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RESEARCH PRODUCT
No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study
Guy RosnerWalter Hernán PavicicClaudia PerneCarlos A. VaccaroElke Holinski-federLeticia MoreiraWouter H. De Vos Tot Nederveen CappelStefan AretzEinar Andreas RødlandPolly A. NewcombKarin AlvarezAriadna SánchezLone SundeLone SundeWolff SchmiegelJoan BrunetMarc S. GreenblattChristina TherkildsenKarl HeinimannLior H. KatzFiona LallooJürgen WeitzAnna LepistöAnna LepistöRolf H. SijmonsMaartje NielsenHans F. A. VasenDeepak VangalaMonika MorakJukka-pekka MecklinToni T. SeppäläSigve NakkenSigve NakkenStefanie HolzapfelDouglas TjandraDouglas TjandraFinlay A. MacraePäivi PeltomäkiDaniel D. BuchananDaniel D. BuchananStephen N. ThibodeauAdriana Della ValleJames HillAnnika LindblomBernardo BonanniReinhard BüttnerFrancisco López-köstnerGiulia Martina CavestroJohn BurnEmma J CrosbieLucio BertarioSanne W. Ten BroekeD. G. R. EvansKate GreenVerena Steinke-langeEivind HovigEivind HovigMiquel Serra-burrielFrancesc BalaguerKirsi PylvänäinenGabriela MösleinRevital KarivThomas HansenMaria Grazia TibilettiTamara Alejandra PiñeroNils RahnerMagnus Von Knebel DoeberitzMagnus Von Knebel DoeberitzIngrid WinshipIngrid WinshipNathan GluckLars Joachim LindbergChristoph EngelMev Dominguez-valentinJohn-paul PlazzerJulian R. SampsonMarta PinedaJohn L. HopperPablo KalfayanHeike GörgensAung Ko WinSteven GallingerLoic Le MarchandMark A. JenkinsMarkus LoefflerNoralane M. LindorInge BernsteinPål MøllerLaura Renkonen-sinisaloLaura Renkonen-sinisaloFlorencia NeffaHuw ThomasGabriel CapelláJane C. FigueiredoMiriam MintsPatricia EsperonMatilde NavarroRobert Hüneburgsubject
cancer incidence0302 clinical medicineMalalties hereditàriesMissense mutation8Q23.3CàncerCancerGenetics0303 health sciencesmedicine.diagnostic_testFactors de risc en les malaltiesMISMATCH REPAIR GENESRMLH1General MedicinePenetranceLynch syndrome3. Good healthsyöpägeenit030220 oncology & carcinogenesisMedicinesyöpätauditilmaantuvuusGenetic diseasescongenital hereditary and neonatal diseases and abnormalitiesmissense11Q23.1Risk factors in diseasesCANCER-RISKMLH1Articleaberrant splicing03 medical and health sciencesAGEmedicineGenetic predispositionddc:610<i>MSH2</i>Lynchin oireyhtymäpenetrance030304 developmental biologyGenetic testingMLH1; MSH2; penetrance; cancer incidence; truncating; missense; aberrant splicing; Lynch syndromeperinnölliset tauditbusiness.industryMUTATIONSHMSH2Cancernutritional and metabolic diseasesmedicine.diseasedigestive system diseasesMSH2Lynch syndromeMSH23121 General medicine internal medicine and other clinical medicine<i>MLH1</i>businesstruncatingdescription
Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-07-01 |