Distinct gene expression profiles of proximal and distal colorectal cancer: implications for cytotoxic and targeted therapy

Abstract

Colorectal cancer (CRC) is a heterogeneous disease with genetic profiles and clinical outcomes dependent on the anatomic location of the primary tumor. How location impacts the molecular makeup of a tumor and how prognostic and predictive biomarkers differ between proximal versus distal colon cancers is not well established. We investigated the associations between tumor location, KRAS and BRAF mutation status, and the mRNA expression of proteins involved in major signaling pathways, including tumor growth (EGFR), angiogenesis (VEGFR2), DNA repair (ERCC1) and fluoropyrimidine metabolism (TS). FFPE tumor specimens from 431 advanced CRC patients were analyzed. The presence of 7 different KRAS base substitutions and the BRAF V600E mutation was determined. ERCC1, TS, EGFR and VEGFR2 mRNA expression levels were detected by RT-PCR. BRAF mutations were significantly more common in the proximal colon (p<0.001), whereas KRAS mutations occurred at similar frequencies throughout the colorectum. Rectal cancers had significantly higher ERCC1 and VEGFR2 mRNA levels compared to distal and proximal colon tumors (p=0.001), and increased TS levels compared to distal colon cancers (p=0.02). Mutant KRAS status was associated with lower ERCC1, TS, EGFR, and VEGFR2 gene expression in multivariate analysis. In a subgroup analysis, this association remained significant for all genes in the proximal colon and for VEGFR2 expression in rectal cancers. The mRNA expression patterns of predictive and prognostic biomarkers as well as associations with KRAS and BRAF mutation status depend on primary tumor location. Prospective studies are warranted to confirm these findings and determine the underlying mechanisms.

Correlation betweenDPYDgene variation andKRASwild type status in colorectal cancer

“…The study of Maus et al ,24 which is comparable to our study, revealed higher TS expression levels in rectal compared with distal colon cancer. Therefore, we searched for a possible association between DPYD variants and clinicopathological parameters.…”

“…To the best of our knowledge, these correlations have not been reported previously. However, polymorphisms and low mRNA expression of thymidylate synthase (TS), which is another enzyme with known impact on response and toxicity to 5-FU chemotherapy in patients with CRC,21–23 were found to be associated with mutant KRAS 24. This finding and our results point to a possible interaction between tumour-specific markers and host-specific factors.…”

Prognostic Implication of KRAS Status after Hepatectomy for Colorectal Liver Metastases Varies According to Primary Colorectal Tumor Location

“…Previous studies support the concept that primary tumor factors can drive prognosis after resection of metastatic 29 Of note, several investigators have reported on methylation differences across tumor sites and specifically that CpG island methylator phenotype is more common in RS CRC. 30,31 Conversely, CRC with a LS origin has been associated with higher levels of epiregulin and amphiregulin that, in turn, may confer a more indolent biologic behavior in KRAS tumors.…”

“…30,31 Conversely, CRC with a LS origin has been associated with higher levels of epiregulin and amphiregulin that, in turn, may confer a more indolent biologic behavior in KRAS tumors. 29 Several limitations should be considered when interpreting the data. As with all retrospective analyses, some bias likely occurred in the selection of patients for surgery.…”

NDC80 promotes proliferation and metastasis of colon cancer cells

“…This approach is effective for patients in the early stages of this disease, but achieves poor outcomes for those with advanced cancer and microcarcinoma. With the development of molecular biology and related sciences, gene targeting therapy has become a research topic of significant interest in tumor treatment Maus et al, 2015). Gene targeting relies on the selection of a gene for treatment, therefore, the identification of a specific target affecting tumors is important.…”