Prognosis of stage III colorectal carcinomas with FOLFOX adjuvant chemotherapy can be predicted by molecular subtype.

Yujin Kwon,Hoguen Kim,Hyun Jung Lee,Minhee Park,Seongju Yun,Tae Il Kim,Won Kyu Kim,Sora Kim,Soonmyung Paik,Byungsoh Min,Mi Jang,Sungpil Hong

doi:10.18632/oncotarget.17023

Abstract

Individualizing adjuvant chemotherapy is important in patients with advanced colorectal cancers (CRCs), and the ability to identify molecular subtypes predictive of good prognosis for stage III CRCs after adjuvant chemotherapy could be highly beneficial. We performed microarray-based gene expression analysis on 101 fresh-frozen primary samples from patients with stage III CRCs treated with FOLFOX adjuvant chemotherapy and 35 matched non-neoplastic mucosal tissues. CRC samples were classified into four molecular subtypes using nonnegative matrix factorization, and for comparison, we also grouped CRC samples using the proposed consensus molecular subtypes (CMSs). Of the 101 cases, 80 were classified into a CMS group, which shows a 79% correlation between the CMS classification and our four molecular subtypes. We found that two of our subtypes showed significantly higher disease-free survival and overall survival than the others. Group 2, in particular, which showed no disease recurrence or death, was characterized by high microsatellite instability (MSI-H, 6/21), abundant mucin production (12/21), and right-sided location (12/21); this group strongly correlated with CMS1 (microsatellite instability immune type). We further identified the molecular characteristics of each group and selected 10 potential biomarker genes from each. When these were compared to the previously reported molecular classifier genes, we found that 31 out of 40 selected genes were matched with those previously reported. Our findings indicate that molecular classification can reveal specific molecular subtypes correlating with clinicopathologic features of CRCs and can have predictive value for the prognosis for stage III CRCs with FOLFOX adjuvant chemotherapy.

Highlights

Colorectal carcinomas (CRCs) have variable clinical, pathologic, and molecular features
To further analyze colon cancer-specific gene expression, we used unsupervised hierarchical clustering analysis of the 4,823 differentially expressed gene (DEG) and found that colorectal cancer (CRC) samples grouped into four separate clusters, distinct from the non-neoplastic colon mucosa tissues (Figure 1B)
To classify the 101 colorectal tumors according to the gene profiles of those tumors, we performed nonnegative matrix factorization (NMF) consensus clustering using 1,764 tumor-specific DEGs that displayed a |fold change|>2 and P-value

Summary

Introduction

Colorectal carcinomas (CRCs) have variable clinical, pathologic, and molecular features. These are classified based on the histologic findings, and tumor staging is determined by assessing spread at the time of diagnosis. Determining the prognosis for individual patients with CRC is important, both for disease management, and for patient life planning. Prognosis is based predominantly on the pathologic stage of disease. II and III cancer is difficult, due to the fact that these patients have intermediate survival rates, and predicting individual responses to adjuvant chemotherapy is currently impossible. For stage III CRCs, standard therapy involves curative surgery, followed by adjuvant chemotherapy with the FOLFOX regimen. No biomarkers or classification system for accurately determining prognoses after this chemotherapeutic regimen in stage III CRCs is available

Methods

Results

Conclusion