title: Yield of routine molecular analyses in colorectal cancer patients ≤70 years to detect underlying Lynch syndrome.
abstract: Although early detection of Lynch syndrome (LS) is important, a considerable proportion of patients with LS remains unrecognized. We aimed to study the yield of LS detection by routine molecular analyses in colorectal cancer (CRC) patients until 70 years of age. We prospectively included consecutive CRC patients ≤70 years. Tumour specimens were analysed for microsatellite instability (MSI), immunohistochemical mismatch-repair protein expression and MLH1-promoter methylation. Tumours were classified as either: (a) likely caused by LS; (b) sporadic microsatellite-unstable (MSI-H); or (c) microsatellite-stable (MSS). Predictors of LS were determined by multivariable logistic regression. A total of 1117 CRC patients (57% males, median age 61 years) were included. Fifty patients (4.5%, 95% CI 3.4-5.9) were likely to have LS, and 71 had a sporadic MSI-H tumour (6.4%, 95% CI 5.1-8.0). Thirty-five patients likely to have LS (70%) were aged > 50 years. A molecular profile compatible with LS was detected in 10% (15/144) of patients aged ≤50, in 4% (15/377) of those aged 51-60 and in 3% (20/596) of patients > 61 years. Compared to MSS cases, patients likely to have LS were significantly younger (OR 3.9, 95% CI 1.7-8.7) and more often had right-sided CRCs (OR 14, 95% CI 6.0-34). In conclusion, molecular screening for LS in CRC patients ≤70 years leads to identification of a molecular profile compatible with LS in 4.5% of patients, with most of them not fulfilling the age criterion (≤50 years) routinely used for LS assessment. Routine use of MSI testing may be considered in CRC patients up to the age of 70 years, with a central role for the pathologist in the selection of patients.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. m.g.f.vanlier@erasmusmc.nl
authors.forename: Margot G F
authors.initials: MG
authors.lastname: van Lier
authors.forename: Celine H M
authors.initials: CH
authors.lastname: Leenen
authors.forename: Anja
authors.initials: A
authors.lastname: Wagner
authors.forename: Dewkoemar
authors.initials: D
authors.lastname: Ramsoekh
authors.forename: Hendrikus J
authors.initials: HJ
authors.lastname: Dubbink
authors.forename: Ans M W
authors.initials: AM
authors.lastname: van den Ouweland
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Westenend
authors.forename: Eelco J R
authors.initials: EJ
authors.lastname: de Graaf
authors.forename: Leonieke M M
authors.initials: LM
authors.lastname: Wolters
authors.forename: Wietske W
authors.initials: WW
authors.lastname: Vrijland
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Kuipers
authors.forename: Monique E
authors.initials: ME
authors.lastname: van Leerdam
authors.forename: Ewout W
authors.initials: EW
authors.lastname: Steyerberg
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000236:Adenoma / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000367:Age Factors; D000368:Aged; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000032:analysis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009426:Netherlands; D009687:Nuclear Proteins / Q000235:genetics; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes