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Lynch syndrome, hereditary cancer, mutation, mismatch repair gene

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https://www.readbyqxmd.com/read/29146522/germline-genetic-features-of-young-individuals-with-colorectal-cancer
#1
Elena M Stoffel, Erika Koeppe, Jessica Everett, Peter Ulintz, Mark Kiel, Jenae Osborne, Linford Williams, Kristen Hanson, Stephen B Gruber, Laura S Rozek
BACKGROUND & AIMS: The incidence of colorectal cancer (CRC) in individuals younger than 50 years old is increasing. We sought to ascertain the proportion of young CRC cases associated with genetic predisposition. METHODS: We performed a retrospective study of individuals diagnosed with CRC at an age younger than 50 years, evaluated by the clinical genetics service at a single tertiary care cancer center from 1998 through 2015. We collected data on patient histories, tumor phenotypes, and results of germline DNA sequencing...
November 12, 2017: Gastroenterology
https://www.readbyqxmd.com/read/29096939/familial-colorectal-cancer-type-x-fcctx-and-the-correlation-with-various-genes-a-systematic-review
#2
REVIEW
Mahdieh Nejadtaghi, Hamideh Jafari, Effat Farrokhi, Keihan Ghatreh Samani
Familial Colorectal Cancer Type X (FCCTX) is a type of hereditary nonpolyposis colorectal cancer in accordance to Amsterdam criteria-1 for Lynch syndrome, with no related mutation in mismatch repair gene. FCCTX is microsatellite stable and is accounted for 40% of families with Amsterdam criteria-1 with a high age of onset. Thus, the carcinogenesis of FCCTX is different compared to Lynch syndrome. In addition to the microsatellite stability and the presence of less predominant tumors in proximal colon, various clinical features have also been associated with FCCTX in comparison with Lynch syndrome such as no increased risk of extra-colonic cancers, older age of diagnosis and higher adenoma/carcinoma rate...
October 18, 2017: Current Problems in Cancer
https://www.readbyqxmd.com/read/29071502/phenotypic-and-genotypic-heterogeneity-of-lynch-syndrome-a-complex-diagnostic-challenge
#3
REVIEW
Henry T Lynch, Stephen Lanspa, Trudy Shaw, Murray Joseph Casey, Marc Rendell, Mark Stacey, Theresa Townley, Carrie Snyder, Megan Hitchins, Joan Bailey-Wilson
Lynch syndrome is the hereditary disorder that most frequently predisposes to colorectal cancer as well as predisposing to a number of extracolonic cancers, most prominently endometrial cancer. It is caused by germline mutations in the mismatch repair genes. Both its phenotype and genotype show marked heterogeneity. This review gives a historical overview of the syndrome, its heterogeneity, its genomic landscape, and its implications for complex diagnosis, genetic counseling and putative implications for immunotherapy...
October 25, 2017: Familial Cancer
https://www.readbyqxmd.com/read/29065108/towards-gene-and-gender-based-risk-estimates-in-lynch-syndrome-age-specific-incidences-for-13-extra-colorectal-cancer-types
#4
Christina Therkildsen, Steen Ladelund, Lars Smith-Hansen, Lars Joachim Lindberg, Mef Nilbert
BACKGROUND: In Lynch syndrome, inherited mismatch repair (MMR) defects predispose to colorectal cancer and to a wide spectrum of extra-colorectal tumours. Utilising a cohort study design, we aimed to determine the risk of extra-colorectal cancer and to identify yet unrecognised tumour types. METHODS: Data from 1624 Lynch syndrome mutation carriers in the Danish hereditary non-polyposis colorectal cancer register were used to estimate the sex- and age-specific incidence rate ratios (IRRs) for 30 extra-colorectal malignancies with comparison to the general population...
October 24, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29061399/-lynch-syndrome-and-endometrial-cancer
#5
REVIEW
Anne-Sophie Bats, Léa Rossi, Marie-Aude Le Frere-Belda, Céline Narjoz, Caroline Cournou, Marie Gosset, Charlotte Ngo, Myriam Delomenie, Claude Nos, Hélène Blons, Pierre Laurent-Puig, Fabrice Lecuru
Lynch syndrome is a hereditary predisposition to many tumors, in the forefront of which endometrial cancer in women. It is related to the mutation of a mismatch repair gene, involved in DNA mismatch repair. This mutation leads to a loss of expression of the corresponding protein, and to genome instability in tumor cells. Cumulative risk at the age of 70 years is over 40 %. Endometrial cancers related to Lynch syndrome are most of the time sentinel (They reveal the predisposition in half of families.) and are characterized by young age at onset (before 60 years) and low body mass index compared with patients presenting sporadic tumors...
October 21, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/28973356/setd6-dominant-negative-mutation-in-familial-colorectal-cancer-type-x
#6
Lorena Martín-Morales, Michal Feldman, Zlata Vershinin, Pilar Garre, Trinidad Caldés, Dan Levy
Familiar colorectal cancer type X (FCCTX) comprises families that fulfill the Amsterdam criteria for hereditary non-polyposis colorectal cancer, but that lack the mismatch repair deficiency that defines the Lynch syndrome. Thus, the genetic cause that increases the predisposition to colorectal and other related cancers in families with FCCTX remains to be elucidated. Using whole-exome sequencing, we have identified a truncating mutation in the SETD6 gene (c.791_792insA, p.Met264IlefsTer3) in all the affected members of a FCCTX family...
November 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28938854/lynch-syndrome-and-sextuple-primary-malignancies
#7
Donatas Danys, Eugenijus Stratilatovas, Vaidas Cereska, Tomas Poskus
Lynch syndrome or hereditary nonpolyposis colorectal cancer is the most common of hereditary colorectal cancer and accounts for 1-3%. Lynch and Chapelle estimated that it accounts 5-8% for all colorectal cancers. It is an autosomal dominant syndrome characterized by predisposition of various cancers (colorectal, stomach, endometrial, ovarian, renal, small bowel, and hepatobiliary tract) at earlier age than in general population and occurs as a result of mutation in DNA mismatch repair genes. This article presents a rare clinical of a 61-year-old female diagnosed with extracolonic Lynch syndrome with six metachronous tumours acquiring in digestive tract during the period from 1993 to 2014 (over 21 years)...
September 22, 2017: Acta Chirurgica Belgica
https://www.readbyqxmd.com/read/28895526/molecular-testing-for-lynch-syndrome-in-people-with-colorectal-cancer-systematic-reviews-and-economic-evaluation
#8
Tristan Snowsill, Helen Coelho, Nicola Huxley, Tracey Jones-Hughes, Simon Briscoe, Ian M Frayling, Chris Hyde
BACKGROUND: Inherited mutations in deoxyribonucleic acid (DNA) mismatch repair (MMR) genes lead to an increased risk of colorectal cancer (CRC), gynaecological cancers and other cancers, known as Lynch syndrome (LS). Risk-reducing interventions can be offered to individuals with known LS-causing mutations. The mutations can be identified by comprehensive testing of the MMR genes, but this would be prohibitively expensive in the general population. Tumour-based tests - microsatellite instability (MSI) and MMR immunohistochemistry (IHC) - are used in CRC patients to identify individuals at high risk of LS for genetic testing...
September 2017: Health Technology Assessment: HTA
https://www.readbyqxmd.com/read/28840050/gastric-medullary-carcinoma-with-sporadic-mismatch-repair-deficiency-and-a-tp53-r273c-mutation-an-unusual-case-with-wild-type-braf
#9
Brett M Lowenthal, Theresa W Chan, John A Thorson, Kaitlyn J Kelly, Thomas J Savides, Mark A Valasek
Medullary carcinoma has long been recognized as a subtype of colorectal cancer associated with microsatellite instability and Lynch syndrome. Gastric medullary carcinoma is a very rare neoplasm. We report a 67-year-old male who presented with a solitary gastric mass. Total gastrectomy revealed a well-demarcated, poorly differentiated carcinoma with an organoid growth pattern, pushing borders, and abundant peritumoral lymphocytic response. The prior cytology was cellular with immunohistochemical panel consistent with upper gastrointestinal/pancreaticobiliary origin...
2017: Case Reports in Pathology
https://www.readbyqxmd.com/read/28820751/importance-of-pcr-based-tumor-testing-in-the-evaluation-of-lynch-syndrome-associated-endometrial-cancer
#10
Amanda S Bruegl, Annessa Kernberg, Russell R Broaddus
Lynch syndrome (LS) is a hereditary cancer syndrome caused by a germline mutation in a DNA mismatch repair gene, usually MLH1, MSH2, MSH6, or PMS2. The most common cancers associated with LS are colorectal adenocarcinoma and endometrial carcinoma. Identification of women with LS-associated endometrial cancer is important, as these women and their affected siblings and children are at-risk of developing these same cancers. Germline testing of all endometrial cancer patients is not cost effective, and screening using young age of cancer diagnosis and/or presence of family history of syndrome-associated is underutilized and ineffective...
November 2017: Advances in Anatomic Pathology
https://www.readbyqxmd.com/read/28819720/immunohistochemical-null-phenotype-for-mismatch-repair-proteins-in-colonic-carcinoma-associated-with-concurrent-mlh1-hypermethylation-and-msh2-somatic-mutations
#11
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
https://www.readbyqxmd.com/read/28764791/metachronous-colorectal-carcinoma-with-massive-submucosal-invasion-detected-by-annual-surveillance-in-a-lynch-syndrome-patient-a-case-report
#12
Masashi Utsumi, Kohji Tanakaya, Yutaka Mushiake, Tomoyoshi Kunitomo, Isao Yasuhara, Fumitaka Taniguchi, Takashi Arata, Koh Katsuda, Hideki Aoki, Hitoshi Takeuchi
BACKGROUND: Lynch syndrome is the most common form of hereditary colorectal carcinoma. It is characterized by the presence of germline mutations in DNA mismatch repair genes. Mutation carriers have a lifetime risk of developing colorectal carcinoma of approximately 80%. Current treatment guidelines recommend periodic surveillance for colorectal carcinoma in patients with Lynch syndrome. However, the optimal interval between colonoscopies has not yet been determined. CASE PRESENTATION: We describe a 54-year-old man with Lynch syndrome who was undergoing annual colonoscopy surveillance for the development of colorectal carcinoma...
August 1, 2017: World Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28749454/the-association-of-low-penetrance-variants-in-dna-repair-genes-with-colorectal-cancer-a-systematic-review-and-meta-analysis
#13
Nikhil Aggarwal, Neil D Donald, Salim Malik, Subothini S Selvendran, Mark Jw McPhail, Kevin J Monahan
OBJECTIVES: Approximately 35% of colorectal cancer (CRC) risk is attributable to heritable factors known hereditary syndromes, accounting for 6%. The remainder may be due to lower penetrance polymorphisms particularly of DNA repair genes. DNA repair pathways, including base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), direct reversal repair (DRR), and double-strand break repair are complex, evolutionarily conserved, and critical in carcinogenesis. Germline mutations in these genes are associated with high-penetrance CRC syndromes such as Lynch syndrome...
July 27, 2017: Clinical and Translational Gastroenterology
https://www.readbyqxmd.com/read/28699072/expending-role-of-microsatellite-instability-in-diagnosis-and-treatment-of-colorectal-cancers
#14
REVIEW
Liisa Chang, Minna Chang, Hanna M Chang, Fuju Chang
BACKGROUND: Colorectal carcinomas with high-frequency microsatellite instability (MSI-H) account for 15% of all colorectal cancers, including 12% of sporadic cases and 3% of cancers associated with Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer syndrome, HNPCC). Lynch syndrome is an autosomal dominant hereditary cancer syndrome, caused by germline mutations in mismatch repair genes, including MLH1, MSH2, MSH6 and PMS2. METHODS: Published articles from peer-reviewed journals were obtained from PubMed, Google Scholar and Clinicaltrials...
December 2017: Journal of Gastrointestinal Cancer
https://www.readbyqxmd.com/read/28696559/genetic-testing-for-hereditary-nonpolyposis-colorectal-cancer-hnpcc
#15
Babi Ramesh Reddy Nallamilli, Madhuri Hegde
Hereditary nonpolyposis colorectal cancer (HNPCC), also called Lynch syndrome, is an autosomal dominant cancer syndrome that confers an elevated risk of early-onset colorectal cancer (CRC) and increased lifetime risk for other cancers of the endometrium, stomach, small intestine, hepatobiliary system, kidney, ureter, and ovary. Lynch syndrome accounts for up to 3% of all CRC, making it the most common hereditary colorectal cancer syndrome. Germline mutations in methyl-directed mismatch repair (MMR) genes give rise to microsatellite instability (MSI) in tumor DNA...
July 11, 2017: Current Protocols in Human Genetics
https://www.readbyqxmd.com/read/28607805/simplified-microsatellite-instability-detection-protocol-provides-equivalent-sensitivity-to-robust-detection-strategies-in-lynch-syndrome-patients
#16
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/28573495/rnf43-is-mutated-less-frequently-in-lynch-syndrome-compared-with-sporadic-microsatellite-unstable-colorectal-cancers
#17
Lochlan J Fennell, Mark Clendenning, Diane M McKeone, Saara H Jamieson, Samanthy Balachandran, Jennifer Borowsky, John Liu, Futoshi Kawamata, Catherine E Bond, Christophe Rosty, Matthew E Burge, Daniel D Buchanan, Barbara A Leggett, Vicki L J Whitehall
The WNT signaling pathway is commonly altered during colorectal cancer development. The E3 ubiquitin ligase, RNF43, negatively regulates the WNT signal through increased ubiquitination and subsequent degradation of the Frizzled receptor. RNF43 has recently been reported to harbor frequent truncating frameshift mutations in sporadic microsatellite unstable (MSI) colorectal cancers. This study assesses the relative frequency of RNF43 mutations in hereditary colorectal cancers arising in the setting of Lynch syndrome...
June 1, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28531214/suspected-lynch-syndrome-associated-msh6-variants-a-functional-assay-to-determine-their-pathogenicity
#18
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 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28514183/multigene-panel-testing-provides-a-new-perspective-on-lynch-syndrome
#19
COMPARATIVE STUDY
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...
August 1, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28481244/incomplete-segregation-of-msh6-frameshift-variants-with-phenotype-of-lynch-syndrome
#20
Raffaella Liccardo, Marina De Rosa, Giovanni Battista Rossi, Nicola Carlomagno, Paola Izzo, Francesca Duraturo
Abstract: Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer, involves mutations in mismatch repair genes. The aim of this study was to identify mutations in MSH6 from 97 subjects negative for mutations in MLH1 and MSH2. By direct sequencing, we identified 27 MSH6 variants, of which, nine were novel. To verify the pathogenicity of these novel variants, we performed in silico and segregation analyses. Three novel variants were predicted by in silico analysis as damaging mutations and segregated with the disease phenotype; while a novel frameshift deletion variant that was predicted to yield a premature stop codon did not segregate with the LS phenotype in three of four cases in the family...
May 6, 2017: International Journal of Molecular Sciences
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