Colorectal carcinoma is one of the most common cancers in the western world, being the third most common cause of cancer-related morbidity and mortality. The outcome of patients with metastatic colorectal carcinoma (mCRC) following first line therapy, especially with a Kras mutation is poor with median survival of less than one year. The purpose of this study was to identify therapeutically actionable somatic events in mCRC patient samples, so as to obtain select targeted treatment strategies for individual patients. Fresh frozen needle biopsies of liver metastases were collected from three mCRC patients along with whole blood for the extraction of constitutional DNA. All patients had greater than 2 prior regimens and had known K-ras mutations. Whole genome sequencing was performed using Illumina paired-end chemistry on HiSeq2000 sequencing system, which yielded coverage of greater than 30X for both the normal and tumor samples. Somatic genomic alterations (point mutations and indels, copy number alterations, translocations and rearrangements) were analyzed using our custom pipeline for paired analysis. We found that all 3 tumor samples had KRAS mutations, while 2 samples had mutations in the APC gene and the PIK3CA gene. Other genes with therapeutic implications in single tumor samples were INPPL1, INPP4B and SMAD4. No EGFR amplifications were detected in our sample set. Pathway analysis revealed K-RAS regulation and apoptosis and survival pathways in these tumor samples. Analysis of paired-end data from these three tumors did not reveal the presence of translocations at the recently discovered TCF7L2 locus (Bass et al, Nature Genetics, 2011). The concomitant mutations in MAPK (KRAS) and PI3K (PIK3CA, INPPL1, INPP4B) pathways suggest that combination therapies might be required for effective treatment of these tumors. By harnessing the power of Next-Gen Sequencing, our study has revealed a series of therapeutically actionable events in mCRC that might provide insights into treating these difficult to treat advanced tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5072. doi:1538-7445.AM2012-5072