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Genomic Landscape of Colorectal Mucosa and Adenomas
Cancer prevention research (Philadelphia, Pa.), 2016-06, Vol.9 (6), p.417-427
Borras, Ester
San Lucas, F Anthony
Chang, Kyle
Zhou, Ruoji
Masand, Gita
Fowler, Jerry
Mork, Maureen E
You, Y Nancy
Taggart, Melissa W
McAllister, Florencia
Jones, David A
Davies, Gareth E
Edelmann, Winfried
Ehli, Erik A
Lynch, Patrick M
Hawk, Ernest T
Capella, Gabriel
Scheet, Paul
Vilar, Eduardo
2016
Details
Autor(en) / Beteiligte
Borras, Ester
San Lucas, F Anthony
Chang, Kyle
Zhou, Ruoji
Masand, Gita
Fowler, Jerry
Mork, Maureen E
You, Y Nancy
Taggart, Melissa W
McAllister, Florencia
Jones, David A
Davies, Gareth E
Edelmann, Winfried
Ehli, Erik A
Lynch, Patrick M
Hawk, Ernest T
Capella, Gabriel
Scheet, Paul
Vilar, Eduardo
Titel
Genomic Landscape of Colorectal Mucosa and Adenomas
Ist Teil von
Cancer prevention research (Philadelphia, Pa.), 2016-06, Vol.9 (6), p.417-427
Ort / Verlag
United States
Erscheinungsjahr
2016
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
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.
Sprache
Englisch
Identifikatoren
ISSN: 1940-6207
eISSN: 1940-6215
DOI: 10.1158/1940-6207.capr-16-0081
Titel-ID: cdi_proquest_miscellaneous_1793905032
Format
–
Schlagworte
Adenoma - genetics
,
Adenoma - pathology
,
Adult
,
Cell Transformation, Neoplastic - genetics
,
Colorectal Neoplasms - genetics
,
Colorectal Neoplasms - pathology
,
DNA Mutational Analysis
,
Female
,
Humans
,
Intestinal Mucosa - pathology
,
Male
,
Wnt Signaling Pathway - genetics
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