Genomic Landscape of Colorectal Mucosa and Adenomas

Abstract

Purpose 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. Experimental Design 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 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. Results Adenomas had lower mutational rates than did colorectal cancers and showed recurrent alterations in known cancer-driver genes (APC, KRAS, FBXW7, TCF7L2) and allelic imbalances 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. Conclusions 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.

Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing

“…Informed consent was obtained from all individuals and the study was approved by the Institutional Review Board. Pathological characterization, tissue preservation, and sample preparation for molecular analyses followed previously reported protocols 40 . Expression data derived from normal left colonic tissue was obtained from a previously published study and was generated from patients undergoing screening colonoscopy with no polyps found on exam 41 (GSE76987).…”

Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and MUTYH-associated Polyposis

“…or FAP-associated colorectal adenomas (37,39) and that are also mutated in sporadic duodenal adenocarcinomas (40,41). They may be mutated later in duodenal tumorigenesis.…”

Future cancer research priorities in the USA: a Lancet Oncology Commission

“…Although the seminal genetic model of tumori-genesis was defined in the colon nearly 30 years ago, 58 limited numbers of adenomas have been analysed by next-generation sequencing. 59 The interaction between immunity and neoplasia is now established as a fundamental principle of cancer development and progression. Premalignant lesions are regions of histologically abnormal tissue that often precede invasive carcinoma.…”