Craig C Teerlink1, Jeff Stevens2, Rolando Hernandez3, Julio C Facelli4, Lisa A Cannon-Albright5. 1. Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. Electronic address: craig.teerlink@utah.edu. 2. Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. Electronic address: jstevens@genetics.utah.edu. 3. Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA. Electronic address: Rolando.Hernandez@utah.edu. 4. Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA; Center for Clinical and Translational Science, University of Utah School of Medicine, Salt Lake City, UT 84108, USA. Electronic address: Julio.Facelli@utah.edu. 5. Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT 84148, USA; Huntsman Cancer Institute, Salt Lake City, UT 84112, USA. Electronic address: lisa.albright@utah.edu.
Abstract
BACKGROUND: Germline predisposition variants associated with colorectal cancer (CRC) have been identified but all are not yet identified. We sought to identify the responsible predisposition germline variant in an extended high-risk CRC pedigree that exhibited evidence of linkage to the 18q12.2 region (TLOD = +2.81). METHODS: DNA from two distantly related carriers of the hypothesized predisposition haplotype on 18q12.2 was sequenced to identify candidate variants. The candidate rare variants shared by the related sequenced subjects were screened in 3,094 CRC cases and 5x population-matched controls from UKBiobank to test for association. Further segregation of the variant was tested via Taqman assay in other sampled individuals in the pedigree. RESULTS: Analysis of whole genome sequence data for the two related hypothesized predisposition haplotype carriers, restricted to the shared haplotype boundaries, identified multiple (n = 6) rare candidate non-coding variants that were tested for association with CRC risk in UKBiobank. A rare intronic variant ofCELF4 gene, rs568643870, was significantly associated with CRC (p = 0.004, OR = 5.0), and segregated with CRC in other members of the linked pedigree. CONCLUSION: Evidence of segregation in a high-risk pedigree, case-control association in an external dataset, and identification of additional CRC-affected carriers in the linked pedigree support a role for a rareCELF4 intronic variant in CRC risk.
BACKGROUND: Germline predisposition variants associated with colorectal cancer (CRC) have been identified but all are not yet identified. We sought to identify the responsible predisposition germline variant in an extended high-risk CRC pedigree that exhibited evidence of linkage to the 18q12.2 region (TLOD = +2.81). METHODS: DNA from two distantly related carriers of the hypothesized predisposition haplotype on 18q12.2 was sequenced to identify candidate variants. The candidate rare variants shared by the related sequenced subjects were screened in 3,094 CRC cases and 5x population-matched controls from UKBiobank to test for association. Further segregation of the variant was tested via Taqman assay in other sampled individuals in the pedigree. RESULTS: Analysis of whole genome sequence data for the two related hypothesized predisposition haplotype carriers, restricted to the shared haplotype boundaries, identified multiple (n = 6) rare candidate non-coding variants that were tested for association with CRC risk in UKBiobank. A rare intronic variant ofCELF4 gene, rs568643870, was significantly associated with CRC (p = 0.004, OR = 5.0), and segregated with CRC in other members of the linked pedigree. CONCLUSION: Evidence of segregation in a high-risk pedigree, case-control association in an external dataset, and identification of additional CRC-affected carriers in the linked pedigree support a role for a rareCELF4 intronic variant in CRC risk.
Authors: Alexandre Bureau; Samuel G Younkin; Margaret M Parker; Joan E Bailey-Wilson; Mary L Marazita; Jeffrey C Murray; Elisabeth Mangold; Hasan Albacha-Hejazi; Terri H Beaty; Ingo Ruczinski Journal: Bioinformatics Date: 2014-04-16 Impact factor: 6.937
Authors: S V Tavtigian; J Simard; D H Teng; V Abtin; M Baumgard; A Beck; N J Camp; A R Carillo; Y Chen; P Dayananth; M Desrochers; M Dumont; J M Farnham; D Frank; C Frye; S Ghaffari; J S Gupte; R Hu; D Iliev; T Janecki; E N Kort; K E Laity; A Leavitt; G Leblanc; J McArthur-Morrison; A Pederson; B Penn; K T Peterson; J E Reid; S Richards; M Schroeder; R Smith; S C Snyder; B Swedlund; J Swensen; A Thomas; M Tranchant; A M Woodland; F Labrie; M H Skolnick; S Neuhausen; J Rommens; L A Cannon-Albright Journal: Nat Genet Date: 2001-02 Impact factor: 38.330
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Authors: Bryony A Thompson; Angela K Snow; Cathryn Koptiuch; Wendy K Kohlmann; Ryan Mooney; Sara Johnson; Chad D Huff; Yao Yu; Craig C Teerlink; Bing-Jian Feng; Deborah W Neklason; Lisa A Cannon-Albright; Sean V Tavtigian Journal: Clin Genet Date: 2020-06 Impact factor: 4.296
Authors: Jeroen R Huyghe; Stephanie A Bien; Tabitha A Harrison; Hyun Min Kang; Sai Chen; Stephanie L Schmit; David V Conti; Conghui Qu; Jihyoun Jeon; Christopher K Edlund; Peyton Greenside; Michael Wainberg; Fredrick R Schumacher; Joshua D Smith; David M Levine; Sarah C Nelson; Nasa A Sinnott-Armstrong; Demetrius Albanes; M Henar Alonso; Kristin Anderson; Coral Arnau-Collell; Volker Arndt; Christina Bamia; Barbara L Banbury; John A Baron; Sonja I Berndt; Stéphane Bézieau; D Timothy Bishop; Juergen Boehm; Heiner Boeing; Hermann Brenner; Stefanie Brezina; Stephan Buch; Daniel D Buchanan; Andrea Burnett-Hartman; Katja Butterbach; Bette J Caan; Peter T Campbell; Christopher S Carlson; Sergi Castellví-Bel; Andrew T Chan; Jenny Chang-Claude; Stephen J Chanock; Maria-Dolores Chirlaque; Sang Hee Cho; Charles M Connolly; Amanda J Cross; Katarina Cuk; Keith R Curtis; Albert de la Chapelle; Kimberly F Doheny; David Duggan; Douglas F Easton; Sjoerd G Elias; Faye Elliott; Dallas R English; Edith J M Feskens; Jane C Figueiredo; Rocky Fischer; Liesel M FitzGerald; David Forman; Manish Gala; Steven Gallinger; W James Gauderman; Graham G Giles; Elizabeth Gillanders; Jian Gong; Phyllis J Goodman; William M Grady; John S Grove; Andrea Gsur; Marc J Gunter; Robert W Haile; Jochen Hampe; Heather Hampel; Sophia Harlid; Richard B Hayes; Philipp Hofer; Michael Hoffmeister; John L Hopper; Wan-Ling Hsu; Wen-Yi Huang; Thomas J Hudson; David J Hunter; Gemma Ibañez-Sanz; Gregory E Idos; Roxann Ingersoll; Rebecca D Jackson; Eric J Jacobs; Mark A Jenkins; Amit D Joshi; Corinne E Joshu; Temitope O Keku; Timothy J Key; Hyeong Rok Kim; Emiko Kobayashi; Laurence N Kolonel; Charles Kooperberg; Tilman Kühn; Sébastien Küry; Sun-Seog Kweon; Susanna C Larsson; Cecelia A Laurie; Loic Le Marchand; Suzanne M Leal; Soo Chin Lee; Flavio Lejbkowicz; Mathieu Lemire; Christopher I Li; Li Li; Wolfgang Lieb; Yi Lin; Annika Lindblom; Noralane M Lindor; Hua Ling; Tin L Louie; Satu Männistö; Sanford D Markowitz; Vicente Martín; Giovanna Masala; Caroline E McNeil; Marilena Melas; Roger L Milne; Lorena Moreno; Neil Murphy; Robin Myte; Alessio Naccarati; Polly A Newcomb; Kenneth Offit; Shuji Ogino; N Charlotte Onland-Moret; Barbara Pardini; Patrick S Parfrey; Rachel Pearlman; Vittorio Perduca; Paul D P Pharoah; Mila Pinchev; Elizabeth A Platz; Ross L Prentice; Elizabeth Pugh; Leon Raskin; Gad Rennert; Hedy S Rennert; Elio Riboli; Miguel Rodríguez-Barranco; Jane Romm; Lori C Sakoda; Clemens Schafmayer; Robert E Schoen; Daniela Seminara; Mitul Shah; Tameka Shelford; Min-Ho Shin; Katerina Shulman; Sabina Sieri; Martha L Slattery; Melissa C Southey; Zsofia K Stadler; Christa Stegmaier; Yu-Ru Su; Catherine M Tangen; Stephen N Thibodeau; Duncan C Thomas; Sushma S Thomas; Amanda E Toland; Antonia Trichopoulou; Cornelia M Ulrich; David J Van Den Berg; Franzel J B van Duijnhoven; Bethany Van Guelpen; Henk van Kranen; Joseph Vijai; Kala Visvanathan; Pavel Vodicka; Ludmila Vodickova; Veronika Vymetalkova; Korbinian Weigl; Stephanie J Weinstein; Emily White; Aung Ko Win; C Roland Wolf; Alicja Wolk; Michael O Woods; Anna H Wu; Syed H Zaidi; Brent W Zanke; Qing Zhang; Wei Zheng; Peter C Scacheri; John D Potter; Michael C Bassik; Anshul Kundaje; Graham Casey; Victor Moreno; Goncalo R Abecasis; Deborah A Nickerson; Stephen B Gruber; Li Hsu; Ulrike Peters Journal: Nat Genet Date: 2018-12-03 Impact factor: 41.307