| Abstract |
Colorectal cancer remains a major cause of cancer mortality in Europe in both men and women. Despite the current high incidence and mortality, both declined the last 40 years in the Western world. Cancer prevention through screening tests and better treatment modalities are thought to be the major factors of this improvement. Furthermore, it was shown that patients with high-risk stage II and stage III colon cancer (CC) who received treatment that adhered to National Comprehensive Cancer Network guidelines had a survival benefit.
For stage III disease, combination chemotherapy with a backbone of fluoropyrimidine and oxaliplatin (FOLFOX, CAPOX) is the current standard of care, since it leads to prolongation of both disease-free survival (DFS) and overall survival (OS). The results for addition of Oxaliplatin in OS and DFS for patients with stage II CC with high risk features (such as T4 tumors, obstruction or perforation and vessel invasion) showed a marginal but significant. Despite that, it has long been recognized patients’ individual risk of recurrence varies widely even in patients with same stage in CC. Since today, microsatellite instability (MSI) status is the only biomarker used in daily clinical practice. Project goals and expected results are to investigate specific gene signatures related with increased risk of recurrence and death from the disease, as well as predict and assess response to the “standard adjuvant treatment” of the 5FU combined with LOHP. Secondly, to determine and develop a gene expression profile in proportion with KRAS and BRAF mutational status and likewise with Microsatellite Instability (MSI). Also, to study the expression of genes associated either with the increase of metastatic potential such as NEDD9, PKM2, cMYC or with resistance to LOHP and 5FU such as ERCC1 and TS, respectively, in neoplasm’s that present or not the LKB1 loss of expression or KRAS, BRAF mutations. Finally, to study the genetic mechanism of LKB1 loss (loss of heterozygosity) in sporadic colon cancer. Formalin-fixed, paraffin-embedded (FFPE) tissues from 262 consecutive patients with histologically confirmed stage-II/III CC (group A), 118 metastatic CRC (mCRC) patients treated with oxaliplatin-based chemotherapy (group B) and 104 mCRC patients treated with FOLFIRI (group C), were collected and the mRNA expression levels of the PKM2, ERCC1, cMYC, TS were analyzed by RT-qPCR. In addition, KRAS and BRAF mutations were analyzed by Sanger sequencing. Furthermore, the protein expression of LKB1 and MSI status analyzed, only for stage-II/III CC patients.
High PKM2 mRNA expression was correlated with left-sided located primaries, high-grade tumors, microsatellite-stable tumors, pericolic lymph nodes involvement and cMYC mRNA expression. High PKM2mRNA expression was correlated with significantly lower Disease Free Survival (DFS) and Overall Survival in group-A patients. Similarly, PKM2mRNA expression was associated with significantly decreased Progression Free Survival (PFS) and OS in the group-B. In the contrary, no significant association for the PKM2mRNA expression has been observed with either PFS or OS in group-C. To conclude, the current study provides the evidence for the predictive significance of PKM2mRNA expression oxaliplatin-based treatment resistance, and the findings merits validation in a larger prospective cohort.
Last but not least, LKB1 expression loss was observed in 117 patients (group A) and correlated with right-sided located primaries, pericolic lymph nodes involvement, BRAFV600E mutations and TS mRNA expression. Patients with LKB1 expression loss experienced significantly lower DFS and OS compared to patients with LKB1expressing tumors. Multivariate analysis revealed LKB1 expression loss as independent prognostic factor for both decreased DFS and decreased OS. Therefore, loss of tumoral LKB1 protein expression constitutes an adverse prognostic factor in patients with operable CC.
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