LGR5 and CD133 as prognostic and predictive markers for fluoropyrimidine-based adjuvant chemotherapy in colorectal cancer.

BACKGROUND: Expression of leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5) gene is associated with a metastatic phenotype and poor prognosis in colorectal cancer (CRC). CD133 expression is a putative cancer stem cell marker and a proposed prognostic marker in CRC, whereas the predictive value of CD133 expression for effect of adjuvant chemotherapy in CRC is unclear. MATERIAL AND METHODS: For the study of LGR5 mRNA and CD133 expression, tissue microarrays from 409 primary CRC stage II and III tumors, where patients had been randomized to adjuvant chemotherapy or surgery only, were available. LGR5 mRNA and CD133 expression were assessed by in situ hybridization (ISH) and immunohistochemistry (IHC), respectively. LGR5 mRNA and CD133 expression as prognostic and predictive markers were evaluated by univariate and multivariate analyses. RESULTS: For all CRC patients, positive LGR5 mRNA and CD133 expression were associated with classic adenocarcinoma histology type (p = 0.001 and p = 0.014, respectively). Positive LGR5 mRNA expression was also associated with smaller tumor diameter for CRC stage II (p = 0.005), but not for CRC stage III (p = 0.054). For CRC stage II, lack of LGR5 mRNA expression was associated with longer time to recurrence (TTR) in Kaplan-Meier (p = 0.045) and in multivariate Cox analysis (HR 0.27, 95% CI 0.08-0.95, p = 0.041). For colon cancer stage III patients, lack of CD133 expression was associated with better effect of adjuvant chemotherapy (p = 0.016) in Kaplan-Meier univariate analysis, but the interaction between CD133 and adjuvant chemotherapy was not statistically significant in multivariate analysis (HR 0.59, 95% CI 0.18-1.89, p = 0.374). CONCLUSION: LGR5 mRNA expression is a prognostic factor for CRC stage II patients, whereas the value of CD133 expression as prognostic and predictive biomarker is inconclusive.

A four-microRNA classifier as a novel prognostic marker for tumor recurrence in stage II colon cancer.

About 20 percent of TNM-stage II colon cancer patients who are treated by surgical resection develop recurrence, and adjuvant chemotherapy in this group is still debated among researchers and clinicians. Currently, adverse histopathological and clinical factors are used to select patients for adjuvant chemotherapy following surgery. However, additional biomarkers to classify patients at risk of recurrence are needed. We have conducted a study using fresh frozen tumor tissue from 54 TNM-stage II colon cancer patients and performed microRNA profiling using next-generation sequencing. For the selection of the prognostic microRNAs, a LASSO Cox Regression model was employed. For the validation, we used the publically available TCGA-COAD cohort (n = 122). A prognostic panel of four micorRNAs (hsa-miR-5010-3p, hsa-miR-5100, hsa-miR-656-3p and hsa-miR-671-3p) was identified in the study cohort and validated in the TCGA-COAD cohort. The four-microRNA classifier successfully identified high-risk patients in the study cohort (P < 0.001) and the validation cohort (P = 0.005). Additionally, a number of established risk factors and the four-miRNA classifier were used to construct a nomogram to evaluate risk of recurrence. We identified a four-microRNA classifier in patients with TNM-stage II colon cancer that can be used to discriminate between patients at low- and high risk of recurrence.

Identification of a sixteen-microRNA signature as prognostic biomarker for stage II and III colon cancer.

Despite advances in colon cancer research and novel therapies, high risk of recurrence remains a major challenge. This study reports miRNA expression profiling as a biomarker for the prognosis of TNM stage II and III colon cancer. Fresh frozen biopsies from the study cohort (N=111) were analyzed for miRNA by RT-qPCR and LASSO regression analysis was used to build a classifier of miRNAs. The prognostic accuracy was tested and the classifier was validated in an independent colon cohort (TCGA-COAD, N=209). The LASSO regression analysis identified a 16-miRNA signature including miR-143-5p, miR-27a-3p, miR-31-5p, miR-181a-5p, miR-30b-5p, miR-30d-5p, miR-146a-5p, miR-23a-3p, miR-150-5p, miR-210-3p, miR-25-3p, miR-196a-5p, miR-148a-3p, miR-222-3p, miR-30c-5p and miR-223-3p. A low 16-miRNA signature was associated with better 5-year disease-free survival (DFS) in the study cohort than a high signature (93 % versus 58 %; p< 0.001). The signature was an independent prognostic factor for better 5-year DFS in multivariate analyses (HR 21.4; 95% CI: 4.21-108.7; p< 0.001). The results in the validation cohort were consistent with the study cohort in univariate (77 % versus 65 %; p= 0.045) and multivariate analyses (HR 2.0; 95% CI: 1.04-3.89; p=0.039). We identified a 16-miRNA signature as a reliable prognostic biomarker for classification of colon cancer stage II and III patients into groups with low and high risk for recurrence.