The Prevalence of the GNAS Gene Mutation in Colorectal Adenocarcinoma in Uganda: A Cross-Sectional Study Design

Wismayer R, Matthews R, Whalley C, Kiwanuka J, Kakembo FE, Thorn S, Wabinga H, Odida M and Tomlinson I

Published on: 2025-04-04

Abstract

Introduction: In Uganda, the incidence of colorectal cancer (CRC) is rising, though still relatively low compared to developed countries, with a 5-year survival rate of 5.6%. Western literature shows that GNAS mutations are linked with failed treatment outcomes and a poor prognosis in CRC. The global prevalence of the GNAS mutation in colorectal tumours varies. The objective of this study was to determine the prevalence of pathological GNAS gene mutations and compare to clinicopathological features of CRC in Ugandan patients. Methodology: This was a cross-sectional study were formalin-fixed paraffin embedded (FFPE) CRC blocks were obtained from 2008-2021. The histopathological diagnosis of colorectal adenocarcinoma, grade and LVI status was obtained by two consultant pathologists from the H&E slides. Data was abstracted from the medical case files for AJCC stage, topography and demographics. DNA was extracted from CRC FFPE tissue blocks and using the Qiagen custom design panel, library preparation was completed. There were 56 genes which were represented in the custom panel. The GNAS gene was sequenced using the above library preparation and NGS sequencing. Categorical data was summarised using proportions and frequencies corresponding to the GNAS mutation status. Categorical and continuous variables were analyzed using the Fischer’s exact tests and chi-square tests. A p-value of ≤0.05 was considered statistically significant. Results: Out of 127 FFPE CRC tumour samples, there were 36(28.3%) colorectal tumours that were GNAS mutation positive. Out of the MSI tumours there were 18(50%) GNAS positive tumours and 34(37.4%) GNAS negative tumours (p=0.192). There were 4(11.1%) GNAS positive tumours compared to 16(17.6%) GNAS negative tumours with stage IV disease (p=0.301). Out of the tumours that were GNAS mutation positive, 40(31.5%) were KRAS mutation negative and 4(3.1%) were KRAS mutation positive (p=0.447). Conclusions: In Uganda, the prevalence of GNAS mutations is similar to the prevalence from Japan, however different to the prevalence reported in other countries. There was no relation between GNAS mutation and demographics, topography, grade, LVI status, stage, MSI status and K-ras mutation status in Ugandan CRC patients.