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2. Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer

Author

Bien, S.A. Su, Y.-R. Conti, D.V. Harrison, T.A. Qu, C. Guo, X. Lu, Y. Albanes, D. Auer, P.L. Banbury, B.L. Berndt, S.I. Bézieau, S. Brenner, H. Buchanan, D.D. Caan, B.J. Campbell, P.T. Carlson, C.S. Chan, A.T. Chang-Claude, J. Chen, S. Connolly, C.M. Easton, D.F. Feskens, E.J.M. Gallinger, S. Giles, G.G. Gunter, M.J. Hampe, J. Huyghe, J.R. Hoffmeister, M. Hudson, T.J. Jacobs, E.J. Jenkins, M.A. Kampman, E. Kang, H.M. Kühn, T. Küry, S. Lejbkowicz, F. Le Marchand, L. Milne, R.L. Li, L. Li, C.I. Lindblom, A. Lindor, N.M. Martín, V. McNeil, C.E. Melas, M. Moreno, V. Newcomb, P.A. Offit, K. Pharaoh, P.D.P. Potter, J.D. Qu, C. Riboli, E. Rennert, G. Sala, N. Schafmayer, C. Scacheri, P.C. Schmit, S.L. Severi, G. Slattery, M.L. Smith, J.D. Trichopoulou, A. Tumino, R. Ulrich, C.M. van Duijnhoven, F.J.B. Van Guelpen, B. Weinstein, S.J. White, E. Wolk, A. Woods, M.O. Wu, A.H. Abecasis, G.R. Casey, G. Nickerson, D.A. Gruber, S.B. Hsu, L. Zheng, W. Peters, U.

Abstract

Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10− 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10− 4, replication P = 6.7 × 10− 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci. © 2019, The Author(s).

Published
2019

3. Discovery of common and rare genetic risk variants for colorectal cancer

Author

Huyghe, J.R. Bien, S.A. Harrison, T.A. Kang, H.M. Chen, S. Schmit, S.L. Conti, D.V. Qu, C. Jeon, J. Edlund, C.K. Greenside, P. Wainberg, M. Schumacher, F.R. Smith, J.D. Levine, D.M. Nelson, S.C. Sinnott-Armstrong, N.A. Albanes, D. Alonso, M.H. Anderson, K. Arnau-Collell, C. Arndt, V. Bamia, C. Banbury, B.L. Baron, J.A. Berndt, S.I. Bézieau, S. Bishop, D.T. Boehm, J. Boeing, H. Brenner, H. Brezina, S. Buch, S. Buchanan, D.D. Burnett-Hartman, A. Butterbach, K. Caan, B.J. Campbell, P.T. Carlson, C.S. Castellví-Bel, S. Chan, A.T. Chang-Claude, J. Chanock, S.J. Chirlaque, M.-D. Cho, S.H. Connolly, C.M. Cross, A.J. Cuk, K. Curtis, K.R. de la Chapelle, A. Doheny, K.F. Duggan, D. Easton, D.F. Elias, S.G. Elliott, F. English, D.R. Feskens, E.J.M. Figueiredo, J.C. Fischer, R. FitzGerald, L.M. Forman, D. Gala, M. Gallinger, S. Gauderman, W.J. Giles, G.G. Gillanders, E. Gong, J. Goodman, P.J. Grady, W.M. Grove, J.S. Gsur, A. Gunter, M.J. Haile, R.W. Hampe, J. Hampel, H. Harlid, S. Hayes, R.B. Hofer, P. Hoffmeister, M. Hopper, J.L. Hsu, W.-L. Huang, W.-Y. Hudson, T.J. Hunter, D.J. Ibañez-Sanz, G. Idos, G.E. Ingersoll, R. Jackson, R.D. Jacobs, E.J. Jenkins, M.A. Joshi, A.D. Joshu, C.E. Keku, T.O. Key, T.J. Kim, H.R. Kobayashi, E. Kolonel, L.N. Kooperberg, C. Kühn, T. Küry, S. Kweon, S.-S. Larsson, S.C. Laurie, C.A. Le Marchand, L. Leal, S.M. Lee, S.C. Lejbkowicz, F. Lemire, M. Li, C.I. Li, L. Lieb, W. Lin, Y. Lindblom, A. Lindor, N.M. Ling, H. Louie, T.L. Männistö, S. Markowitz, S.D. Martín, V. Masala, G. McNeil, C.E. Melas, M. Milne, R.L. Moreno, L. Murphy, N. Myte, R. Naccarati, A. Newcomb, P.A. Offit, K. Ogino, S. Onland-Moret, N.C. Pardini, B. Parfrey, P.S. Pearlman, R. Perduca, V. Pharoah, P.D.P. Pinchev, M. Platz, E.A. Prentice, R.L. Pugh, E. Raskin, L. Rennert, G. Rennert, H.S. Riboli, E. Rodríguez-Barranco, M. Romm, J. Sakoda, L.C. Schafmayer, C. Schoen, R.E. Seminara, D. Shah, M. Shelford, T. Shin, M.-H. Shulman, K. Sieri, S. Slattery, M.L. Southey, M.C. Stadler, Z.K. Stegmaier, C. Su, Y.-R. Tangen, C.M. Thibodeau, S.N. Thomas, D.C. Thomas, S.S. Toland, A.E. Trichopoulou, A. Ulrich, C.M. Van Den Berg, D.J. van Duijnhoven, F.J.B. Van Guelpen, B. van Kranen, H. Vijai, J. Visvanathan, K. Vodicka, P. Vodickova, L. Vymetalkova, V. Weigl, K. Weinstein, S.J. White, E. Win, A.K. Wolf, C.R. Wolk, A. Woods, M.O. Wu, A.H. Zaidi, S.H. Zanke, B.W. Zhang, Q. Zheng, W. Scacheri, P.C. Potter, J.D. Bassik, M.C. Kundaje, A. Casey, G. Moreno, V. Abecasis, G.R. Nickerson, D.A. Gruber, S.B. Hsu, L. Peters, U.

Abstract

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10 −8 , bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development. © 2018, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Published
2019

4. Correction to: Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer (Human Genetics, (2019), 138, 4, (307-326), 10.1007/s00439-019-01989-8)

Author

Bien, S.A. Su, Y.-R. Conti, D.V. Harrison, T.A. Qu, C. Guo, X. Lu, Y. Albanes, D. Auer, P.L. Banbury, B.L. Berndt, S.I. Bézieau, S. Brenner, H. Buchanan, D.D. Caan, B.J. Campbell, P.T. Carlson, C.S. Chan, A.T. Chang-Claude, J. Chen, S. Connolly, C.M. Easton, D.F. Feskens, E.J.M. Gallinger, S. Giles, G.G. Gunter, M.J. Hampe, J. Huyghe, J.R. Hoffmeister, M. Hudson, T.J. Jacobs, E.J. Jenkins, M.A. Kampman, E. Kang, H.M. Kühn, T. Küry, S. Lejbkowicz, F. Le Marchand, L. Milne, R.L. Li, L. Li, C.I. Lindblom, A. Lindor, N.M. Martín, V. McNeil, C.E. Melas, M. Moreno, V. Newcomb, P.A. Offit, K. Pharaoh, P.D.P. Potter, J.D. Qu, C. Riboli, E. Rennert, G. Sala, N. Schafmayer, C. Scacheri, P.C. Schmit, S.L. Severi, G. Slattery, M.L. Smith, J.D. Trichopoulou, A. Tumino, R. Ulrich, C.M. van Duijnhoven, F.J.B. Van Guelpen, B. Weinstein, S.J. White, E. Wolk, A. Woods, M.O. Wu, A.H. Abeçasis, G.R. Casey, G. Nickerson, D.A. Gruber, S.B. Hsu, L. Zheng, W. Peters, U.

Abstract

Every author has erroneously been assigned to the affiliation “62”. The affiliation 62 belongs to the author Graham Casey. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Published
2019

5. Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

Author

Cheng, T.H.T., Thompson, D., Painter, J., O'Mara, T., Gorman, M., Martin, L., Palles, C., Jones, A., Buchanan, D.D., Win, A.K., Hopper, J., Jenkins, M., Lindor, N.M., Newcomb, P.A., Gallinger, S., Conti, D., Schumacher, F., Casey, G., Giles, G.G., Pharoah, P., Peto, J., Cox, A., Swerdlow, A., Couch, F., Cunningham, J.M., Goode, E.L., Winham, S.J., Lambrechts, D., Fasching, P., Burwinkel, B., Brenner, H., Brauch, H., Chang-Claude, J., Salvesen, H.B., Kristensen, V., Darabi, H., Li, J., Liu, T., Lindblom, A., Hall, P., Echeverry de Polanco, M., Sans, M., Carracedo, A., Castellvi-Bel, S., Rojas-Martinez, A., Jr, A.S., Teixeira, M.R., Dunning, A.M., Dennis, J., Otton, G., Proietto, T., Holliday, E., Attia, J., Ashton, K., Scott, R.J., McEvoy, M., Dowdy, S.C., Fridley, B.L., Werner, H.M.J., Trovik, J., Njolstad, T.S., Tham, E., Mints, M., Runnebaum, I., Hillemanns, P., Doerk, T., Amant, F., Schrauwen, S., Hein, A., Beckmann, M.W., Ekici, A., Czene, K., Meindl, A., Bolla, M.K., Michailidou, K., Tyrer, J.P., Wang, Q., Ahmed, S., Healey, C.S., Shah, M., Annibali, D., Depreeuw, J., Al-Tassan, N.A., Harris, R., Meyer, B.F., Whiffin, N., Hosking, F.J., Kinnersley, B., Farrington, S.M., Timofeeva, M., Tenesa, A., Campbell, H., Haile, R.W., Hodgson, S., Carvajal-Carmona, L., Cheadle, J.P., Easton, D., Dunlop, M., Houlston, R., Spurdle, A., Tomlinson, I., and Other departments

Subjects
Male, CARCINOMA, MICROSATELLITE INSTABILITY, DNA-POLYMERASE, LOCI, MTHFR C677T, VARIANTS, LYNCH-SYNDROME, Article, BREAST-CANCER, Humans, Genetic Predisposition to Disease, Alleles, Adaptor Proteins, Signal Transducing, RISK, Homeodomain Proteins, Science & Technology, Polymorphism, Genetic, MUTATIONS, Intracellular Signaling Peptides and Proteins, Proteins, Endometrial Neoplasms, Neoplasm Proteins, Multidisciplinary Sciences, Repressor Proteins, Science & Technology - Other Topics, Female, Colorectal Neoplasms, Genome-Wide Association Study
Abstract

High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers. ispartof: Scientific Reports vol:5 pages:17369- ispartof: location:England status: published

Published
2015

7. 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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