Abstract
The heritability of colorectal cancer (CRC) is incompletely understood, and the contribution of undiscovered rare variants may be important. In search of rare disease-causing variants, we exome sequenced 22 CRC patients who were diagnosed before the age of 40 years. Exome sequencing data from 95 familial CRC patients were available as a validation set. Cases with known CRC syndromes were excluded. All patients were from Finland, a country known for its genetically homogenous population. We searched for rare nonsynonymous variants with allele frequencies below 0.1% in 3,374 Finnish and 58,112 non-Finnish controls. In addition, homozygous and compound heterozygous variants were studied. No genes with rare loss-of-function variants were present in more than one early-onset CRC patient. Three genes (ADAMTS4, CYTL1, and SYNE1) harbored rare loss-of-function variants in both early-onset and familial CRC cases. Five genes with homozygous variants in early-onset CRC cases were found (MCTP2, ARHGAP12, ATM, DONSON, and ROS1), including one gene (MCTP2) with a homozygous splice site variant. All discovered homozygous variants were exclusive to one early-onset CRC case. Independent replication is required to associate the discovered varian...Continue Reading
References
May 21, 1998·The New England Journal of Medicine·L A AaltonenA de la Chapelle
Jul 13, 2000·The New England Journal of Medicine·P LichtensteinK Hemminki
Jan 24, 2002·Proceedings of the National Academy of Sciences of the United States of America·Shaun P ScottMartin F Lavin
Sep 28, 2002·Human Molecular Genetics·Jonathan K Pritchard, Nancy J Cox
Dec 18, 2007·Cell·Klarisa RikovaMichael J Comb
Jan 4, 2008·Cancer Research·Sari TuupanenLauri A Aaltonen
Nov 14, 2008·The New England Journal of Medicine·William D Foulkes
May 19, 2010·Nature Reviews. Genetics·Elizabeth T Cirulli, David B Goldstein
Dec 14, 2011·American Journal of Epidemiology·Steven J LubbeRichard S Houlston
Feb 22, 2012·Science·Daniel G MacArthurChris Tyler-Smith
May 30, 2012·Nature Genetics·Adam KiezunShamil R Sunyaev
Jan 29, 2013·Neuron·Elaine T LimMark J Daly
Mar 30, 2013·Science·O Kilpivaara, L A Aaltonen
Jun 19, 2013·Human Molecular Genetics·Seema R LalaniJohn W Belmont
Aug 31, 2013·PLoS Genetics·Slavé PetrovskiDavid B Goldstein
Oct 23, 2013·PLoS Genetics·Alexandra E GylfeLauri A Aaltonen
Jul 6, 2014·American Journal of Human Genetics·Seunggeung LeeXihong Lin
Citations
Oct 20, 2015·Journal of Affective Disorders·Martin PreisigCaroline L Vandeleur
Jun 10, 2016·Cellular Oncology (Dordrecht)·M M HahnA Geurts van Kessel
Jun 9, 2016·Chinese Journal of Cancer·Vittoria DisciglioLoris De Cecco
Sep 14, 2016·Psychiatry Research·Patricia GassóJosefina Castro-Fornieles
Oct 8, 2016·Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association·Laura Valle
Feb 24, 2016·PLoS Genetics·Richarda M de VoerRoland P Kuiper
Dec 12, 2019·Inflammation·Haiyan XueFengxue Zhu
Jun 14, 2017·Familial Cancer·Naim Abu FrehaZohar Levi
May 16, 2019·Cellular and Molecular Life Sciences : CMLS·Sipin ZhuJiake Xu
Jun 27, 2020·Journal of Clinical Medicine·Mariona TerradasLaura Valle
Nov 25, 2020·International Journal of Molecular Sciences·Iris B A W Te PaskeRicharda M de Voer
Dec 13, 2019·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Anthony M MusolfJoan E Bailey-Wilson
May 30, 2020·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Melissa RotunnoElizabeth M Gillanders
May 8, 2021·Frontiers in Oncology·Zaoqu LiuXinwei Han
Jul 16, 2021·Genetics in Medicine : Official Journal of the American College of Medical Genetics·B DalmassoUNKNOWN MelaNostrum consortia