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

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.


To evaluate the various biological tumor markers collectively for early diagnosis which could act as prognostic biomarkers and helps in future therapeutics of PC in Kashmir valley.


A total of 50 confirmed PC cases were included in the study 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). Mutational analysis was performed to evaluate the mutations in Kirsten rat sarcoma (KRAS), Breast cancer type 2 (BRCA-2), and deleted in pancreatic cancer-4 (DPC-4) genes. However, epigenetic modifications (methylation of CpG islands) 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.


We found significantly elevated levels of biological markers CA 19-9 (P ≤ 0.05), TPS (P ≤ 0.05), CEA (P ≤ 0.001), and VEGF (P ≤ 0.001). Molecular genetic analysis revealed that KRAS gene mutation is predominant in codon 12 (16 subjects, P ≤ 0.05), and 13 (12 subjects, P ≤ 0.05). However, we did not find a mutation in DPC-4 (1203G > T) and BRCA-2 (617delT) genes. Furthermore, epigenetic modification revealed that CpG methylation in 21 (P ≤ 0.05) and 4 subjects in the promoter regions of the p16 and hMLH1 gene, respectively.


In conclusion, CA 19-9, TPS, CEA, and VEGF levels were significantly elevated and collectively have potential as diagnostic and prognostic markers in PC. Global data of mutation in the KRAS gene commonly in codon 12 and rare in codon 13 could augment the predisposition towards PC. Additionally, methylation of the p16 gene could also modulate transcription of genes thereby increasing the predisposition and susceptibility towards PC.

Keywords: Pancreatic cancer, Genetic mutations, Epigenetic modifications, Biomarkers, Risk factors, Diagnostics

Core Tip: This study demonstrates that the collective evaluation of genetic mutations, epigenetic modifications in key genes and elevated levels of serum carbohydrate antigen 19-9, tissue polypeptide specific antigen, carcinoembryonic antigen, and vascular endothelial growth factor-A could be used as predictive biomarkers for diagnostics and prognostics in pancreatic cancer patients of the ethnic Kashmiri population. This could be useful to track the disease status of pancreatic cancer patients who are on a different regimen of chemotherapeutic interventions. To validate these results in the ethnic Kashmiri population, future studies need comprehensive, cohort, and replicative studies with large sample size.