Dataset Information

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study.

ABSTRACT: 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. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. 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. 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. 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.

SUBMITTER: Dominguez-Valentin M

PROVIDER: S-EPMC8269121 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in <i>MLH1</i> and <i>MSH2</i>: A Prospective Lynch Syndrome Database Study.

Dominguez-Valentin Mev M Plazzer John-Paul JP Sampson Julian R JR Engel Christoph C Aretz Stefan S Jenkins Mark A MA Sunde Lone L Bernstein Inge I Capella Gabriel G Balaguer Francesc F Macrae Finlay F Winship Ingrid M IM Thomas Huw H Evans Dafydd Gareth DG Burn John J Greenblatt Marc M de Vos Tot Nederveen Cappel Wouter H WH Sijmons Rolf H RH Nielsen Maartje M Bertario Lucio L Bonanni Bernardo B Tibiletti Maria Grazia MG Cavestro Giulia Martina GM Lindblom Annika A Valle Adriana Della AD Lopez-Kostner Francisco F Alvarez Karin K Gluck Nathan N Katz Lior L Heinimann Karl K Vaccaro Carlos A CA Nakken Sigve S Hovig Eivind E Green Kate K Lalloo Fiona F Hill James J Vasen Hans F A HFA Perne Claudia C Büttner Reinhard R Görgens Heike H Holinski-Feder Elke E Morak Monika M Holzapfel Stefanie S Hüneburg Robert R von Knebel Doeberitz Magnus M Loeffler Markus M Rahner Nils N Weitz Jürgen J Steinke-Lange Verena V Schmiegel Wolff W Vangala Deepak D Crosbie Emma J EJ Pineda Marta M Navarro Matilde M Brunet Joan J Moreira Leticia L Sánchez Ariadna A Serra-Burriel Miquel M Mints Miriam M Kariv Revital R Rosner Guy G Piñero Tamara Alejandra TA Pavicic Walter Hernán WH Kalfayan Pablo P Broeke Sanne W Ten SWT Mecklin Jukka-Pekka JP Pylvänäinen Kirsi K Renkonen-Sinisalo Laura L Lepistö Anna A Peltomäki Päivi P Hopper John L JL Win Aung Ko AK Buchanan Daniel D DD Lindor Noralane M NM Gallinger Steven S Marchand Loïc Le LL Newcomb Polly A PA Figueiredo Jane C JC Thibodeau Stephen N SN Therkildsen Christina C Hansen Thomas V O TVO Lindberg Lars L Rødland Einar Andreas EA Neffa Florencia F Esperon Patricia P Tjandra Douglas D Möslein Gabriela G Seppälä Toni T TT Møller Pål P

Journal of clinical medicine 20210628 13

<h4>Background</h4>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 differen ...[more]

PMID: 34203177

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Project description:BackgroundAbnormalities of pre-mRNA splicing are increasingly recognized as an important mechanism through which gene mutations cause disease. However, apart from the mutations in the donor and acceptor sites, the effects on splicing of other sequence variations are difficult to predict. Loosely defined exonic and intronic sequences have been shown to affect splicing efficiency by means of silencing and enhancement mechanisms. Thus, nucleotide substitutions in these sequences can induce aberrant splicing. Web-based resources have recently been developed to facilitate the identification of nucleotide changes that could alter splicing. However, computer predictions do not always correlate with in vivo splicing defects. The issue of unclassified variants in cancer predisposing genes is very important both for the correct ascertainment of cancer risk and for the understanding of the basic mechanisms of cancer gene function and regulation. Therefore we aimed to verify how predictions that can be drawn from in silico analysis correlate with results obtained in an in vivo splicing assay.ResultsWe analysed 99 hMLH1 and hMSH2 missense mutations with six different algorithms. Transfection of three different cell lines with 20 missense mutations, showed that a minority of them lead to defective splicing. Moreover, we observed that some exons and some mutations show cell-specific differences in the frequency of exon inclusion.ConclusionOur results suggest that the available algorithms, while potentially helpful in identifying splicing modulators especially when they are located in weakly defined exons, do not always correspond to an obvious modification of the splicing pattern. Thus caution must be used in assessing the pathogenicity of a missense or silent mutation with prediction programs. The variations observed in the splicing proficiency in three different cell lines suggest that nucleotide changes may dictate alternative splice site selection in a tissue-specific manner contributing to the widely observed phenotypic variability in inherited cancers.

Dataset Information

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study.

Publications

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in <i>MLH1</i> and <i>MSH2</i>: A Prospective Lynch Syndrome Database Study.

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