title: Genomic Landscape of Colorectal Mucosa and Adenomas.
abstract: The molecular basis of the adenoma-to-carcinoma transition has been deduced using comparative analysis of genetic alterations observed through the sequential steps of intestinal carcinogenesis. However, comprehensive genomic analyses of adenomas and at-risk mucosa are still lacking. Therefore, our aim was to characterize the genomic landscape of colonic at-risk mucosa and adenomas. We analyzed the mutation profile and copy number changes of 25 adenomas and adjacent mucosa from 12 familial adenomatous polyposis patients using whole-exome sequencing and validated allelic imbalances (AI) in 37 adenomas using SNP arrays. We assessed for evidence of clonality and performed estimations on the proportions of driver and passenger mutations using a systems biology approach. Adenomas had lower mutational rates than did colorectal cancers and showed recurrent alterations in known cancer driver genes (APC, KRAS, FBXW7, TCF7L2) and AIs in chromosomes 5, 7, and 13. Moreover, 80% of adenomas had somatic alterations in WNT pathway genes. Adenomas displayed evidence of multiclonality similar to stage I carcinomas. Strong correlations between mutational rate and patient age were observed in at-risk mucosa and adenomas. Our data indicate that at least 23% of somatic mutations are present in at-risk mucosa prior to adenoma initiation. The genomic profiles of at-risk mucosa and adenomas illustrate the evolution from normal tissue to carcinoma via greater resolution of molecular changes at the inflection point of premalignant lesions. Furthermore, substantial genomic variation exists in at-risk mucosa before adenoma formation, and deregulation of the WNT pathway is required to foster carcinogenesis. Cancer Prev Res; 9(6); 417-27. ©2016 AACR.
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ester
authors.initials: E
authors.lastname: Borras
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: F Anthony
authors.initials: FA
authors.lastname: San Lucas
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kyle
authors.initials: K
authors.lastname: Chang
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ruoji
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gita
authors.initials: G
authors.lastname: Masand
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jerry
authors.initials: J
authors.lastname: Fowler
authors.affiliation: Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Mork
authors.affiliation: Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Y Nancy
authors.initials: YN
authors.lastname: You
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Melissa W
authors.initials: MW
authors.lastname: Taggart
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Florencia
authors.initials: F
authors.lastname: McAllister
authors.affiliation: Immunobiology & Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
authors.forename: David A
authors.initials: DA
authors.lastname: Jones
authors.affiliation: Avera Institute for Human Genetics, Sioux Falls, South Dakota.
authors.forename: Gareth E
authors.initials: GE
authors.lastname: Davies
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.affiliation: Avera Institute for Human Genetics, Sioux Falls, South Dakota.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Ehli
authors.affiliation: Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Lynch
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ernest T
authors.initials: ET
authors.lastname: Hawk
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, Barcelona, Spain.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capella
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Paul
authors.initials: P
authors.lastname: Scheet
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas. Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. evilar@mdanderson.org.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Vilar
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology*; D008297:Male; D060449:Wnt Signaling Pathway / Q000235:genetics