Gene‐dosage dependent overexpression at the 13q amplicon identifies DIS3 as candidate oncogene in colorectal cancer progression

Abstract

Colorectal cancer (CRC) development is in most cases marked by the accumulation of genomic alterations including gain of the entire q-arm of chromosome 13. This aberration occurs in 40%-60% of all CRC and is associated with progression from adenoma to carcinoma. To date, little is known about the effect of the 13q amplicon on the expression of the therein located genes and their functional relevance. We therefore aimed to identify candidate genes at the 13q amplicon that contribute to colorectal adenoma to carcinoma progression in a gene dosage-dependent manner. Integrative analysis of whole genome expression and DNA copy number signatures resulted in the identification of 36 genes on 13q of which significant overexpression in carcinomas compared with adenomas was linked to a copy number gain. Five genes showing high levels of overexpression in carcinomas versus adenomas were further tested by quantitative reverse transcription-PCR in two independent sample sets of colorectal tumors (n = 40 and n = 47). DIS3 and LRCH1 revealed significant overexpression in carcinomas compared with adenomas in a 13q gain dependent manner. Silencing of DIS3 affected important tumorigenic characteristics such as viability, migration, and invasion. In conclusion, significant overexpression of DIS3 and LRCH1 associated with adenoma to carcinoma progression is linked to the CRC specific gain of 13q. The functional relevance of this copy number aberration was corroborated for DIS3, thereby identifying this gene as novel candidate oncogene contributing to the 13q-driven adenoma to carcinoma progression.

Genome-wide DNA methylation analysis reveals a prognostic classifier for non-metastatic colorectal cancer (ProMCol classifier)

“…The same applies to the CpG site (cg01131395) within the gene LRCH1 that is located on chromosome 13q, where frequent aberrations associated with the progression from colorectal adenoma to carcinoma have been identified before 39 40. Increased LRCH1 messenger RNA (mRNA) expression has been observed in carcinomas in comparison with adenomas 41. Assuming a direct link between epigenetic regulation and gene expression, this finding is in line with our observation of lower methylation at this specific CpG site being associated with poorer prognosis.…”

Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors

“…Recurrent amplification-dependent overexpression of AXL , which encodes a receptor tyrosine kinase, was identified in two sarcoma samples. Among the 16 genes, AXL 32 and DIS3 33 have been previously reported to be associated with oncogenesis.…”

“…Sixteen genes ( AXIN1 , AXL , CD70 , CNKSR1 , DIS3 , DST , EZH1 , FAM175A , FLCN , FOXO1 , HAU3 , MTR , PER1 , PIK3CB , TSC2 , and ZNF384 ) were identified only in the 327 tumors that had undetermined drivers after the initial analyses. Of these, AXL and DIS3 have previously been suggested to have oncogenic functions 32, 33 . Recurrent amplification-dependent overexpression of AXL was observed only in two sarcomas (myxofibrosarcoma and leiomyosarcoma).…”

Molecular characterization of colorectal adenomas reveals POFUT1 as a candidate driver of tumor progression

“…Pairwise correlation analysis was performed between DNA copy number, RNA and protein expression for colorectal adenomas and CRCs. 27,29 Other genomic regions with the highest number of perturbed genes considered almost all chromosomes involved in the CAEs. S6 and Table S8).…”