Citations 2
No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study
Dominguez–Valentin, Mev , Plazzer, John‐Paul , Sampson, Julian R. , Engel, Christoph , Aretz, Stefan , Sunde, Lone , Capellá, Gabriel , Balaguer, Francesc , Thomas, Huw , Evans, D. Gareth , Burn, John , Greenblatt, Marc S. , Cappel, Wouter H. de Vos tot Nederveen , Nielsen, Maartje , Bonanni, Bernardo , Tibiletti, Maria Grazia , Lindblom, Annika , Valle, Adriana Della , López-Köstner, Francisco, Gluck, Nathan , Katz, Lior H. , Heinimann, Karl , Vaccaro, Carlos , Nakken, Sigve , Hovig, Eivind , Green, Kate, Lalloo, Fiona, Hill, James , Perne, Claudia , Görgens, Heike, Holinski‐Feder, Elke , Holzapfel, Stefanie, Hüneburg, Robert , Doeberitz, Magnus von Knebel , Loeffler, Markus , Rahner, Nils, Steinke‐Lange, Verena , Schmiegel, Wolff , Vangala, Deepak , Crosbie, Emma J. , Pineda, Marta , Navarro, Matilde, Brunet, Joan , Moreira, Leticia , Sánchez, Ariadna , Serra‐Burriel, Miquel , Mints, Miriam, Kariv, Revital , Rosner, Guy , Piñero, Tamara Alejandra , Pavicic, Walter , Kalfayan, Pablo, Broeke, Sanne W. ten , Mecklin, Jukka‐Pekka , Pylvänäinen, Kirsi , Renkonen‐Sinisalo, Laura , Lepistö, Anna , Peltomäki, Païvi , Win, Aung Ko , Buchanan, Daniel D. , Lindor, Noralane M. , Gallinger, Steven , Marchand, Loı̈c Le , Figueiredo, Jane C. , Thibodeau, Stephen N. , Hansen, Thomas van Overeem , Lindberg, Lars Joachim , Rødland, Einar Andreas , Neffa, Florencia , Esperón, Patricia, Tjandra, Douglas , Seppälä, Toni T. , Møller, Pål , Capella, Gabriel , Balaguer, Francesc , Evans, D Gareth , Burn, John , de Vos Tot Nederveen Cappel, Wouter H , Nielsen, Maartje , Bonanni, Bernardo , Gluck, Nathan , Vaccaro, Carlos A , Nakken, Sigve , Hovig, Eivind , Hüneburg, Robert , Steinke-Lange, Verena , Vangala, Deepak , Crosbie, Emma J , Pineda, Marta , Brunet, Joan , Moreira, Leticia , Sánchez, Ariadna , Pavicic, Walter Hernán , Broeke, Sanne W Ten , Pylvänäinen, Kirsi , Win, Aung K , Buchanan, Daniel D , Marchand, Loïc Le , Rødland, Einar Andreas , Esperon, Patricia , Tjandra, Douglas , Seppälä, Toni T , Sunde, Lone , Engel, Christoph , Hansen, Thomas van Overeem , Lindblom, Annika , Jenkins, Mark A. , Bernstein, Inge , Macrae, Finlay , Winship, Ingrid , Sijmons, Rolf H. , Bertario, Lucio , Cavestro, Giulia Martina , Álvarez, Karin , Vasen, Hans F. A. , Büttner, Reinhard , Morak, Monika , Weitz, Jürgen , Mints, Miriam , Hopper, John L. , Newcomb, Polly A. , Therkildsen, Christina , Möslein, Gabriela
Journal of Clinical Medicine | June 28, 2021 | Volume: 10 | Issue: 13 | Pages: 2856
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.
Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer
Rodriguez‐Broadbent, Henry , Law, Philip , Sud, Amit , Palin, Kimmo , Tuupanen, Sari, Gylfe, Alexandra E., Hänninen, Ulrika A. , Cajuso, Tatiana , Tanskanen, Tomas , Kondelin, Johanna , Kaasinen, Eevi , Sarin, Antti‐Pekka , Rissanen, Harri , Knekt, Paul , Jousilahti, Pekka , Palotie, Aarno , Renkonen‐Sinisalo, Laura , Lepistö, Anna , Böhm, Jan , Mecklin, Jukka‐Pekka , Tassan, Nada Al , Palles, Claire , Martin, Lynn , Barclay, Ella, Farrington, Susan M. , Timofeeva, Maria , Wakil, Salma M. , Campbell, Harry , Idziaszczyk, Shelley, Kaplan, Richard , Kerr, Rachel , Kerr, David , Passarelli, Michael N. , Figueiredo, Jane C. , Buchanan, Daniel D. , Win, Aung Ko , Jenkins, Mark A. , Lindor, Noralane M. , Gallinger, Steven , Conti, David V. , Schumacher, Fredrick R. , Casey, Graham , Aaltonen, Lauri A. , Cheadle, Jeremy P. , Tomlinson, Ian , Dunlop, Malcolm G. , Houlston, Richard S. , Law, Philip J , Buchanan, Daniel D , Win, Aung K , Ripatti, Samuli , Eriksson, Johan G. , Pukkala, Eero , Salomaa, Veikko , Palotie, Aarno V. , Meyer, Brian F. , Smith, Christopher G. , Maughan, Tim , Hopper, John L. , Newcomb, Polly A. , Houlston, Richard S , Jenkins, Mark A , Kaplan, Richard , Kerr, Rachel , Palles, Claire , Conti, David V
International Journal of Cancer | March 25, 2017 | Volume: 140 | Issue: 12 | Pages: 2701-2708
While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low‐density lipoprotein (LDL), and high‐density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP‐CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20–1.79, p = 1.68 × 10−4). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92–1.18, p = 0.49), 0.94 (95% CI: 0.84–1.05, p = 0.27), and 0.98 (95% CI: 0.85–1.12, p = 0.75) respectively. A genetic risk score for 3‐hydoxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49–0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.