Epidemiological, clinical and molecular characterization of Lynch-like syndrome : A population-based study

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http://hdl.handle.net/10138/302078

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Porkka , N , Lahtinen , L , Ahtiainen , M , Böhm , J P , Kuopio , T , Eldfors , S , Mecklin , J-P , Seppälä , T T & Peltomäki , P 2019 , ' Epidemiological, clinical and molecular characterization of Lynch-like syndrome : A population-based study ' , International Journal of Cancer , vol. 145 , no. 1 , pp. 87-98 . https://doi.org/10.1002/ijc.32085

Title: Epidemiological, clinical and molecular characterization of Lynch-like syndrome : A population-based study
Author: Porkka, Noora; Lahtinen, Laura; Ahtiainen, Maarit; Böhm, Jan P.; Kuopio, Teijo; Eldfors, Samuli; Mecklin, Jukka-Pekka; Seppälä, Toni T.; Peltomäki, Päivi
Contributor: University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Clinicum
University of Helsinki, Department of Medical and Clinical Genetics
Date: 2019-07-01
Language: eng
Number of pages: 12
Belongs to series: International Journal of Cancer
ISSN: 0020-7136
URI: http://hdl.handle.net/10138/302078
Abstract: Colorectal carcinomas that are mismatch repair (MMR)-deficient in the absence of MLH1 promoter methylation or germline mutations represent Lynch-like syndrome (LLS). Double somatic events inactivating MMR genes are involved in the etiology of LLS tumors. Our purpose was to define the clinical and broader molecular hallmarks of LLS tumors and the population incidence of LLS, which remain poorly characterized. We investigated 762 consecutive colorectal carcinomas operated in Central Finland in 2000-2010. LLS cases were identified by a stepwise protocol based on MMR protein expression, MLH1 methylation and MMR gene mutation status. LLS tumors were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations in 578 cancer-relevant genes. Among 107 MMR-deficient tumors, 81 (76%) were attributable to MLH1 promoter methylation and 9 (8%) to germline mutations (Lynch syndrome, LS), leaving 14 LLS cases (13%) (3 remained unclassified). LLS carcinomas were diagnosed at a mean age of 65 years (vs. 44 years in LS, p <0.001), had a proximal to distal ratio of 1:1, and all were BRAF V600E-negative. Two somatic events in MMR genes were identifiable in 11 tumors (79%). As novel findings, the tumors contained an average of 31 nonsynonymous somatic mutations/Mb and 13/14 were CIMP-positive. In conclusion, we establish the epidemiological, clinical and molecular characteristics of LLS in a population-based study design. Significantly more frequent CIMP-positivity and lower rates of somatic mutations make a distinction to LS. The absence of BRAF V600E mutation separates LLS colorectal carcinomas from MLH1-methylated colorectal carcinomas with CIMP-positive phenotype.
Subject: lynch syndrome
lynch-like syndrome
colorectal carcinoma
MSI
DNA mismatch repair
CpG Island Methylator phenotype
NONPOLYPOSIS COLORECTAL-CANCER
ISLAND METHYLATOR PHENOTYPE
MISMATCH-REPAIR DEFICIENCY
MICROSATELLITE INSTABILITY
BRAF MUTATION
SOMATIC MUTATIONS
COPY NUMBER
TUMORS
COLON
FREQUENCY
3122 Cancers
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