Case Control Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 28, 2021; 27(36): 6093-6109
Published online Sep 28, 2021. doi: 10.3748/wjg.v27.i36.6093
Evaluation of biomarkers, genetic mutations, and epigenetic modifications in early diagnosis of pancreatic cancer
Bilal Rah, Manzoor Ahmad Banday, Gh Rasool Bhat, Omar J Shah, Humira Jeelani, Fizalah Kawoosa, Tahira Yousuf, Dil Afroze
Bilal Rah, Gh Rasool Bhat, Humira Jeelani, Tahira Yousuf, Dil Afroze, Advanced Centre for Human Genetics, Sher-i-Kashmir Institute of Medical Sciences, Srinagar 190011, Jammu and Kashmir, India
Manzoor Ahmad Banday, Department of Medical Oncology, Sher-i-Kashmir Institute of Medical Sciences, Srinagar 190011, Jammu and Kashmir, India
Omar J Shah, Department of Surgical Gastroenterology, Sher-i-Kashmir Institute of Medical Sciences, Srinagar 190011, Jammu and Kashmir, India
Fizalah Kawoosa, Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Science, Srinagar 190011, Jammu and Kashmir, India
Author contributions: Rah B performed data analysis and manuscript writing; Banday MA contributed to study design, data analysis and gave directions; Bhat GR contributed to data analysis and proofreading; Shah OJ contributed by providing patient samples; Jeelani H contributed to manuscript writing; Kawoosa F contributed to sample collection and experimentation; Yousuf T contributed to manuscript writing; and Afroze D contributed to study design, data analysis and gave directions; All authors gave the final approval of the current version of the manuscript for publication and agreed to be accountable for the current work.
Institutional review board statement: The study was reviewed and approved by the Institutional Ethics committee (IEC), Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: No additional data are available
STROBE statement: The authors have read the STROBE Statement, and the manuscript was prepared and revised according to the STROBE Statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Dil Afroze, PhD, Full Professor, Advanced Centre for Human Genetics, Sher-i-Kashmir Institute of Medical Sciences, Main Road, Srinagar 190011, Jammu and Kashmir, India.
Received: April 7, 2021
Peer-review started: April 7, 2021
First decision: May 27, 2021
Revised: June 10, 2021
Accepted: July 13, 2021
Article in press: July 13, 2021
Published online: September 28, 2021
Research background

Pancreatic cancer (PC) is one of the deadliest malignancies with an alarming mortality rate. Despite significant advancement in diagnostics and therapeutics, early diagnosis remains elusive causing poor prognosis, marred by mutations and epigenetic modifications in key genes which contribute to disease progression.

Research motivation

To explore the various biological tumor markers collectively and mutational analysis of key regulatory genes for early diagnosis and prognosis of PC.

Research objectives

To evaluate various biological tumor markers collectively in PC and their association with genetic mutation and epigenetic modification of key regulatory genes that could act as early diagnostic and prognostic biomarkers and will help in future therapeutics of PC in Kashmir valley.

Research methods

The current study includes 50 confirmed PC cases to evaluate the levels of carbohydrate antigen 19-9 (CA 19-9), tissue polypeptide specific antigen (TPS), carcinoembryonic antigen (CEA), vascular endothelial growth factor-A (VEGF-A), and epidermal growth factor receptor (EGFR) by enzyme-linked immunosorbent assay (ELISA) method. Mutational analysis of key genes Kirsten rat sarcoma (KRAS), Breast cancer type 2 (BRCA-2), and deleted in pancreatic cancer-4 (DPC-4) genes was performed to evaluate the mutations at hotspot regions. Furthermore, epigenetic modifications were performed in the promoter regions of cyclin-dependent kinase inhibitor 2A (p16; CDKN2A), MutL homolog 1 (hMLH1), and Ras association domain-containing protein 1 (RASSF1A) genes.

Research results

Besides significant elevation in levels of tumor markers CA 19-9 (P ≤ 0.05), TPS (P ≤ 0.05), CEA (P ≤ 0.001), and VEGF (P ≤ 0.001), our mutational analysis observed that KRAS gene mutation is predominant in codon 12 (16 subjects, P ≤ 0.05), and 13 (12 subjects, P ≤ 0.05). Additionally, epigenetic modification analysis suggests that CpG methylation was observed in 21 (P ≤ 0.05) and 4 subjects in the promoter regions of the p16 and hMLH1 gene, respectively.

Research conclusions

The study revealed the significant elevation of serum biological markers in PC patients and the causal association of hotspot mutations and epigenetic modification of key with PC pathogenesis thus indicates the potential of biological markers, mutational status, and epigenetic modifications of key genes collectively for predisposition, susceptibility as well as diagnostics and prognostics of PC.

Research perspectives

The study strongly suggests that the elevated levels of serum CA 19-9, TPS, CEA, and VEGF-A can be used as predictive biomarkers in PC subjects. Additionally, mutational analysis epigenetic modifications in the promoter region of key genes may act as prognostic biomarkers to benefit the patients who are on a different regimen of chemotherapeutic interventions. Further to validate these results, future studies need comprehensive, cohort, and explicative studies with large sample sizes.