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1. Rare loss of function variants in candidate genes and risk of colorectal cancer

Author

Benjamin Voight, David Jacobs, Fridtjof Thomas, Sandosh Padmanabhan, Kamakshi Lakshminarayan, James Pankow, Adam Gordon, Christie Ballantyne, Carlos D. Bustamante, Kathryn Lunetta, Brian Shirts, Aaron Quinlan, Michael Konstan, Margaret Rosenfeld, John Carr, John Hardy, Matthew Budoff, Sudha Seshadri, Aaron Chidekel, Bette Caan, William M Gershan, Stephen Rich, John P. Ioannidis, Pamela Schreiner, Robert Wise, and Joshua Akey

Subjects
0301 basic medicine, Oncology, Adult, Male, Candidate gene, medicine.medical_specialty, Adolescent, Colorectal cancer, Biology, Article, 03 medical and health sciences, Deoxyribonuclease (Pyrimidine Dimer), Risk Factors, Internal medicine, Genotype, Genetic variation, Genetics, medicine, Humans, neoplasms, Genetics (clinical), Genetic testing, Aged, Aged, 80 and over, BRCA2 Protein, medicine.diagnostic_test, BRIP1, Family aggregation, Genetic Variation, Middle Aged, medicine.disease, digestive system diseases, Fanconi Anemia Complementation Group Proteins, 030104 developmental biology, Genetic Loci, Cohort, Female, Colorectal Neoplasms, RNA Helicases
Abstract

PURPOSE: Although ~25% of colorectal cancer or polyps (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. METHODS: We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. RESULTS: We found a significant enrichment of PDVs in cases versus controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR=1.9, p=0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p=0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p=0.0001), BRCA2 (p=0.01) and BRIP1 (p=0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. CONCLUSION: These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.

Published
2018

2. Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Author

Robert C. Green, Katrina A.B. Goddard, Gail P. Jarvik, Laura M. Amendola, Paul S. Appelbaum, Jonathan S. Berg, Barbara A. Bernhardt, Leslie G. Biesecker, Sawona Biswas, Carrie L. Blout, Kevin M. Bowling, Kyle B. Brothers, Wylie Burke, Charlisse F. Caga-anan, Arul M. Chinnaiyan, Wendy K. Chung, Ellen W. Clayton, Gregory M. Cooper, Kelly East, James P. Evans, Stephanie M. Fullerton, Levi A. Garraway, Jeremy R. Garrett, Stacy W. Gray, Gail E. Henderson, Lucia A. Hindorff, Ingrid A. Holm, Michelle Huckaby Lewis, Carolyn M. Hutter, Pasi A. Janne, Steven Joffe, David Kaufman, Bartha M. Knoppers, Barbara A. Koenig, Ian D. Krantz, Teri A. Manolio, Laurence McCullough, Jean McEwen, Amy McGuire, Donna Muzny, Richard M. Myers, Deborah A. Nickerson, Jeffrey Ou, Donald W. Parsons, Gloria M. Petersen, Sharon E. Plon, Heidi L. Rehm, J. Scott Roberts, Dan Robinson, Joseph S. Salama, Sarah Scollon, Richard R. Sharp, Brian Shirts, Nancy B. Spinner, Holly K. Tabor, Peter Tarczy-Hornoch, David L. Veenstra, Nikhil Wagle, Karen Weck, Benjamin S. Wilfond, Kirk Wilhelmsen, Susan M. Wolf, Julia Wynn, Joon-Ho Yu, Michelle Amaral, Laura Amendola, Samuel J. Aronson, Shubhangi Arora, Danielle R. Azzariti, Greg S. Barsh, E.M. Bebin, Barbara B. Biesecker, Brian L. Brown, Amber A. Burt, Peter H. Byers, Muge G. Calikoglu, Sara J. Carlson, Nizar Chahin, Kurt D. Christensen, Wendy Chung, Allison L. Cirino, Ellen Clayton, Laura K. Conlin, Greg M. Cooper, David R. Crosslin, James V. Davis, Kelly Davis, Matthew A. Deardorff, Batsal Devkota, Raymond De Vries, Pamela Diamond, Michael O. Dorschner, Noreen P. Dugan, Dmitry Dukhovny, Matthew C. Dulik, Kelly M. East, Edgar A. Rivera-Munoz, Barbara Evans, Jessica Everett, Nicole Exe, Zheng Fan, Lindsay Z. Feuerman, Kelly Filipski, Candice R. Finnila, Kristen Fishler, Bob Ghrundmeier, Karen Giles, Marian J. Gilmore, Zahra S. Girnary, Katrina Goddard, Steven Gonsalves, Adam S. Gordon, Michele C. Gornick, William M. Grady, David E. Gray, Robert Green, Robert S. Greenwood, Amanda M. Gutierrez, Paul Han, Ragan Hart, Patrick Heagerty, Naomi Hensman, Susan M. Hiatt, Patricia Himes, Fuki M. Hisama, Carolyn Y. Ho, Lily B. Hoffman-Andrews, Celine Hong, Martha J. Horike-Pyne, Sara Hull, Seema Jamal, Brian C. Jensen, Steve Joffe, Jennifer Johnston, Dean Karavite, Tia L. Kauffman, Dave Kaufman, Whitley Kelley, Jerry H. Kim, Christine Kirby, William Klein, Bartha Knoppers, Sek Won Kong, Ian Krantz, Joel B. Krier, Neil E. Lamb, Michele P. Lambert, Lan Q. Le, Matthew S. Lebo, Alexander Lee, Kaitlyn B. Lee, Niall Lennon, Michael C. Leo, Kathleen A. Leppig, Katie Lewis, Michelle Lewis, Neal I. Lindeman, Nicole Lockhart, Bob Lonigro, Edward J. Lose, Philip J. Lupo, Laura Lyman Rodriguez, Frances Lynch, Kalotina Machini, Calum MacRae, Daniel S. Marchuk, Josue N. Martinez, Aaron Masino, Heather M. McLaughlin, Carmit McMullen, Piotr A. Mieczkowski, Jeff Miller, Victoria A. Miller, Rajen Mody, Sean D. Mooney, Elizabeth G. Moore, Elissa Morris, Michael Murray, David Ng, Nelly M. Oliver, Will Parsons, Donald L. Patrick, Jeffrey Pennington, Denise L. Perry, Gloria Petersen, Sharon Plon, Katie Porter, Bradford C. Powell, Sumit Punj, Carmen Radecki Breitkopf, Robin A. Raesz-Martinez, Wendy H. Raskind, Dean A. Reigar, Jacob A. Reiss, Carla A. Rich, Carolyn Sue Richards, Christine Rini, Scott Roberts, Peggy D. Robertson, Jill O. Robinson, Marguerite E. Robinson, Myra I. Roche, Edward J. Romasko, Elisabeth A. Rosenthal, Joseph Salama, Maria I. Scarano, Jennifer Schneider, Christine E. Seidman, Bryce A. Seifert, Brian H. Shirts, Lynette M. Sholl, Javed Siddiqui, Elian Silverman, Shirley Simmons, Janae V. Simons, Debra Skinner, Elena Stoffel, Natasha T. Strande, Shamil Sunyaev, Virginia P. Sybert, Jennifer Taber, Deanne M. Taylor, Christian R. Tilley, Ashley Tomlinson, Susan Trinidad, Ellen Tsai, Peter Ubel, Eliezer M. Van Allen, Jason L. Vassy, Pankaj Vats, Victoria L. Vetter, Raymond D. Vries, Sarah A. Walser, Rebecca C. Walsh, Allison Werner-Lin, Jana Whittle, Ben Wilfond, Kirk C. Wilhelmsen, Yaping Yang, Carol Young, and Brian J. Zikmund-Fisher

Subjects
0301 basic medicine, Adult, Evidence-based practice, Biomedical Research, Best practice, Exploratory research, MEDLINE, Genomics, Computational biology, 030105 genetics & heredity, Bioinformatics, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Population Groups, Genetics, Medicine, Genomic medicine, Humans, Genetics(clinical), Exome, Child, Genetics (clinical), Exome sequencing, Medical education, Clinical Trials as Topic, business.industry, Genome, Human, Correction, High-Throughput Nucleotide Sequencing, Human genetics, United States, 3. Good health, National Human Genome Research Institute (U.S.), 030104 developmental biology, Cardiovascular Diseases, Evidence-Based Practice, Human genome, business, Psychology, Software
Abstract

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

Published
2016

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