by ecancer reporter Janet Fricker

In the latest results from The Cancer Genome Atlas Network (TGGA) 24 genes have been found to be significantly mutated in colorectal carcinoma (CRC), reports “Nature”.

The TCGA, launched in 2006, is a joint project of the National Cancer Institute and National Human Genome Research Institute in the US to profile genomic changes in 20 different cancer types.

To this end the initiative has brought together scientists from a wide range of disciplines and research institutes both to provide tissue samples, and perform gene expression analysis, DNA sequencing and other analyses. The cancers investigated have been selected both due to their public health impact and poor prognosis, with results on glioblastoma and ovarian cancer already published.

In the current study to characterize somatic alterations in CRC the team conducted a genome-scale analysis of 276 samples analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of 97 of these samples underwent whole genome sequencing.

Results showed that in total 16% of CRCs were hypermutated and that three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase e (POLE) mutations.

Furthermore, 24 genes were found to be significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations the team showed frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations included potentially drug-targetable amplifications of ERBB2 and a newly discovered amplification of IGF2.

“Our data suggest a number of therapeutic approaches to CRC. Included are WNT-signalling inhibitors and small-molecule b-catenin inhibitors, which are showing initial promise.  We find that several proteins in the RTK–RAS and PI3K pathways, including IGF2, IGFR, ERBB2, ERBB3, MEK, AKT and MTOR could be targets for Inhibition,” write the authors.

Reference

The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature  doi:10.1038/nature11252