Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer

Abstract

Metastasis is the main cause of mortality in patients with colorectal cancer. However, most of the targeted therapies and predictive molecular biomarkers were developed based mainly on primary tumors. The current study was conducted to determine the degree of discordance between potential predictive and/or prognostic molecular markers in primary colorectal tumors and corresponding metastases, as this could have an impact on the efficacy of targeted therapies in the advanced colorectal cancer. KRAS, PIK3CA and BRAF mutations were determined by Sanger sequencing and mutant-enriched polymerase chain reaction (PCR) assays in 83 paired samples, MET gene copy number by quantitative PCR in 59, MET expression by immunohistochemistry in 73 and nuclear and cytoplasmic expression of PTEN by immunohistochemistry in 78 and 71 pairs, respectively. A certain degree of discordance between primary tumors and corresponding metastases was demonstrated for all examined biomarkers except BRAF mutations. PIK3CA exon 9 mutations in primary tumors and loss of PTEN nuclear expression in metastases correlated with KRAS mutations. KRAS wild-type status in primary tumors was associated with loss of PTEN cytoplasmic expression and high gene copy number of MET. Survival and clinical data were available for 68 patients. The multiple regression analysis revealed that the right-sided tumor localization and overexpression of MET were associated with shorter overall survival.

FOLFIRI and Cetuximab Every Second Week for First-Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer According to Phosphatase and Tensin Homolog Expression: A Phase II Study

“…It has been suggested that only PIK3CA mutations in exon 20 negatively affect the efficacy of EGFR-targeted therapies in patients with KRAS WT. 26 Although our findings clearly show our study was underpowered to detect a prognostic effect of PIK3CA mutations, they also lend support to a previous hypothesis, 27 suggesting that PIK3CA mutation in exon 9 segregates with KRAS mutations; the latter was an exclusion criterion for enrollment into the study.…”

Hypomethylation of long interspersed nuclear element-1 (LINE-1) leads to activation of proto-oncogenes in human colorectal cancer metastasis

“…Since MET gene amplification in CRC has been previously reported,39 42 43 we also analysed MET gene copy number variations in CRC cell lines as well as NM, PC and LM tissues. Although MET expression was upregulated in MSS cell lines and 5-aza-dC-treated cell lines, MET gene copy number was not significantly different between MSI and MSS cell lines, as well as between CRC cell lines treated with the 5-aza-dC and non-treated cells (see online supplementary figure S6A).…”

“…Interestingly, neither MET host promoter methylation nor the host MET transcript correlated with MET protein expression; rather it was regulated by the methylation status of the LINE-1 element. With regards to the activation mechanism of MET expression in CRC, MET gene amplification has been reported previously,39 42 43 but there has been a lack of consensus on copy number variations and disease pathogenesis due to differences in analytical methods and the MET gene locus interrogated in these previous articles. In our study, MET gene copy numbers were significantly higher in primary CRC and liver metastasis compared with normal mucosa, while no significant differences were observed between matched primary CRC and liver metastasis.…”

KRAS Genotypic Changes of Circulating Tumor Cells during Treatment of Patients with Metastatic Colorectal Cancer

“…Several studies have shown discordant mutation status between primary tumors and corresponding metastasis in a proportion (5%–30%) of CRC patients [3], [4], [5], [6]. Furthermore, recent studies suggest that acquired resistance is partly achieved by the selection of pre-existing minor sub-clones harboring mutations conferring resistance to anti-EGFR therapy [7], [8].…”