Drug sensitivity prediction models reveal a link between DNA repair defects and poor prognosis in HNSCC.

Head and neck squamous cell carcinoma (HNSCC) is characterized by the frequent manifestation of DNA crosslink repair defects. We established novel expression-based DNA repair defect markers to determine the clinical impact of such repair defects. Using hypersensitivity to the DNA crosslinking agents mitomycin C and olaparib as proxies for functional DNA repair defects in a panel of 25 HNSCC cell lines, we applied machine learning to define gene expression models that predict repair defects. The expression profiles established predicted hypersensitivity to DNA damaging agents and were associated with mutations in crosslink repair genes, as well as downregulation of DNA damage response and repair genes, in two independent datasets. The prognostic value of the repair defect prediction profiles was assessed in two retrospective cohorts with a total of 180 advanced HPV-negative HNSCC patients, who were treated with cisplatin-based chemo-radiotherapy. DNA repair defects, as predicted by the profiles, were associated with poor outcome in both patient cohorts. The poor prognosis association was particularly strong in normoxic tumor samples and was linked to an increased risk of distant metastasis. In vitro, only crosslink repair defective HNSCC cell lines are highly migratory and invasive. This phenotype could also be induced in cells by inhibiting rad51 in repair competent and reduced by DNA-PK inhibition. In conclusion, DNA crosslink repair prediction expression profiles reveal a poor prognosis association in HNSCC.

[1]  F. Hoebers,et al.  Acute Hypoxia Profile is a Stronger Prognostic Factor than Chronic Hypoxia in Advanced Stage Head and Neck Cancer Patients , 2019, Cancers.

[2]  Michiel W M van den Brekel,et al.  Role of variant allele fraction and rare SNP filtering to improve cellular DNA repair endpoint association , 2018, PloS one.

[3]  Lodewyk F.A. Wessels,et al.  Fanconi anemia and homologous recombination gene variants are associated with functional DNA repair defects in vitro and poor outcome in patients with advanced head and neck squamous cell carcinoma , 2018, Oncotarget.

[4]  Michael T. Zimmermann,et al.  Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas , 2018, Cell reports.

[5]  Ruud H. Brakenhoff,et al.  The molecular landscape of head and neck cancer , 2018, Nature Reviews Cancer.

[6]  Samuel F. Bakhoum,et al.  Chromosomal instability drives metastasis through a cytosolic DNA response , 2017, Nature.

[7]  S. Loi,et al.  Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. , 2017, New England Journal of Medicine.

[8]  A. Adeyemo,et al.  Assessing the spectrum of germline variation in Fanconi anemia genes among patients with head and neck carcinoma before age 50 , 2017, Cancer.

[9]  A. Al-Mamgani,et al.  The impact of cumulative dose of cisplatin on outcome of patients with head and neck squamous cell carcinoma , 2017, European Archives of Oto-Rhino-Laryngology.

[10]  S. Boulton,et al.  Mechanisms of DNA–protein crosslink repair , 2017, Nature Reviews Molecular Cell Biology.

[11]  M. Robson,et al.  Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation , 2017, The New England journal of medicine.

[12]  Y. Pommier,et al.  Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action , 2016, Science Translational Medicine.

[13]  S. Bhide,et al.  Delayed DNA double-strand break repair following platin-based chemotherapy predicts treatment response in head and neck squamous cell carcinoma , 2016, British Journal of Cancer.

[14]  John P. A. Ioannidis,et al.  What does research reproducibility mean? , 2016, Science Translational Medicine.

[15]  S. Cantor,et al.  Replication Fork Stability Confers Chemoresistance in BRCA-deficient Cells , 2016, Nature.

[16]  M. Cohn,et al.  Cellular response to DNA interstrand crosslinks: the Fanconi anemia pathway , 2016, Cellular and Molecular Life Sciences.

[17]  E. Rankin,et al.  Hypoxic control of metastasis , 2016, Science.

[18]  Jason Kaplan,et al.  Genomic landscape of DNA repair genes in cancer , 2016, Oncotarget.

[19]  P. Jeggo,et al.  DNA repair, genome stability and cancer: a historical perspective , 2015, Nature Reviews Cancer.

[20]  Elizabeth E. Hoskins,et al.  Defects in the Fanconi Anemia Pathway in Head and Neck Cancer Cells Stimulate Tumor Cell Invasion through DNA-PK and Rac1 Signaling , 2015, Clinical Cancer Research.

[21]  M. O’Connor,et al.  Targeting the DNA Damage Response in Cancer. , 2015, Molecular cell.

[22]  M. Johnson,et al.  Circulating microRNAs in Sera Correlate with Soluble Biomarkers of Immune Activation but Do Not Predict Mortality in ART Treated Individuals with HIV-1 Infection: A Case Control Study , 2015, PloS one.

[23]  J. Efstathiou,et al.  DNA Damage Response Assessments in Human Tumor Samples Provide Functional Biomarkers of Radiosensitivity. , 2015, Seminars in radiation oncology.

[24]  S. Feller,et al.  Defects in the Fanconi Anemia Pathway and Chromatid Cohesion in Head and Neck Cancer. , 2015, Cancer research.

[25]  L. Wessels,et al.  Pretreatment microRNA Expression Impacting on Epithelial-to-Mesenchymal Transition Predicts Intrinsic Radiosensitivity in Head and Neck Cancer Cell Lines and Patients , 2015, Clinical Cancer Research.

[26]  L. Walker,et al.  Meeting the challenges of interpreting variants of unknown clinical significance in BRCA testing. , 2015, The New Zealand medical journal.

[27]  L. Levin,et al.  Biodiversity on the Rocks: Macrofauna Inhabiting Authigenic Carbonate at Costa Rica Methane Seeps , 2015, PloS one.

[28]  I. Huijbers,et al.  Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer , 2015, Proceedings of the National Academy of Sciences.

[29]  T. Stracker,et al.  ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion , 2015, eLife.

[30]  M. Dutreix,et al.  DNA-PKcs plays role in cancer metastasis through regulation of secreted proteins involved in migration and invasion , 2015, Cell cycle.

[31]  James M Ford,et al.  Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  R. Tollenaar,et al.  Worse Breast Cancer Prognosis of BRCA1/BRCA2 Mutation Carriers: What's the Evidence? A Systematic Review with Meta-Analysis , 2015, PloS one.

[33]  David J. Anderson,et al.  Ventromedial hypothalamic neurons control a defensive emotion state , 2015, eLife.

[34]  B. Arun,et al.  Cancers Associated with Brca1 and Brca2 Mutations Other than Breast and Ovarian Cancers Associated with Brca1 and Brca2 Mutations Other than Breast and Ovarian , 2022 .

[35]  E. Yagüe,et al.  Leptin induces upregulation of sphingosine kinase 1 in oestrogen receptor-negative breast cancer via Src family kinase-mediated, janus kinase 2-independent pathway , 2014, Breast Cancer Research.

[36]  K. Knudsen,et al.  Beyond DNA repair: DNA-PK function in cancer. , 2014, Cancer discovery.

[37]  A. Sieuwerts,et al.  Functional Ex Vivo Assay to Select Homologous Recombination–Deficient Breast Tumors for PARP Inhibitor Treatment , 2014, Clinical Cancer Research.

[38]  Anita Grigoriadis,et al.  Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers , 2014, Breast Cancer Research.

[39]  Li V. Yang,et al.  In vitro cell migration and invasion assays. , 2014, Journal of visualized experiments : JoVE.

[40]  Jeffrey E. Green,et al.  Transcriptional Roles of PARP1 in Cancer , 2014, Molecular Cancer Research.

[41]  Ralph R. Weichselbaum,et al.  DNA Repair Pathway Gene Expression Score Correlates with Repair Proficiency and Tumor Sensitivity to Chemotherapy , 2014, Science Translational Medicine.

[42]  Samy Lamouille,et al.  Molecular mechanisms of epithelial–mesenchymal transition , 2014, Nature Reviews Molecular Cell Biology.

[43]  G. Mills,et al.  Genome-wide Transcriptome Profiling of Homologous Recombination DNA Repair , 2014, Nature Communications.

[44]  S. Rodenhuis,et al.  Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy , 2014, Breast Cancer Research.

[45]  Sheena M. Scroggins,et al.  Germline and Somatic Mutations in Homologous Recombination Genes Predict Platinum Response and Survival in Ovarian, Fallopian Tube, and Peritoneal Carcinomas , 2013, Clinical Cancer Research.

[46]  A. Jimeno,et al.  Epithelial stem cell mutations that promote squamous cell carcinoma metastasis. , 2013, The Journal of clinical investigation.

[47]  Edward Y. Chen,et al.  Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool , 2013, BMC Bioinformatics.

[48]  J. Grandis,et al.  The Fanconi anemia pathway: repairing the link between DNA damage and squamous cell carcinoma. , 2013, Mutation research.

[49]  Shridar Ganesan,et al.  Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. , 2013, Cancer discovery.

[50]  Christine Unger,et al.  In vitro cell migration and invasion assays. , 2013, Mutation research.

[51]  Klemens Vierlinger,et al.  Meta-Analysis of Gene Expression Signatures Defining the Epithelial to Mesenchymal Transition during Cancer Progression , 2012, PloS one.

[52]  Michael Peyton,et al.  An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance , 2012, Clinical Cancer Research.

[53]  John Quackenbush,et al.  Profiles of Genomic Instability in High-Grade Serous Ovarian Cancer Predict Treatment Outcome , 2012, Clinical Cancer Research.

[54]  R. Jewkes,et al.  Perceptions and Experiences of Research Participants on Gender-Based Violence Community Based Survey: Implications for Ethical Guidelines , 2012, PloS one.

[55]  A. D’Andrea,et al.  A DNA Repair Pathway–Focused Score for Prediction of Outcomes in Ovarian Cancer Treated With Platinum-Based Chemotherapy , 2012, Journal of the National Cancer Institute.

[56]  S. Ramaswamy,et al.  Systematic identification of genomic markers of drug sensitivity in cancer cells , 2012, Nature.

[57]  R. Bristow,et al.  Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. , 2010, Cancer research.

[58]  P. Maxwell,et al.  Novel In Vitro Assays for the Characterization of EMT in Tumourigenesis , 2010, Cellular oncology : the official journal of the International Society for Cellular Oncology.

[59]  A. Ghanate,et al.  Snail and Slug Mediate Radioresistance and Chemoresistance by Antagonizing p53‐Mediated Apoptosis and Acquiring a Stem‐Like Phenotype in Ovarian Cancer Cells , 2009, Stem cells.

[60]  R. Crystal,et al.  A SNAIL1–SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial–mesenchymal transition , 2009, Nature Cell Biology.

[61]  K. Venkatasubbarao,et al.  Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. , 2008, Cancer research.

[62]  Richard P. Hill,et al.  Hypoxia and metabolism: Hypoxia, DNA repair and genetic instability , 2008, Nature Reviews Cancer.

[63]  F. Couch,et al.  Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers , 2008, Nature.

[64]  Paul Lizardi,et al.  Down-Regulation of Rad51 and Decreased Homologous Recombination in Hypoxic Cancer Cells , 2004, Molecular and Cellular Biology.

[65]  I. Tan,et al.  High‐dose superselective intra‐arterial cisplatin and concomitant radiation (radplat) for advanced head and neck cancer , 2004, Head & neck.

[66]  D. Brachman,et al.  Molecular biology of head and neck cancer. , 1994, Seminars in oncology.