Genetic analysis of key players in PI3K signaling cascade of colorectal carcinoma

Q: What was the main goal of this study on colorectal carcinoma?

To evaluate associations between PI3K pathway genetic variants (seven SNPs and two hotspot mutations) and colorectal carcinoma susceptibility, clinical outcome, and therapeutic potential.

Q: How were the SNPs assessed in the case-control study?

Seven SNPs were genotyped in 495 colorectal carcinoma cases and 495 controls using ARMS-PCR.

Q: What analyses were used to study genetic associations and survival?

Pairwise linkage disequilibrium was calculated, Pearson’s chi-square tested variant association with CRC risk, and Kaplan-Meier analysis evaluated associations with clinicopathological parameters and overall survival, along with Breslow and Tarone-Ware tests.

Sep 22, 2026

Upload by Sophia Brooks

Study investigates whether specific genetic variants within the PI3K signaling cascade influence susceptibility and clinical outcome in colorectal carcinoma. A case-control cohort of 495 colorectal cancer patients and 495 controls was genotyped using ARMS-PCR for seven SNPs, alongside analysis of two hotspot mutations. Mutant allele distributions differed across variants, linkage disequilibrium was evaluated, and survival associations were assessed with Kaplan-Meier and statistical tests. Structural modeling and QMEAND/Ramachandran indicators were applied to interpret protein changes, supporting candidate biomarker potential pending validation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Background

Disease burden and genetic risk

Role of the PIK3CA/AKT/mTOR pathway

Study design and methods

Case-control cohort and ARMS-PCR genotyping

Hotspot mutation and sequencing

Linkage disequilibrium and risk testing

Survival and drug assessment

Protein structure modeling

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Genetic analysis of key players in PI3K signaling cascade of colorectal carcinoma Hira Pervaiz1, Nosheen Masood1􀀍, Parvez Azam Malik2, Jahangir Sarwar Khan3, Mumtaz Ahmad Khan4 & Hassaan Malik5 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 andrs10138227 (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. Keywords Colorectal carcinoma (CRC), Single nucleotide polymorphism (SNP), PIK3CA/AKT/mTOR pathway, Tetra ARMS-PCR, Linkage disequilibrium (LD) Colorectal cancer (CRC) is a major health problem and highly frequent cancer worldwide. Globally CRC incidence consist of 9.4% cancer mortality, lower than lung cancer which includes 18% mortality. Global burden of fresh colorectal cancer cases is projected to range 3.2 million and 1.6 million deaths in 2040, grounded on prediction of aging, population growth, and human progress. The upsurge in CRC incidence is primarily due to increased exposure to environmental risk factors resulting from shifting lifestyle and diet headed for Westernization1,2. Genetic risk factors comprised of 60% of colorectal carcinoma cases. This genetic colorectal cancer arises mainly due to epigenetic modifications or somatic gene mutations. The remaining 40% of CRC showed vulnerability to heritable components that include family history but not having any evident genetic predisposition. The environmental risk factors significantly contribute to colorectal carcinoma, even in patients having a family history, genetic alterations may be the cause of the disease progression3. The PIK3CA/AKT/mTOR signaling pathway has an important role in proliferation, angiogenesis, metastasis and resistance to apoptosis that is essential in the development and maintenance of colorectal carcinomas. PIK3CA effect on cancer progression is facilitated by AKT which is a downstream effector ofPIK3CA, activated by the phosphorylation of AKT kinase at the Threonine 308 residue. AKT is overexpressed in numerous cancers comprising colorectal, breast pancreatic and ovarian. Previous researches have shown that AKTphosphorylation in CRC is associated with the proliferation of cells, and apoptosis inhibition along with various clinicopathological factors like invasion grade, vessel infiltration, tumor stage and lymph nodes metastasis. AKT also regulates downstream target of mTOR that has a significant role in metabolism, angiogenesis, growth, and protein translation. mTOR is a direct substrate for AKT kinases a

FAQs

What was the main goal of this study on colorectal carcinoma?

To evaluate associations between PI3K pathway genetic variants (seven SNPs and two hotspot mutations) and colorectal carcinoma susceptibility, clinical outcome, and therapeutic potential.

How were the SNPs assessed in the case-control study?

Seven SNPs were genotyped in 495 colorectal carcinoma cases and 495 controls using ARMS-PCR.

What analyses were used to study genetic associations and survival?

Pairwise linkage disequilibrium was calculated, Pearson’s chi-square tested variant association with CRC risk, and Kaplan-Meier analysis evaluated associations with clinicopathological parameters and overall survival, along with Breslow and Tarone-Ware tests.

Sep 22, 2026

Upload by Sophia Brooks