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1. Mendelian randomization study of height and risk of colorectal cancer

Author

Thrift, A.P., Gong, J., Peters, U., Chang-Claude, J., Rudolph, A., Slattery, M.L., Chan, A.T., Esko, T., Wood, A.R., Yang, J., Vedantam, S., Gustafsson, S., Pers, T.H., GIANT Consortium (Albrecht, E., Gieger, C., Grallert, H., Heid, I.M., Illig, T., Müller-Nurasyid, M., Peters, A., Thorand, B., Wichmann, H.-E.), Baron, J.A., Bézieau, S., Kuery, S., Ogino, S., Berndt, S.I., Casey, G., Haile, R.W., Du, M., Harrison, T.A., Thornquist, M., Duggan, D.J., Le Marchand, L., Lemire, M., Lindor, N.M., Seminara, D., Song, M., Thibodeau, S.N., Cotterchio, M., Win, A.K., Jenkins, M.A., Hopper, J.L., Ulrich, C.M., Potter, J.D., Newcomb, P.A., Schoen, R.E., Hoffmeister, M., Brenner, H., White, E.S., Hsu, L.A., and Campbell, P.T.

Subjects
Male, Gerontology, medicine.medical_specialty, Mendelian Randomization Causal Analysis, Epidemiology, Logistic regression, Risk Factors, Mendelian randomization, Humans, Medicine, Sex Distribution, Body Height, Colorectal Cancer, Aged, Rectal Neoplasms, business.industry, Confounding, Case-control study, General Medicine, Odds ratio, Mendelian Randomization Analysis, Middle Aged, digestive system diseases, Confidence interval, Genetic epidemiology, Case-Control Studies, Colonic Neoplasms, Female, business, Demography
Abstract

Background: For men and women, taller height is associated with increased risk of all cancers combined. For colorectal cancer (CRC), it is unclear whether the differential association of height by sex is real or is due to confounding or bias inherent in observational studies. We performed a Mendelian randomization study to examine the association between height and CRC risk. Methods: To minimize confounding and bias, we derived a weighted genetic risk score predicting height (using 696 genetic variants associated with height) in 10 226 CRC cases and 10 286 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for associations between height, genetically predicted height and CRC. Results: Using conventional methods, increased height (per 10-cm increment) was associated with increased CRC risk (OR = 1.08, 95% CI = 1.02–1.15). In sex-specific analyses, height was associated with CRC risk for women (OR = 1.15, 95% CI = 1.05–1.26), but not men (OR = 0.98, 95% CI = 0.92–1.05). Consistent with these results, carrying greater numbers of (weighted) height-increasing alleles (per 1-unit increase) was associated with higher CRC risk for women and men combined (OR = 1.07, 95% CI = 1.01–1.14) and for women (OR = 1.09, 95% CI = 1.01–1.19). There was weaker evidence of an association for men (OR = 1.05, 95% CI = 0.96–1.15). Conclusion: We provide evidence for a causal association between height and CRC for women. The CRC-height association for men remains unclear and warrants further investigation in other large studies.

Published
2015
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2. Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study

Author

Seçil Aksoy, Michael O. Woods, Heinric Williams, Bruno Buecher, Finlay A. Macrae, Lotte N. Krogh, Jay Qiu, Wan K.W. Juhari, Jan T. Lowery, Anne-Marie Gerdes, Magnus von Knebel Doeberitz, Luigi Ricciardiello, Karsten Schulmann, Jose Luis Soto, Kristina Lagerstedt-Robinson, Kiwamu Akagi, Raj Ramesar, Uffe Birk Jensen, Angel Alonso, Robert Hüneburg, Olivier Caron, Michel Longy, Jan Lubinski, Kate Green, Annabel Goodwin, D. Gareth Evans, Julie Wods, Leigha Senter, Matthew F. Kalady, Mark Clendenning, Barbara A. Leggett, Ravindran Ankathil, Swati G. Patel, Julian Barwell, Katherine M. Tucker, Grant Lee, Pascaline Berthet, Dawn M. Nixon, Sonia S. Kupfer, Naohiro Tomita, Susan Parry, Trinidad Caldés, Robert W. Haile, Edenir Inêz Palmero, Karin Alvarez, Cassandra B. Nichols, Mark A. Jenkins, N. Jewel Samadder, Loic LeMarchand, John Burn, Francisco Lopez, Rodney J. Scott, Pierre Laurent-Puig, Julie Arnold, Christina Therkildsen, Hans K. Schackert, Pilar Garre, Reinhard Buettner, Adriana Della Valle, Patricia Esperon, Wolff Schmiegel, Karl Heinimann, Inge Bernstein, Matthias Kloor, Nicoline Hoogerbrugge, Rui Manuel Reis, Fränzel J.B. Van Duijnhoven, Christoph Engel, Mohd Nizam Zahary, Sylviane Olschwang, Sapna Syngal, Valérie Bonadona, Nicholas Pachter, Matilde Navarro, Albert de la Chapelle, Beate Betz, Jukka-Pekka Mecklin, Catherine Noguès, Elena M. Stoffel, Toni T. Seppälä, Chrystelle Colas, Anneke Lucassen, Allan D. Spigelman, Youenn Drouet, Elisa J. Cops, Uri Ladabaum, Steve Thibodeau, Jeffrey N. Weitzel, Fiona Lalloo, Patrick J. Morrison, Maurizio Genuardi, Kohji Tanakaya, Patrick M. Lynch, Frederik J. Hes, William D. Foulkes, Carmen Guillén-Ponce, Jenny von Salomé, Emilia Rogoża-Janiszewska, Andrew Latchford, John L. Hopper, Carrie Snyder, Verónica Barca-Tierno, Gabriela Möslein, Lauren M. Gima, Melissa C. Southey, Paul A. James, Marion Dhooge, Claudia Perne, Steven Gallinger, Heather Hampel, Amanda B. Spurdle, Ingrid Winship, Emmanuelle Fourme, Rish K. Pai, Daniela Turchetti, Marta Pineda, Jürgen Weitz, James Hill, Daniel D. Buchanan, Carlos A. Vaccaro, Noralane M. Lindor, Rachel Pearlman, Pål Møller, Christian P. Strassburg, Jane C. Figueiredo, Aída Falcón de Vargas, Silke Zachariae, Karolin Bucksch, Joanne Ngeow, Silke Redler, Henrik Okkels, Maija R.J. Kohonen-Corish, Hans F. A. Vasen, Verena Steinke-Lange, Roselyne Guimbaud, Deepak Vangala, Isabelle Coupier, Nils Rahner, Berrin Tunca, Sanne W. Bajwa-ten Broeke, Niels de Wind, Sophie Lejeune, José Gaston Guillem, Karin Wadt, Polly A. Newcomb, Elke Holinski-Feder, Florencia Neffa, Rodrigo Santa Cruz Guindalini, Paul E. Wise, Julian R. Sampson, Graham Casey, Lene Juel Rasmussen, Rolf H. Sijmons, Tadeusz Dębniak, Ann-Sofie Backman, Joji Utsunomiya, Melyssa Aronson, Aung Ko Win, Yves-Jean Bignon, Judy W. C. Ho, Robyn L. Ward, Mev Dominguez-Valentin, Karolina Malińska, Elizabeth E. Half, John-Paul Plazzer, Marjolijn J. L. Ligtenberg, Rachel Austin, Nicola K. Poplawski, Marcia Cruz-Correa, Nagahide Matsubara, Charlotte Kvist Lautrup, Thomas Hansen, Tatsuro Yamaguchi, Thomas John, David J. Amor, Ilana Solomon, Yun-Hee Choi, Meghan J. van Wanzeele, Rakefet Shtoyerman, Vanessa Huntley, Maartje Nielsen, Deborah Neklason, Kevin J. Monahan, Gülçin Tezcan, Stefan Aretz, Talya Boisjoli, Sophie Giraud, Thierry Frebourg, Christophe Rosty, Heike Görgens, Lone Sunde, Allyson Templeton, Jacob Nattermann, Mala Pande, Joan Brunet, Nancy Uhrhammer, James M. Church, Florencia Spirandelli, Laurent Briollais, James G. Dowty, Jeanette C. Reece, Rachel Susman, Fay Kastrinos, Kirsi Pylvänäinen, Gabriel Capellá, Helène Schuster, Min H. Chew, Markus Loeffler, Christine Lasset, Michael J. Hall, Capuccine Delnatte, Floor A. Duijkers, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Digital Precision Cancer Medicine (iCAN), ATG - Applied Tumor Genomics, HUS Abdominal Center, Clinical sciences, Medical Genetics, Win A.K., Dowty J.G., Reece J.C., Lee G., Templeton A.S., Plazzer J.-P., Buchanan D.D., Akagi K., Aksoy S., Alonso A., Alvarez K., Amor D.J., Ankathil R., Aretz S., Arnold J.L., Aronson M., Austin R., Backman A.-S., Bajwa-ten Broeke S.W., Barca-Tierno V., Barwell J., Bernstein I., Berthet P., Betz B., Bignon Y.-J., Boisjoli T., Bonadona V., Briollais L., Brunet J., Bucksch K., Buecher B., Buettner R., Burn J., Caldes T., Capella G., Caron O., Casey G., Chew M.H., Choi Y.-H., Church J., Clendenning M., Colas C., Cops E.J., Coupier I., Cruz-Correa M., de la Chapelle A., de Wind N., Debniak T., Della Valle A., Delnatte C., Dhooge M., Dominguez-Valentin M., Drouet Y., Duijkers F.A., Engel C., Esperon P., Evans D.G., Falcon de Vargas A., Figueiredo J.C., Foulkes W., Fourme E., Frebourg T., Gallinger S., Garre P., Genuardi M., Gerdes A.-M., Gima L.M., Giraud S., Goodwin A., Gorgens H., Green K., Guillem J., Guillen-Ponce C., Guimbaud R., Guindalini R.S.C., Half E.E., Hall M.J., Hampel H., Hansen T.V.O., Heinimann K., Hes F.J., Hill J., Ho J.W.C., Holinski-Feder E., Hoogerbrugge N., Huneburg R., Huntley V., James P.A., Jensen U.B., John T., Juhari W.K.W., Kalady M., Kastrinos F., Kloor M., Kohonen-Corish M.R., Krogh L.N., Kupfer S.S., Ladabaum U., Lagerstedt-Robinson K., Lalloo F., Lasset C., Latchford A., Laurent-Puig P., Lautrup C.K., Leggett B.A., Lejeune S., LeMarchand L., Ligtenberg M., Lindor N., Loeffler M., Longy M., Lopez F., Lowery J., Lubinski J., Lucassen A.M., Lynch P.M., Malinska K., Matsubara N., Mecklin J.-P., Moller P., Monahan K., Morrison P.J., Nattermann J., Navarro M., Neffa F., Neklason D., Newcomb P.A., Ngeow J., Nichols C., Nielsen M., Nixon D.M., Nogues C., Okkels H., Olschwang S., Pachter N., Pai R.K., Palmero E.I., Pande M., Parry S., Patel S.G., Pearlman R., Perne C., Pineda M., Poplawski N.K., Pylvanainen K., Qiu J., Rahner N., Ramesar R., Rasmussen L.J., Redler S., Reis R.M., Ricciardiello L., Rogoza-Janiszewska E., Rosty C., Samadder N.J., Sampson J.R., Schackert H.K., Schmiegel W., Schulmann K., Schuster H., Scott R., Senter L., Seppala T.T., Shtoyerman R., Sijmons R.H., Snyder C., Solomon I.B., Soto J.L., Southey M.C., Spigelman A., Spirandelli F., Spurdle A.B., Steinke-Lange V., Stoffel E.M., Strassburg C.P., Sunde L., Susman R., Syngal S., Tanakaya K., Tezcan G., Therkildsen C., Thibodeau S., Tomita N., Tucker K.M., Tunca B., Turchetti D., Uhrhammer N., Utsunomiya J., Vaccaro C., van Duijnhoven F.J.B., van Wanzeele M.J., Vangala D.B., Vasen H.F.A., von Knebel Doeberitz M., von Salome J., Wadt K.A.W., Ward R.L., Weitz J., Weitzel J.N., Williams H., Winship I., Wise P.E., Wods J., Woods M.O., Yamaguchi T., Zachariae S., Zahary M.N., Hopper J.L., Haile R.W., Macrae F.A., Moslein G., and Jenkins M.A.

Subjects
0301 basic medicine, Proband, Oncology, Male, Heredity, DNA mismatch repair, [SDV]Life Sciences [q-bio], SUSCEPTIBILITY, Settore MED/03 - GENETICA MEDICA, 0302 clinical medicine, Residence Characteristics, Risk Factors, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], PMS2, ComputingMilieux_MISCELLANEOUS, MLH1, Age Factors, Middle Aged, Penetrance, Lynch syndrome, 3. Good health, Pedigree, Phenotype, 030220 oncology & carcinogenesis, Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis, Female, Adult, medicine.medical_specialty, PENETRANCE, congenital, hereditary, and neonatal diseases and abnormalities, GENES, 3122 Cancers, colorectal cancer, BREAST, Risk Assessment, 03 medical and health sciences, Sex Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Retrospective Studies, business.industry, MUTATIONS, Cancer, medicine.disease, digestive system diseases, MSH2, MSH6, MODEL, INDIVIDUALS, 030104 developmental biology, Lynch Syndrome, Gene-Environment Interaction, business
Abstract

Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

Published
2021
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