Combined analysis of somatic mutations and gene expression reveals nuclear speckles-associated enhanced stemness in gingivobuccal carcinoma under DNA damage response

Smokeless tobacco chewing habits in India lead to a high prevalence of Gingivobuccal oral squamous cell carcinoma (OSCC-GB). Cancer stem cells (CSCs) are a sub-population of cancer cells within a tumor with stem-like properties and are believed to contribute to tumor initiation, progression, increased resistance to drug therapy, and promote post-therapeutic cancer relapse. An RNA-sequencing data-based combined analysis of somatic mutations and gene expression was performed to explore the role of CSCs in disease progression using the novel Indian-origin OSCC-GB cell line ‘IIOC019’ from a patient with tobacco-chewing habit. The identified DNA damage-related known mutational signature (1 bp T/(A) nucleotide insertions and C>T mutations) indicates the impact of smokeless tobacco-related carcinogens in the IIOC019 cell line. The differentially expressed somatic variants, functional impact predictions, and survival analysis reveal the role of DNA damage response (DDR)-related genes in OSCC-GB, with the SON gene as a significant player. The study suggests that the loss-of-function in a somatic variant of the SON gene is linked to nuclear speckles-associated enhanced stemness and increased risk of disease progression in OSCC-GB under DDR conditions. The newly identified CSC-associated somatic variants appear to promote cancer spread, local recurrence, and resistance to chemotherapy or radiotherapy, contributing to the high mortality rates among Indian OSCC-GB patients.