Molecular pathogenesis of microsatellite instability-high early-stage colorectal adenocarcinoma in India

Prasanth Ariyannur; Veena P. Menon; Keechilat Pavithran; Roopa R. Paulose; Reenu A. Joy; Damodaran M. Vasudevan

doi:10.1515/dmpt-2024-0033

Article

Molecular pathogenesis of microsatellite instability-high early-stage colorectal adenocarcinoma in India

Prasanth Ariyannur , Veena P. Menon , Keechilat Pavithran , Roopa R. Paulose , Reenu A. Joy and Damodaran M. Vasudevan

Published/Copyright: July 24, 2024

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From the journal Drug Metabolism and Personalized Therapy Volume 39 Issue 3

Abstract

Objectives

The prevalence of microsatellite instability (MSI) subtype among all colon cancers in India is about 30 %, approximately two times more than that of western population suggesting different molecular pathogeneses.

Methods

A NanoString analysis-based Pan cancer differential expression (DE) profile was determined in a primary cohort of early-stage CRC (tumor=10, normal=7), and correlated against MSI status. Using RT-PCR, tumor-specific DE genes were validated in another cohort of MSI-high CRC (n=15).

Results

Among the most differentially expressed genes, AXIN2, ETV4, and RNF43 were tumor cell-specific signals, while a set of genes including COL11A1, COMP, INHBA, SPP1, MMP3, TLR2, and others were immune cell-specific signals, that had a differential expression between MSI and MSS groups. When overlapped with The Cancer Genome Atlas (TCGA) studies using the Tumor immune estimation resource tool (TIMER), and protein-protein interaction analysis by STRING.db, these genes were segregated to representative tumor cells and immune cells. On validation, the tumor-specific gene signals were inversely associated with TLR4 expression.

Conclusions

The differential expression distribution of AXIN2, ETV4, and RNF43 among tumor and immune cells, suggests more than one pathological subset in the MSI-H subgroup of early-stage CRC in the Indian population.

Keywords: microsatellite instability; DNA mismatch repair; colon adenocarcinoma; colorectal cancer; Wnt; AXIN2; RNF43; ETV4

Corresponding author: Dr. Prasanth Ariyannur, Molecular Oncology Laboratory, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India; Department of Health Sciences Research, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India; and Karkinos Healthcare Pvt Ltd, 3rd Floor JLN Stadium Metro Station, Kaloor, Kochi, Kerala, 682017, India, E-mail: p.ariyannur@gmail.com

Funding source: Indian Council for Medical Research

Award Identifier / Grant number: 33/7/2019

Acknowledgment

We want to thank Dr. Divya, Dr. Aditi, Dr. Pooja, Dr. Monica from the GI Oncopathology fellowship program, and Ms. Sheeba, Ms. Bindu, Ms. Nisha from the Department of Pathology, Amrita Institute of Medical Sciences, Kochi, for their valuable contribution on tissue handling and processing. Dr. Gopalakrishna Ramasamy from Theracues Private Ltd, Bangalore, for NanoString analysis. Dr. Beena from OmicsGen Laboratory at Kakkanad, Kochi, for their contribution to the PCR analysis. We would also like to thank Dr. Sreekumar Kannoth, Dr. Manu Raj, Mr. Sivakumar Venugopal, Mr. Karthikeyan, Dr. Apsy, and Ms. Sonu from the Department of Health Sciences Research at Amrita Institute of Medical Sciences for their valuable contribution on office proceedings and functioning of the project.

Research ethics: The Scientific Research and Institutional Ethics Committee reviewed and approved the study (IRB-AIMS-2017-124) before preparing samples from pathologically characterized archived specimens. The committee observed that no human subjects directly participated in the study, thus no requirement for a patient consent form. The tissue samples were anonymized for the compilation of archived data, for pilot and validation experiments, as well as for publication of results. The committee reviewed before, during, and after the completion of the study and approved the adherence to the ethical standards stipulated by the institutional ethics committee.
Informed consent: Not applicable.
Author contributions: PA has designed the experiments with VPM and DMV. PA conducted molecular biology experiments. RRP has conducted histopathology and immunohistochemistry examinations. PA compiled the results and analyzed them with DMV and VPM. PA wrote the manuscript. DMV, VPM, KP, RAJ, and RRP reviewed the manuscript. All authors have accepted responsibility for the preparation of the manuscript.
Competing interests: The authors declare no competing interests.
Research funding: This work has been supported by the ICMR (Grant number 33/7/2019), New Delhi, India, and Intramural Seed Grant by Amrita Vishwa Vidyapeetham (AVVP), Coimbatore Tamil Nadu to PA.
Data availability: The raw data and supplementary files are available at https://osf.io/tcdk9/.

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/dmpt-2024-0033).

Received: 2024-04-24

Accepted: 2024-06-16

Published Online: 2024-07-24

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Articles in the same Issue

https://doi.org/10.1515/dmpt-2024-0033

Keywords for this article

microsatellite instability; DNA mismatch repair; colon adenocarcinoma; colorectal cancer; Wnt; AXIN2; RNF43; ETV4