DNA Damage Response Gene Signature as Potential Treatment Markers for Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) is a rapidly progressive cancer that often develops resistance against DNA damage inducers, such as radiotherapy and chemotherapy, which are still the standard of care regimens for this tumor. Thus, the identification of biomarkers capable of monitoring the clinical progression of OSCC and its responsiveness to therapy is strongly required. To meet this need, here we have employed Whole Genome Sequencing and RNA-seq data from a cohort of 316 patients retrieved from the TCGA Pan-Cancer Atlas to analyze the genomic and transcriptomic status of the DNA damage response (DDR) genes in OSCC. Then, we correlated the transcriptomic data with the clinical parameters of each patient. Finally, we relied on transcriptomic and drug sensitivity data from the CTRP v2 portal, performing Pearson’s correlation analysis to identify putative vulnerabilities of OSCC cell lines correlated with DDR gene expression. Our results indicate that several DDR genes show a high frequency of genomic and transcriptomic alterations and that the expression of some of them correlates with OSCC grading and infection by the human papilloma virus. In addition, we have identified a signature of eight DDR genes (namely CCNB1, CCNB2, CDK2, CDK4, CHECK1, E2F1, FANCD2, and PRKDC) that could be predictive for OSCC response to the novel antitumor compounds sorafenib and tipifarnib-P1. Altogether, our data demonstrate that alterations in DDR genes could have an impact on the biology of OSCC. Moreover, here we propose a DDR gene signature whose expression could be predictive of OSCC responsiveness to therapy.

[1]  Rebecca A Dagg,et al.  Targeting DNA damage response pathways in cancer , 2022, Nature Reviews Cancer.

[2]  G. Barillari,et al.  The Multiple Roles of CD147 in the Development and Progression of Oral Squamous Cell Carcinoma: An Overview , 2022, International journal of molecular sciences.

[3]  Nuzlinda Abdul Rahman,et al.  The Predictive Model of Oral Squamous Cell Survival Carcinoma: A Methodology of Validation , 2021, BioMed research international.

[4]  N. Malathi,et al.  Association of Human Papilloma Virus in Oral Squamous Cell Carcinoma: An Alarming Need for Human Papillomavirus 16 Screening in Cancer Patients , 2021, Journal of pharmacy & bioallied sciences.

[5]  Ling Gao,et al.  The Molecular Basis and Therapeutic Aspects of Cisplatin Resistance in Oral Squamous Cell Carcinoma , 2021, Frontiers in Oncology.

[6]  Helen K. Matthews,et al.  Cell cycle control in cancer , 2021, Nature Reviews Molecular Cell Biology.

[7]  S. Gondivkar,et al.  Oral and general health-related quality of life in oral squamous cell carcinoma patients- comparative analysis of different treatment regims. , 2021, Journal of oral biology and craniofacial research.

[8]  Sung-Bae Kim,et al.  Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations , 2021, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  M. Spampinato,et al.  Neoadjuvant presurgical PD-1 inhibition in oral cavity squamous cell carcinoma , 2019, Cell reports. Medicine.

[10]  Caicun Zhou,et al.  Alterations of DNA damage repair in cancer: from mechanisms to applications , 2020, Annals of translational medicine.

[11]  C. R. Leemans,et al.  Head and neck squamous cell carcinoma , 2020, Nature Reviews Disease Primers.

[12]  C. Mussolino,et al.  DNA Damage: From Threat to Treatment , 2020, Cells.

[13]  P. Majumder,et al.  Study of Caspase 8 mutation in oral cancer and adjacent precancer tissues and implication in progression , 2020, PloS one.

[14]  Brian Craft,et al.  Visualizing and interpreting cancer genomics data via the Xena platform , 2020, Nature Biotechnology.

[15]  R. de Bree,et al.  Staging and grading of oral squamous cell carcinoma: An update. , 2020, Oral oncology.

[16]  I. Farooq,et al.  Oral squamous cell carcinoma: metastasis, potentially associated malignant disorders, etiology and recent advancements in diagnosis , 2020, F1000Research.

[17]  S. Cheong,et al.  Translational Genomics and Recent Advances in Oral Squamous Cell Carcinoma. , 2020, Seminars in Cancer Biology.

[18]  A. Olshan,et al.  Long‐term Survival in Head and Neck Cancer: Impact of Site, Stage, Smoking, and Human Papillomavirus Status , 2019, The Laryngoscope.

[19]  R. Franco,et al.  Oral and Oropharyngeal squamous cell carcinoma: prognostic and predictive parameters in the etiopathogenetic route , 2019, Expert review of anticancer therapy.

[20]  Akira Hara,et al.  A Review of HPV-Related Head and Neck Cancer , 2018, Journal of clinical medicine.

[21]  N. Socci,et al.  Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers. , 2018, Cancer research.

[22]  E. Uro-Coste,et al.  [WHO classification of head and neck tumours 2017: Main novelties and update of diagnostic methods]. , 2018, Bulletin du cancer.

[23]  H. Takahashi,et al.  Targeting the DNA Damage Response in OSCC with TP53 Mutations , 2018, Journal of dental research.

[24]  V. Khanna,et al.  Estimation of serum ferritin level in potentially malignant disorders, oral squamous cell carcinoma, and treated cases of oral squamous cell carcinoma , 2017, Journal of cancer research and therapeutics.

[25]  Alan Ashworth,et al.  PARP inhibitors: Synthetic lethality in the clinic , 2017, Science.

[26]  A. Nussenzweig,et al.  Endogenous DNA Damage as a Source of Genomic Instability in Cancer , 2017, Cell.

[27]  Jeffrey N Myers,et al.  TP53 Mutations in Head and Neck Squamous Cell Carcinoma and Their Impact on Disease Progression and Treatment Response , 2016, Journal of cellular biochemistry.

[28]  R. Grenman,et al.  Effect of sorafenib on cisplatin-based chemoradiation in head and neck cancer cells , 2016, Oncotarget.

[29]  Joshua A. Bittker,et al.  Correlating chemical sensitivity and basal gene expression reveals mechanism of action , 2015, Nature chemical biology.

[30]  Shikha Gupta,et al.  Role of human papillomavirus in oral squamous cell carcinoma and oral potentially malignant disorders: A review of the literature , 2015, Indian journal of dentistry.

[31]  Steven J. M. Jones,et al.  Comprehensive genomic characterization of head and neck squamous cell carcinomas , 2015, Nature.

[32]  Fei-Ting Hsu,et al.  Synergistic effect of sorafenib with ionizing radiation on human oral cancer cells. , 2014, In vivo.

[33]  T. Grob,et al.  Sorafenib sensitizes head and neck squamous cell carcinoma cells to ionizing radiation. , 2013, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[34]  R. Gibbs,et al.  Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. , 2013, Cancer discovery.

[35]  R. Gibbs,et al.  Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1 , 2011, Science.

[36]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[37]  Ruud H. Brakenhoff,et al.  The molecular biology of head and neck cancer , 2011, Nature Reviews Cancer.

[38]  J. Bartek,et al.  The DNA-damage response in human biology and disease , 2009, Nature.

[39]  D. Wong,et al.  Overexpression of CDK2 Is a Prognostic Indicator of Oral Cancer Progression , 2001, Japanese journal of cancer research : Gann.

[40]  C. Bowden,et al.  Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. , 2001, Cancer research.

[41]  N. Bresolin,et al.  In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria. , 1991, Molecular and cellular biology.