Abstract
Triggering PI3K signaling cascade is most common in human cancers. This study aimed to screen the association of seven SNPs and two hotspot mutations, clinical outcome and therapeutic potential with susceptibility to colorectal carcinoma (CRC). In this case-control study of 495 CRC and 495 controls, seven SNPs were genotyped by ARMS-PCR. The mutant allele frequencies were significantly higher for five SNPs, E542K and E17K but lower for rs6443624 (P = 0.1480) and rs1883965 (P = 0.4105). DNA sequencing results revealed point mutations were more prevalent in CRC. Pairwise linkage disequilibrium analysis was performed and strong LD was observed between rs6443624 and rs10138227 (D’ = 0.953, r² = 0.435, LOD = 62.61) among CRC. Pearson’s chi-square test showed these variants were associated with CRC risk (P < 0.001). Kaplan Meier analysis revealed that six SNPs (P < 0.005) were strongly associated with clinicopathological parameters and drugs with OS in CRC but not for rs6443624 (P = 0.3). Breslow and Tarone-Ware Test showed significant survival differences but capecitabine revealed the highest survival estimates. Swiss model was used to analyze the changes in protein structure. QMEAND value for E542K is 0.88 ± 0.05 and for E17K is 0.78 ± 0.05 representing high quality structure, however, Ramachandaran structure 97.37% favoured for E542K and 95.23% for E17K. The current study suggests that PI3K pathway variants may be associated with colorectal cancer susceptibility and highlights their potential relevance as candidate biomarkers, pending further validation.
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Acknowledgements
We gratefully acknowledge Fatima Jinnah Women University Rawalpindi and healthy controls/patients for their contribution to this research. We are also grateful to Benazir Bhutto, Holy Family, District Headquarter and PIMS (Pakistan) hospitals for their support and cooperation.
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HP contributed to conceptualizing, methodology, writing-original draft, visualization. NM contributed to supervision, validation, writing-review and editing. PAM, JSK, MAK and HM contributed to resources. All authors have read and approved the final manuscript.
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This study was approved by ethical committee of Fatima Jinnah Women University Rawalpindi (Approval No: FJWU/EC/2024/102, Date: 05-01-2025), Rawalpindi Medical University RMU (Holy Family, Benazir Bhutto, District Headquarter hospitals; Approval No: Ref. No. 531/IREF/RMU/2023, Date: 30-9-2023) and Shaheed Zulfiqar Ali Bhutto Medical University, PIMS, Islamabad (Approval No: F. 1–1/2015/ERB/SZABMU/1203, Date: 30-11-2023). All participants provided their written informed consent before enrollment in this research, and all the methods are carried out in accordance with World Medical Association Declaration of Helsinki.
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Pervaiz, H., Masood, N., Malik, P.A. et al. Genetic analysis of key players in PI3K signaling cascade of colorectal carcinoma. Sci Rep (2026). https://doi.org/10.1038/s41598-026-42006-z
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DOI: https://doi.org/10.1038/s41598-026-42006-z
