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Integrated Analysis Identifies Novel Fusion Transcripts in Laterally Spreading Tumors Suggestive of Distinct Etiology Than Colorectal Cancers

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Abstract

Background

Laterally spreading tumors (LSTs) of the colon and rectum are a class of abnormality which spreads laterally and appears ulcerated. They are a subclass of colorectal cancer (CRCs) with higher invasive potential than CRCs. Moreover, the etiology of LST still remains obscure.

Methods

This study aimed to identify unique fusion transcript(s) in LSTs and evaluate their role in LST development and progression. RNA-Seq data for LST samples from the EMBL-EBI database were used to identify fusion transcripts. An integrated approach using Gene Ontology, pathway analysis, hub gene, and co-expression network analysis functionally characterized fusion transcripts to shed light upon the etiology of LSTs.

Result

We identified 48 unique fusion genes in LSTs. GO terms were enriched in mRNA metabolic (p ≤ 2.06E-06), mRNA stabilization (p ≤ 1.60E-05), in cytosol (1.20E-05), RBP (p ≤ 2.30E-04), and RNA binding activity (p ≤ 3.51E-08) processes. Pathway analysis revealed an inflammatory phenotype of LSTs suggesting a distinct etiology than CRCs as pathways were enriched in salmonella infection (p ≤ 4.41 e-03), proteoglycans in cancer (p ≤ 1.18 e-02), and insulin signaling (p ≤ 2.13 e-02). Our exclusion and inclusion criteria and hub gene analysis finally identified 9 hub genes. Co-expression analysis of hub genes identified the most significant transcription factors (NELFE, MYC, TAF1, MAX) and kinases (MAPK14, CSNK2A1, CDK1, MAPK1) which were implicated in various cancer pathways. Furthermore, an overall survival analysis of hub genes was performed. Our predefined criterion resulted in the enrichment of NPM1-PTMA (NPM1: p ≤ 0.005) and HIST1H2BO-YBX1 (YBX1: p ≤ 0.02) fusion transcripts, significantly associated with the patient’s overall survival.

Conclusion

Our systematic analysis resulted in novel fusion genes in LSTs suggesting a different etiology than CRCs. Fusion transcripts were observed more frequently in non-granular LSTs suggestive of genetically more unstable than granular LST. We hypothesize that NPM1-PTMA and HIST1H2BO-YBX1 could be implicated in LST development and progression and may also serve as a prognostic or diagnostic biomarker in future for better management of LSTs.

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Availability of Data and Materials

Publicly available datasets were analyzed in this study. This data can be found here https://www.ebi.ac.uk/ena/browser/ using accession numbers SRR3147729 to SRR3147748.

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Authors and Affiliations

  1. Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Uttar Pradesh, 211004, Prayagraj, India

    Sandhya Rai, Manish Pratap Singh & Sameer Srivastava

  2. CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Uttar Pradesh, 226031, Lucknow, India

    Manish Pratap Singh

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Contributions

All authors contributed to the study’s conception and design. Sandhya Rai and Manish Pratap Singh performed material preparation, data collection, and analysis. Sandhya Rai wrote the first draft of the manuscript. Sameer Srivastava and Manish Pratap Singh reviewed and commented on the preceding paper. Sameer Srivastava did the framing and critical review of the manuscript. The final manuscript was read and approved by all authors.

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Highlights

• Laterally spreading tumors (LSTs) of the colon and rectum are a class of abnormality which spreads laterally appears ulcerated and may have higher malignant potential.

• Novel fusion genes identified in LSTs are suggestive of distinct etiology than CRCs.

• NPM1-PTMA (NPM1: p ≤ 0.005) and HIST1H2BO-YBX1 (YBX1: p ≤ 0.02) fusion transcripts were found to be, significantly associated with the patient’s overall survival and, therefore, could serve as a prognostic or diagnostic biomarker in future for better management of LSTs.

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Rai, S., Singh, M.P. & Srivastava, S. Integrated Analysis Identifies Novel Fusion Transcripts in Laterally Spreading Tumors Suggestive of Distinct Etiology Than Colorectal Cancers. J Gastrointest Canc 54, 913–926 (2023). https://doi.org/10.1007/s12029-022-00881-5

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