by a heterozygous germline defect in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. High microsatellite instability (MSI-H) and loss of MMR protein expression in tumours reflecting a defective MMR are indicators for LS, as well as a positive family history of early onset CRC. MSH2 and MSH6 form a major functional heterodimer, and MSH3 is an alternative binding partner for MSH2...
May 20, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28525912/clinicopathologic-characteristics-of-endometrial-cancer-in-lynch-syndrome-a-french-multicenter-study
#7
Léa Rossi, Marie-Aude Le Frere-Belda, Pierre Laurent-Puig, Bruno Buecher, Antoine De Pauw, Dominique Stoppa-Lyonnet, Geoffroy Canlorbe, Olivier Caron, Bruno Borghese, Chrystelle Colas, Hélène Delhomelle, Nathalie Chabbert-Buffet, Sophie Grandjouan, Fabrice Lecuru, Anne-Sophie Bats
BACKGROUND: Limited data exist on Lynch syndrome (LS)-related endometrial cancer (EC) features. Amsterdam criteria II, commonly used, have poor sensitivity for detection of LS, which is underdiagnosed. AIM: The aim of this study was to describe the clinical and pathological features of LS-related EC among mutation-proven patients. METHODS: We conducted a retrospective study from 1977 to 2013 in 5 hospitals. The inclusion criteria were patients who had a primary EC associated to LS proven by a germline mutation...
June 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/28523262/case-report-of-menopausal-woman-diagnosed-with-endometrial-cancer-after-colon-cancer-with-germline-mutation-in-msh6-in-korea
#8
Hyun Jung Lee, Min Hee Lee, Min Chul Choi, Sang Geun Jung, Won Duk Joo, Tae Hoen Kim, Chan Lee, Ja-Hyun Jang
We present a case of an endometrial cancer patient with germline mutation in MutS homolog 6 (MSH6), associated with Lynch syndrome. A 60-year-old Korean woman had a personal history of colon cancer 23 years ago. She also had a family history of endometrial cancer and colon cancer of her sisters and brothers. Immunohistochemistry was negative for MutL homolog 1 (MLH1) and positive for MutS homolog 2 (MSH2). Based on these findings, she underwent genetic counseling and testing that revealed a frameshift germline mutation at MSH6 (c...
April 2017: Journal of Menopausal Medicine
https://www.readbyqxmd.com/read/28514183/multigene-panel-testing-provides-a-new-perspective-on-lynch-syndrome
#9
Carin R Espenschied, Holly LaDuca, Shuwei Li, Rachel McFarland, Chia-Ling Gau, Heather Hampel
Purpose Most existing literature describes Lynch syndrome (LS) as a hereditary syndrome leading to high risks of colorectal cancer (CRC) and endometrial cancer mainly as a result of mutations in MLH1 and MSH2. Most of these studies were performed on cohorts with disease suggestive of hereditary CRC and population-based CRC and endometrial cancer cohorts, possibly biasing results. We aimed to describe a large cohort of mismatch repair (MMR) mutation carriers ascertained through multigene panel testing, evaluate their phenotype, and compare the results with those of previous studies...
May 17, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28510097/ago-austria-recommendation-on-screening-and-diagnosis-of-lynch-syndrome-ls
#10
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...
May 16, 2017: Archives of Gynecology and Obstetrics
https://www.readbyqxmd.com/read/28508326/the-association-of-low-penetrance-genetic-risk-modifiers-with-colorectal-cancer-in-lynch-syndrome-patients-a-systematic-review-and-meta-analysis
#11
REVIEW
Neil Donald, Salim Malik, Joshua L McGuire, Kevin J Monahan
Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome accounting for approximately 1000 cases of colorectal cancer (CRC) in the UK annually. LS is characterised by autosomal dominant inheritance and germline mutations in DNA mismatch repair genes. The penetrance is highly variable and the reasons for this have not been fully elucidated. This study investigates whether low penetrance genetic risk factors may result in phenotype modification in LS patients. To conduct a systematic literature review and meta-analysis to assess the association between low penetrance genetic risk modifiers and CRC in LS patients...
May 15, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28507809/t-cell-therapy-targeting-a-public-neoantigen-in-microsatellite-instable-colon-cancer-reduces-in-vivo-tumor-growth
#12
Else M Inderberg, Sébastien Wälchli, Marit R Myhre, Sissel Trachsel, Hilde Almåsbak, Gunnar Kvalheim, Gustav Gaudernack
T-cell receptor (TCR) transfer is an attractive strategy to increase the number of cancer-specific T cells in adoptive cell therapy. However, recent clinical and pre-clinical findings indicate that careful consideration of the target antigen is required to limit the risk of off-target toxicity. Directing T cells against mutated proteins such as frequently occurring frameshift mutations may thus be a safer alternative to tumor-associated self-antigens. Furthermore, such frameshift mutations result in novel polypeptides allowing selection of TCRs from the non-tolerant T-cell repertoire circumventing the problem of low affinity TCRs due to central tolerance...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28507641/a-case-report-of-muir-torre-syndrome-in-a-woman-with-breast-cancer-and-msi-low-skin-squamous-cell-carcinoma
#13
Caroline Kientz, Marie-Odile Joly, Laurence Faivre, Alix Clemenson, Sophie Dalac, Côme Lepage, Caroline Chapusot, Caroline Jacquot, Renaud Schiappa, Marine Lebrun
BACKGROUND: The tumor spectrum in the Lynch syndrome is well defined, comprising an increased risk of developing colonic and extracolonic malignancies. Muir-Torre syndrome is a variant with a higher risk of skin disease. Patients have been described carrying mutations in the mismatch repair genes and presenting tumors with unusual histology or affected organ not part of the Lynch syndrome spectrum. Hence, the real link between Lynch syndrome, or Muir-Torre syndrome, and these tumors remains difficult to assess...
2017: Hereditary Cancer in Clinical Practice
https://www.readbyqxmd.com/read/28501935/early-gastric-adenocarcinoma-arising-within-foveolar-type-dysplasia-in-a-patient-with-muir-torre-variant-lynch-syndrome
#14
Tristan F P McKnight, Amy E Noffsinger, Kara M Klingman, Ovais Ahmed, Rebecca Wilcox
No abstract text is available yet for this article.
May 13, 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/28498244/identifying-lynch-syndrome-in-women-presenting-with-endometrial-carcinoma-under-the-age-of-50-years
#15
Antonios Anagnostopoulos, Vicky H McKay, Iris Cooper, Fiona Campbell, Lynn Greenhalgh, John Kirwan
BACKGROUND: Lynch syndrome (LS) is an inherited disorder associated with genetic predisposition to endometrial, colorectal, ovarian, and other cancers. There is consensus for the necessity of assessment for LS in view of the established survival benefits for identified patients and affected family members. The debate regarding the best screening policy is far from being concluded. OBJECTIVES: The aim of this study was to evaluate a realistic protocol for identifying LS families by assessing young women with a diagnosis of endometrial cancer (EC)...
June 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/28494185/functional-analysis-of-rare-variants-in-mismatch-repair-proteins-augments-results-from-computation-based-predictive-methods
#16
Sanjeevani Arora, Peter J Huwe, Rahmat Sikder, Manali Shah, Amanda J Browne, Randy Lesh, Emmanuelle Nicolas, Sanat Deshpande, Michael J Hall, Roland L Dunbrack, Erica A Golemis
The cancer-predisposing Lynch Syndrome (LS) arises from germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1, MSH2, MSH6,and PMS2. A major challenge for clinical diagnosis of LS is the frequent identification of variants of uncertain significance (VUS) in these genes, as it is often difficult to determine variant pathogenicity, particularly for missense variants. Generic programs such as SIFT and PolyPhen-2, and MMR gene-specific programs such as PON-MMR and MAPP-MMR, are often used to predict deleterious or neutral effects of VUS in MMR genes...
May 11, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28491141/universal-molecular-screening-does-not-effectively-detect-lynch-syndrome-in-clinical-practice
#17
Beatrice Brennan, Christine T Hemmings, Ian Clark, Desmond Yip, Mitali Fadia, Douglas R Taupin
BACKGROUND: Lynch syndrome (LS) due to an inherited damaging mutation in mismatch repair (MMR) genes comprises 3% of all incident colorectal cancer (CRC). Molecular testing using immunohistochemistry (IHC) for MMR proteins is a recommended screening tool to identify LS in incident CRC. This study assessed outcomes of population-based routine molecular screening for diagnosis of LS in a regional center. METHODS: We conducted a prospective, consecutive case series study of universal IHC testing on cases of resected CRC from September 2004-December 2013...
April 2017: Therapeutic Advances in Gastroenterology
https://www.readbyqxmd.com/read/28489507/development-and-validation-of-the-premm5-model-for-comprehensive-risk-assessment-of-lynch-syndrome
#18
Fay Kastrinos, Hajime Uno, Chinedu Ukaegbu, Carmelita Alvero, Ashley McFarland, Matthew B Yurgelun, Matthew H Kulke, Deborah Schrag, Jeffrey A Meyerhardt, Charles S Fuchs, Robert J Mayer, Kimmie Ng, Ewout W Steyerberg, Sapna Syngal
Purpose Current Lynch syndrome (LS) prediction models quantify the risk to an individual of carrying a pathogenic germline mutation in three mismatch repair (MMR) genes: MLH1, MSH2, and MSH6. We developed a new prediction model, PREMM5, that incorporates the genes PMS2 and EPCAM to provide comprehensive LS risk assessment. Patients and Methods PREMM5 was developed to predict the likelihood of a mutation in any of the LS genes by using polytomous logistic regression analysis of clinical and germline data from 18,734 individuals who were tested for all five genes...
May 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28484856/-hereditary-gastric-and-pancreatic-cancer
#19
REVIEW
C Langner
Most cases of gastric and pancreatic cancer are sporadic, but familial clustering can be observed in approximately 10% of cases. Hereditary gastric cancer accounts for a very low percentage of cases (1-3%) and two syndromes have been characterized: hereditary diffuse gastric cancer (HDGC) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Gastric and pancreatic cancer can develop in the setting of other hereditary cancer syndromes, such as hereditary breast and ovarian cancer syndrome (HBOC), Li-Fraumeni syndrome, Lynch syndrome, familial adenomatous polyposis (FAP), or various hamartomatous polyposis syndromes, including juvenile polyposis and Peutz-Jeghers syndrome...
May 8, 2017: Der Pathologe
https://www.readbyqxmd.com/read/28481836/sensitivity-of-the-dn4-in-screening-for-neuropathic-pain-syndromes
#20
Elizabeth G VanDenKerkhof, Larry Stitt, Alexander J Clark, Allan Gordon, Mary Lynch, Patricia K Morley-Forster, Howard J Nathan, Catherine Smyth, Cory Toth, Mark A Ware, Dwight E Moulin
OBJECTIVES: Several tools have been developed to screen for neuropathic pain. This study examined the sensitivity of the Douleur Neuropathique en 4 Questions (DN4) in screening for various neuropathic pain syndromes. METHODS: This prospective observational study was conducted in 7 Canadian academic pain centers between April 2008 and December 2011. All newly admitted patients (n=2199) were approached and 789 eligible participants form the sample for this analysis...
May 5, 2017: Clinical Journal of Pain
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