携带KRAS 13D突变的结直肠癌（CRC）的分子图谱

Background: Colorectal cancer (CRC) is one of the leading causes of cancer related mortality across the world. Approximately 50% of the CRC patients exhibit mutation in the KRAS gene, most frequently found in codons 12 and 13. KRAS 13D mutation tumors are unique in that they are more aggressive and have different treatment response and outcome than tumors with other KRAS gene mutations. This is attributed to the underlying combination of distinct biology. We report a detailed comparative study of stratified KRAS 13D mutant patients with disease, poor outcome, exceptional response and mutant cell lines for distinct co-occurring mutations and gene expression. Methods: RNA-Seq, whole exome sequencing and clinical data of CRC patients with known KRAS mutation type were obtained from Genomic Data Commons (GDC) while CRC cell lines data were obtained from NCBI GEO. The patient dataset included 170 KRAS mutated samples in Cancer Genome Atlas with 31 tumors with KRAS 13 mutations and NCI Exceptional responder's initiative with KRAS mutated samples. Normalized log transformed expression profiles and gene variants were statistically analyzed for differential expression, likelihood ratios, enrichment, correlation, odd ratios, deconvolution and log rank test for outcome using R (v4.5.1) and computing platform provided by GDC. Observations: The KRAS 13 tumors proportionally had higher mutation burden (TMB) and prevalent in ascending colon compared to other location. The KRAS13D tumors were also of mixed CMS (consensus molecular) subtypes. Among the top mutated genes in KRAS mutated tumors there were common co-occurring mutations in both KRAS 12 and KRAS 13 but frequency of mutations in genes RYR2, FAT3, CMSD1 and MUC4 amongst others were enriched more in KRAS 13 mutated tumors. Cell lines expression data identifies specific genes uniquely overexpressed in KRAS 13 mutants and some of them were found to be common with genes over expressed in exceptional responders. The poor outcome patients compared with exceptional responders found differential genes with significance in cellular processes. Log rank test shows few of these genes associated with better or worse outcomes after treatment. Conclusions and ongoing research: We found that a right combination of mutations could give KRAS 13D mutated tumors advantage to become more aggressive, but a background of unique network of gene expression could make the tumors respond well to treatment or resist therapy. We are currently testing the significance of these unique molecular correlates in KRAS 13D patient derived organoids with specific drugs and RAS inhibitor screens to provide insights into resistance and response of some of the KRAS 13D mutated CRC patients.