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

Our plain-English summary of Multi-omics analysis positions DNA2 at the interface of genome integrity programs and tumor behavior in pan-cancer, by D. Pandit, A. Dhillon, S. Chakrabarty, et al (Functional & Integrative Genomics, 2026).

The study

• Authors: D. Pandit, A. Dhillon, S. Chakrabarty, R.S. Bilachi
• Journal: Functional & Integrative Genomics
• Published: 2026;26(1)
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© 2026. The Author(s).

In plain English

This was a computer-based analysis of public cancer databases, not a study of asbestos exposure. The authors studied a DNA repair gene, DNA2, using The Cancer Genome Atlas (TCGA) and other public resources. One analysis covered 32 studies with 10,967 samples. Of 19 cancer types with significant differences, 17 had higher DNA2 in tumors than in normal tissue; KICH kidney tumors had lower levels, and in melanoma (SKCM) metastases had higher levels than primary tumors. In unadjusted (univariate) survival analyses splitting patients at the median, high DNA2 expression was linked to worse overall survival in several cancers, including mesothelioma (hazard ratio 2.67) and adrenocortical carcinoma (hazard ratio 17.06). It was linked to better survival in the groups labelled COAD and THYM. DNA2 alterations were most frequent, about 7%, in endometrial cancer. Higher DNA2 in cancer cell lines went with greater sensitivity to Tozasertib and Daporinad. The authors noted that the survival analyses were not adjusted for age, stage or treatment, and called their findings correlative and hypothesis-generating. They concluded that DNA2 might be a therapeutic target and biomarker.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Pan-cancer bioinformatic (multi-omics) analysis of publicly available databases; no new patients or experiments
• Who was studied: TCGA tumor and normal tissue data across many cancer types, including a mesothelioma (MESO) cohort whose size and site (pleural or peritoneal) are not given in the text. The genetic-alteration analysis used 32 TCGA Pan-Cancer Atlas studies with 10,967 samples. Cancer cell lines and single-cell datasets from public resources were also used.
• Exposure: No asbestos or other environmental exposure was studied. The factor examined was the level of DNA2 gene expression. For survival, patients were split into high and low groups at the median.
• Main results:
  • Among 19 cancer types showing significant differences in DNA2 expression, 17 had higher DNA2 in tumors than in normal healthy tissue.
  • In skin melanoma (SKCM), the significant comparison was metastatic tissue against primary tumor: DNA2 was higher in metastatic tissue (p < 0.001).
  • In KICH tumor samples, DNA2 was lower than in non-cancerous tissue (p < 0.001).
  • In univariate survival analysis, high DNA2 expression was associated with worse overall survival in the mesothelioma (MESO) cohort (HR = 2.67, p = 1.73 × 10⁻⁴). It was also associated with worse survival in adrenocortical carcinoma (ACC; HR = 17.06, p = 5.69 × 10⁻⁶). The article text does not print confidence intervals.
  • Higher DNA2 expression was associated with better survival in COAD (HR = 0.54, p = 0.0124) and THYM (HR = 0.10, p = 0.0333).
  • Across the pan-cancer cohort, DNA2 genetic alterations were most frequent in endometrial cancer, at about 7%.
  • In BRCA, HNSC, KIRC, LIHC, PRAD and UCEC, regulatory T-cell subtypes were positively associated with DNA2 expression. In several solid tumors, NK cells, NKT cells, cytotoxic T cells and MAIT cells showed mainly significant negative correlations.
  • In the GDSC2 cancer cell-line drug dataset, higher DNA2 expression was associated with greater sensitivity to Tozasertib (z = -5.84, p = 7.8e-09) and Daporinad (z = -7.8, p = 1.16e-14).
• The authors' conclusion: The authors concluded that DNA2 might be a therapeutic target and a promising biomarker for prognosis and prediction. They also said their conclusions should be regarded as hypothesis-generating rather than as evidence of causality.
• Limitations the authors state:
  • The survival analysis could not be adjusted for clinical confounders such as age, tumor stage, TNM classification or treatment status.
  • The findings are correlative and should be interpreted cautiously.
  • Immune infiltration was estimated from bulk tumor sequencing data, so the results may be affected by tumor purity and heterogeneity.
  • Sample sizes varied across cancer types, and cross-platform verification is still needed.

Topics

Medical terms in this study, explained in our Lexicon: Overall Survival, Carcinoma, Mesothelioma, Angiogenesis, Biomarker, Prognosis.

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