Abstract 6637: Whole exome analysis of oral squamous cell carcinoma in local patients at tertiary care hospitals in Peshawar, Pakistan

Abstract The Precision Medicine Lab (PML) was established by the Federal Government in 2018 to pilot precision medicine in Pakistan using genomics in oral cancer. Oral squamous cell carcinoma (OSCC)—often called the “poor man's cancer”—constitutes 90% of all head and neck cancers and is the most common cancer in Pakistani males. Supported by a bio-repository of clinical samples and primary cell lines, PML employs a multi-omic approach to identify actionable biomarkers for diagnostic, prognostic, and therapeutic applications. With ethical approvals from IRBs and informed consent, treatment-naive biopsy-confirmed OSCC patients were recruited from two tertiary care hospitals in Peshawar, Pakistan. The cohort predominantly included older individuals (37.84% aged 41-60 years), late-stage cases (78.46% in stage IV), and self-reported non-alcohol consumers (96.9%). Smokeless tobacco use was reported by 44.6%, while 30.8% reported both smoked and smokeless tobacco use. Tumors were mostly located in the buccal mucosa (29.2%), alveolar region (27.7%), or vestibular region (24.6%). Blood and tumor samples were collected for whole exome sequencing, transcriptomics, and metabolomics, along with saliva for oral microbiome analysis. Combined with clinical history and histopathology, this multi-omic dataset enables machine learning experiments. For somatic mutation analysis, raw reads were aligned to the GRCh38.p14 genome, and variants were identified using GATK (v4.5). Mutational analyses with maftools (v2.18.0) in R (v4.3) referenced the COSMIC SBS Signature database (v3.2). Results revealed CASP8 (39%), TP53 (38%), FAT1 (29%), and NOTCH1 (29%) as frequently mutated genes. Pathways such as NOTCH (80.3%), RTK-RAS (64.3%), and Hippo (60.7%) were commonly affected. Deletions were observed in over 60% of samples in chromosomal regions 5q13.2, 6p21.32, 6p21.33, 11p15.5, 19q13.42, and 22q11.23, along with loss of heterozygosity at chromosome 17. The top three mutational signatures included those linked to DNA mismatch repair (SBS6). This study is the first to report the mutational landscape of an OSCC cohort from Pakistan. Our findings highlight potential targets for further investigation and emphasize the utility of a multi-omic approach. With matched primary cell lines for each patient, experimental validation of identified biomarkers is underway to assess their diagnostic, prognostic, and therapeutic relevance. Our integrated dataset offers a resource for machine learning studies to identify novel mutational signatures and actionable biomarkers for OSCC in local populations. Citation Format: Faisal Khan, Hina Zamir, Khudeja Salim, Madina Shirdel, Arsalan Riaz, Aqsa Hussain, Yusra Ilyas, Momal Agha, Zainab Jahan, Saba Saeed, Khadim Shah, Yasir Rehman, Fahim Uddin, Zahid Qayyum, Zubair Durrani, Muhammad Mushtaq Khattak, Johar Ali. Whole exome analysis of oral squamous cell carcinoma in local patients at tertiary care hospitals in Peshawar, Pakistan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6637.