BACKGROUND AND OBJECTIVE: Progression of a colorectal adenoma to invasive cancer occurs in a minority of adenomas and is the most crucial step in colorectal cancer pathogenesis. In the majority of cases, this is associated with gain of a substantial part of chromosome 20q, indicating that multiple genes on the 20q amplicon may drive carcinogenesis. The aim of this study was to identify genes located on the 20q amplicon that promote progression of colorectal adenoma to carcinoma. DESIGN: Functional assays were performed for 32 candidate driver genes for which a positive correlation between 20q DNA copy number and mRNA expression had been demonstrated. Effects of gene knockdown on cell viability, anchorage-independent growth, and invasion were analysed in colorectal cancer cell lines with 20q gain. Colorectal tumour protein expression was examined by immunohistochemical staining of tissue microarrays. RESULTS: TPX2, AURKA, CSE1L, DIDO1, HM13, TCFL5, SLC17A9, RBM39 and PRPF6 affected cell viability and/or anchorage-independent growth. Chromosome 20q DNA copy number status correlated significantly with TPX2 and AURKA protein levels in a series of colorectal adenomas and carcinomas. Moreover, downmodulation of TPX2 and AURKA was shown to inhibit invasion. CONCLUSION: These data identify TPX2 (20q11) and AURKA (20q13.2) as two genes located on distinct regions of chromosome 20q that promote 20q amplicon-driven progression of colorectal adenoma to carcinoma. Therefore the selection advantage imposed by 20q gain in tumour progression is achieved by gain-of-function of multiple cancer-related genes-knowledge that can be translated into novel tests for early diagnosis of progressive adenomas.
BACKGROUND AND OBJECTIVE: Progression of a colorectal adenoma to invasive cancer occurs in a minority of adenomas and is the most crucial step in colorectal cancer pathogenesis. In the majority of cases, this is associated with gain of a substantial part of chromosome 20q, indicating that multiple genes on the 20q amplicon may drive carcinogenesis. The aim of this study was to identify genes located on the 20q amplicon that promote progression of colorectal adenoma to carcinoma. DESIGN: Functional assays were performed for 32 candidate driver genes for which a positive correlation between 20q DNA copy number and mRNA expression had been demonstrated. Effects of gene knockdown on cell viability, anchorage-independent growth, and invasion were analysed in colorectal cancer cell lines with 20q gain. Colorectal tumour protein expression was examined by immunohistochemical staining of tissue microarrays. RESULTS:TPX2, AURKA, CSE1L, DIDO1, HM13, TCFL5, SLC17A9, RBM39 and PRPF6 affected cell viability and/or anchorage-independent growth. Chromosome 20q DNA copy number status correlated significantly with TPX2 and AURKA protein levels in a series of colorectal adenomas and carcinomas. Moreover, downmodulation of TPX2 and AURKA was shown to inhibit invasion. CONCLUSION: These data identify TPX2 (20q11) and AURKA (20q13.2) as two genes located on distinct regions of chromosome 20q that promote 20q amplicon-driven progression of colorectal adenoma to carcinoma. Therefore the selection advantage imposed by 20q gain in tumour progression is achieved by gain-of-function of multiple cancer-related genes-knowledge that can be translated into novel tests for early diagnosis of progressive adenomas.
Authors: Galina A Stepanyuk; Pedro Serrano; Eigen Peralta; Carol L Farr; Herbert L Axelrod; Michael Geralt; Debanu Das; Hsiu-Ju Chiu; Lukasz Jaroszewski; Ashley M Deacon; Scott A Lesley; Marc-André Elsliger; Adam Godzik; Ian A Wilson; Kurt Wüthrich; Daniel R Salomon; James R Williamson Journal: Acta Crystallogr D Struct Biol Date: 2016-03-24 Impact factor: 7.652
Authors: Ryan N Ptashkin; Carlos Pagan; Rona Yaeger; Sumit Middha; Jinru Shia; Kevin P O'Rourke; Michael F Berger; Lu Wang; Robert Cimera; Jiajing Wang; David S Klimstra; Leonard Saltz; Marc Ladanyi; Ahmet Zehir; Jaclyn F Hechtman Journal: Mol Cancer Res Date: 2017-02-09 Impact factor: 5.852
Authors: Lenora W M Loo; Maarit Tiirikainen; Iona Cheng; Annette Lum-Jones; Ann Seifried; James M Church; Robert Gryfe; Daniel J Weisenberger; Noralane M Lindor; Steven Gallinger; Robert W Haile; David J Duggan; Stephen N Thibodeau; Graham Casey; Loïc Le Marchand Journal: Genes Chromosomes Cancer Date: 2013-01-23 Impact factor: 5.006
Authors: Giulia Bertolin; Anne-Laure Bulteau; Marie-Clotilde Alves-Guerra; Agnes Burel; Marie-Thérèse Lavault; Olivia Gavard; Stephanie Le Bras; Jean-Philippe Gagné; Guy G Poirier; Roland Le Borgne; Claude Prigent; Marc Tramier Journal: Elife Date: 2018-08-02 Impact factor: 8.140