Comprehensive transcriptome profiling of Taiwanese colorectal cancer implicates an ethnic basis for pathogenesis

Shao-Min Wu,Chung-Pei Ma,Chia-Yu Yang,Sum-Fu Chiang,Wen-Sy Tsai,Bertrand Chin-Ming Tan,Jian-Hua Wang,Pei-Shan Lu,Jiarong Lin,Yi-Hsuan Lai,Hsuan Liu

doi:10.1038/s41598-020-61273-y

Shao-Min Wu, Chung-Pei Ma + Show 9 more

Open Access

https://doi.org/10.1038/s41598-020-61273-y

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Abstract

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. While both genetic and environmental factors have been linked to the incidence and mortality associated with CRC, an ethnic aspect of its etiology has also emerged. Since previous large-scale cancer genomics studies are mostly based on samples of European ancestry, the patterns of clinical events and associated mechanisms in other minority ethnic patients suffering from CRC are largely unexplored. We collected 104 paired and adjacent normal tissue and CRC tumor samples from Taiwanese patients and employed an integrated approach – paired expression profiles of mRNAs and microRNAs (miRNAs) combined with transcriptome-wide network analyses – to catalog the molecular signatures of this regional cohort. On the basis of this dataset, which is the largest ever reported for this type of systems analysis, we made the following key discoveries: (1) In comparison to the The Cancer Genome Atlas (TCGA) data, the Taiwanese CRC tumors show similar perturbations in expressed genes but a distinct enrichment in metastasis-associated pathways. (2) Recurrent as well as novel CRC-associated gene fusions were identified based on the sequencing data. (3) Cancer subtype classification using existing tools reveals a comparable distribution of tumor subtypes between Taiwanese cohort and TCGA datasets; however, this similarity in molecular attributes did not translate into the predicted subtype-related clinical outcomes (i.e., death event). (4) To further elucidate the molecular basis of CRC prognosis, we developed a new stratification strategy based on miRNA–mRNA-associated subtyping (MMAS) and consequently showed that repressed WNT signaling activity is associated with poor prognosis in Taiwanese CRC. In summary, our findings of distinct, hitherto unreported biosignatures underscore the heterogeneity of CRC tumorigenesis, support our hypothesis of an ethnic basis of disease, and provide prospects for translational medicine.

Highlights

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide
(4) To further elucidate the molecular basis of CRC prognosis, we developed a new stratification strategy based on miRNA–mRNA-associated subtyping (MMAS) and showed that repressed WNT signaling activity is associated with poor prognosis in Taiwanese CRC
The clinical characteristics and demographics of our cohort are outlined in Table 1, which were further analyzed for their association with the overall survival (OS) and disease-free survival (DFS) of the patients (Table 2)

Summary

Introduction

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. While both genetic and environmental factors have been linked to the incidence and mortality associated with CRC, an ethnic aspect of its etiology has emerged. An indicator of the emerging prevalence and reliability of transcriptome-based subtyping systems is the increasing number of studies that have established and applied transcriptome-based subtyping systems to molecularly stratify and understand the clinical outcome of CRC38–41 Among these schemes, the Colorectal Cancer Subtyping Consortium (CRCSC) utilized data from six CRC studies and developed a robust classification system with four consensus molecular subtypes (CMSs)[36]. Each of the four subtypes is characterized by distinct expression profiles of oncogenic/tumor suppressive genes and/or pathways, mutation states of particular genes, and MSI These subtypes correlate with patient survival – CMS1 exhibits poor survival after relapse, whereas CMS4 shows dismal prognosis – strengthening the translational potential of this system in prognosticating CRC. CMS subtyping of a Japanese cohort revealed a worse survival outcome in CMS142, which is a different result from previous observations and reinforces the ethnic or regional basis of pathogenesis

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