Multi-omics analysis positions DNA2 at the interface of genome integrity programs and tumor behavior in pan-cancer

DNA2 coordinates essential maintenance processes, including cell-cycle progression; however, its aberrant activity has been implicated in cancer cell survival under oncogene-induced replication stress. To date, no comprehensive pan-cancer investigation of DNA2 has been conducted. Employing TCGA cohorts and complementary public databases, we executed the first pan-cancer multi-omics study of DNA2, examining transcriptomic, genomic variations, survival, immune infiltration, single-cell functional states, protein-protein interaction enrichment, and pharmacogenomic drug-response data across tumor profiles. DNA2 was considerably overexpressed in 17 tumors compared with matching normal tissues. In endometrial cancer, the highest frequency of genetic changes (~ 7%) was observed. Univariable analyses of survival showed that elevated DNA2 expression was related to worse overall survival in malignancies, including adrenocortical carcinoma (HR = 17.06) and mesothelioma (HR = 2.67). Single-cell omics revealed a tumor-specific correlation between DNA2 expression and functional annotations that encompass DNA damage, angiogenesis, and proliferation. Moreover, DNA2 expression was consistently positively associated with regulatory T-cell subtypes, but negatively related with NK cells, and cytotoxic T cells in multiple tumors as per immune landscape profiling. According to the pharmacogenomic analysis from GDSC2 dataset, tumor cells that express higher DNA2 are more sensitive to Tozasertib, and Daporinad. DNA2 is at the core of several interrelated modules, including flap processing, telomerase extension, and cell-cycle progression, according to the enrichment study. These findings have suggested DNA2 as a therapeutic vulnerability in cancer, a context-dependent biomarker with implications for treatment response, prognosis, and immunity.