TPX2 and AURKA promote 20q amplicon-driven colorectal adenoma to carcinoma progression.
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.


METHODS
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.


CONCLUSIONS
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.
VU University Medical Center, Department of Pathology, De Boelelaan 1117, Amsterdam, The Netherlands. rja.fijneman@vumc.nl
Anke H
AH
Sillars-Hardebol
Beatriz
B
Carvalho
Marianne
M
Tijssen
Jeroen A M
JA
Beliën
Meike
M
de Wit
Pien M
PM
Delis-van Diemen
Fredrik
F
Pontén
Mark A
MA
van de Wiel
Remond J A
RJ
Fijneman
Gerrit A
GA
Meijer
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001707:Biopsy, Needle; D018797:Cell Cycle Proteins / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D012334:RNA, Neoplasm; C122167:TPX2 protein, human; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases