Abstract
<title>Abstract</title> <p>Background TP53 is the most frequently mutated tumor suppressor gene in human malignancies, with mutation rates exceeding 50% in multiple cancer types. While global mutational hotspots are well-characterized, population-specific spectra in South Asian cohorts remain underrepresented, limiting the development of regionally targeted precision therapeutics. Objective To systematically characterize the TP53 mutational landscape across Pakistani cancer cohorts, identify recurrent population-enriched variants, and prioritize targets for mutation-specific therapeutic development. Methods A systematic literature search was conducted across PubMed/MEDLINE, Google Scholar, PMC, Springer, MDPI, Frontiers, and eCancer databases (1995-June 2026), employing Boolean queries for TP53 mutations in Pakistani cancer populations. Nine studies comprising 488 patients met inclusion criteria. A random-effects meta-analysis of proportions was performed using logit transformation via the inverse-variance method (DerSimonian-Laird estimator). Results The pooled TP53 mutational prevalence across primary characterized datasets was 27.6% (95% CI: 7.4%-63.8%), with extreme heterogeneity (I² = 96.4%, Cochran's Q = 138.45, p < 0.0001) driven by tumor-type disparities. Five recurrent mutations were identified across the DNA-binding domain. The p.G244S (c.730G > A) variant was detected in 82 of 109 pancreatic ductal adenocarcinoma patients (75.2%), representing an unprecedented population enrichment not observed in global cohorts (< 0.1% in IARC R24). Globally validated gain-of-function mutations p.R175H and p.R248W were each confirmed in 3 independent patients across multiple studies. No published TP53 sequencing data were identified for Pakistani hepatocellular carcinoma cohorts. Conclusion This review reveals a distinctive Pakistani TP53 mutational signature dominated by the p.G244S variant in PDAC, alongside globally recognized hotspots amenable to emerging precision strategies including small-molecule reactivators and allele-specific siRNAs. The complete absence of HCC sequencing data, in the context of high aflatoxin exposure and viral hepatitis endemicity, represents a critical public health blind spot requiring urgent investigation.</p>