The Genomic Environment of Mutated and / Double Mutated Colorectal Cancers.

BACKGROUND

Colorectal cancer represents the most prevalent gastrointestinal malignancy. Prognosis of metastatic disease has improved in recent years with the introduction of effective systemic therapies, but mean survival remains in the range of two to three years. Targeted therapies based on specific molecular alterations in sub-sets of colorectal cancers have the potential of contributing to therapeutic progress. and are oncogenic kinases commonly mutated in colorectal cancers and can be targeted through small molecule kinase inhibitors.

METHODS

Clinical and genomic data from two extensive series of colorectal cancers were interrogated to define the molecular characteristics of cancers with mutations with and without concomitant mutations in .

RESULTS

Colorectal cancers that are and double mutants represent a small minority of about 5% of colorectal cancers in the two examined series of mostly localized disease. They also represent about one third of all mutated colorectal cancers. Most mutations in are classic V600E mutations. A high prevalence of MSI and CIMP is observed in mutated colorectal cancers with or without mutations. Mutations in tumor suppressors and display a higher prevalence in mutated cancers. The prognosis of mutated colorectal cancers with or without mutations is not significantly different than counterparts with wild type . This contrasts with the known adverse prognostic effect of in metastatic disease and relates to the different prevalence of MSI in mutant localized versus metastatic colorectal cancers.

CONCLUSIONS

mutations are the defining molecular alterations in double mutant and colorectal cancers as determined by increased MSI and CIMP in subsets with and without mutations. Moreover, mutated cancers with and without mutations are characterized by the absence of mutations and a lower prevalence of APC mutations than wild type counterparts. Mismatch-repair-associated gene mutations display higher frequencies in mutated colorectal cancers. Despite the absence of prognosis implications of mutations in the studied cohorts of mostly localized cancers, such mutations could be prognostic in certain subsets. The presence of mutations in other genes, such as and high MSI status present opportunities for combination therapies.