Comprehensive genomic profiling drives precision oncology and expands accessibility to targeted therapies in Uzbek populations

Background: The current, mortality-to-incidence ratio of 67% indicates most cancers are detected at advanced stages in Uzbekistan. In addition, symptoms appear only when the cancer is large or metastatic and advanced cancer is expensive, difficult to treat, and often fatal. Sophisticated infrastructure requires large funding, trained professional and expensive screening procedures. In several instances, treatment regimen is also administered without information on tumor sensitivity and efficacy. Eventually, patients suffer severe toxicity from multiple tests and treatments. To address these events, personalized molecular tests and treatment monitoring approaches are necessary. This study shows the efficacy of comprehensive genomic profiling (CGP) to append the molecular spectrum of cancer patients from Uzbekistan. This may open several treatment and monitoring possibilities in non-invasive scale. Methods: A total of 124 genomically profiled patients by our CGP assay were retrospectively investigated for mutational spectrum. All patients belonged to Uzbek ethnicity with ages between 25 to 85 years. CGP was performed on these patients using next-generation sequencing (NGS) with the OncoIndx® panel. Results: Of the 124 patients profiled genomically, 331 pathogenic/likely pathogenic variants were detected with TP53 constituting 20.2% (67) of all variants. Several frameshift and truncated TP53 variants were identified suggesting an impairment of TP53 protein thereby potentially leading to oncogenic stress, DNA damage, and several major pathway malfunctioning. Further, variants in PIK3CA, APC, KRAS, EGFR, PTEN , and BRCA1/2 were also present with high frequencies in the patient cohort at 8.5% (28), 6.3% (21), 6% (20), 4.5% (15), 2.7% (9), and 1.8% (6) respectively. Together, these variants may suggest major impairments in cell proliferation, and DNA repair pathways. Mismatch Repair (MMR) genes including MSH6, MSH3, MLH1, PMS2, MUTYH , and MSH2 were also found to be mutated at frequencies of 1.2% (4), 0.9% (3), 0.9% (3), 0.3% (1), 0.3% (1), and 0.3% (1) respectively showing damages in MMR pathway. Three patients in the cohort with colon and lung cancers exhibited high microsatellite instability (MSI) whilst genomic findings showed impairments in cell proliferation, MMR, and DNA repair pathways. Conclusion: To conclude, this study highlights the benefit of our CGP assay in identifying diverse oncogenic drivers across multiple pathways and in the study population of the Uzbek ethnicity, it added value in expanding targeted therapeutic opportunities to manage critical pathway impairments.