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<article xsi:noNamespaceSchemaLocation="http://jats.nlm.nih.gov/publishing/1.1/xsd/JATS-journalpublishing1-mathml3.xsd" dtd-version="1.1" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"><front><journal-meta><journal-id journal-id-type="publisher-id">PAR</journal-id><journal-title-group><journal-title>Proceedings of Anticancer Research</journal-title></journal-title-group><issn>2208-3545</issn><eissn>2208-3553</eissn><publisher><publisher-name>Bio-Byword Scientific Publishing Pty. Ltd.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.26689/par.v8i5.7460</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title>ATM is a Prognostic Biomarker of Survival in Head and Neck Squamous Cell Carcinoma Patients</title><url>https://artdesignp.com/journal/PAR/8/5/10.26689/par.v8i5.7460</url><author>AbidMuhammad Umair</author><pub-date pub-type="publication-year"><year>2024</year></pub-date><volume>8</volume><issue>5</issue><history><date date-type="pub"><published-time>2024-09-25</published-time></date></history><abstract>This review examines the role of ATM expression in head and neck squamous cell carcinoma (HNSCC). Analysis revealed significant overexpression of ATM in HNSCC cells compared to normal control samples, suggesting its involvement in cancer proliferation. ATM expression was notably upregulated across various clinical parameters, including different stages of cancer, racial groups, genders, and age groups, highlighting its role in cancer progression. Validation using the GEPIA2 tool confirmed strong ATM expression throughout all four stages of HNSCC, with the highest levels in stage II and the lowest in stage I. Promoter methylation analysis of ATM showed distinct patterns across different demographics and cancer stages, reinforcing its significance. The study also explored the relationship between ATM expression and patient outcomes using the KM plotter tool, finding that high ATM expression was associated with better overall survival (OS), while low ATM expression correlated with better disease-free survival (DFS). Genetic mutation analysis via cBioPortal identified minimal ATM mutations in HNSCC, including in-frame, splice, truncating, and missense mutations, suggesting their role in ATM dysregulation. The STRING tool was used to construct a protein-protein interaction (PPI) network, revealing that the ATM gene interacts with ten key genes (NBN, ATR, CHEK2, MDC1, MSH2, MSH6, MRE11, TP53, TP53BP1, BRCA1), indicating its involvement in various biological functions. Functional annotation of differentially expressed genes (DEGs) through the DAVID web server revealed their participation in critical biological processes, including double-strand break repair, cellular response to DNA damage, and DNA damage checkpoints. KEGG pathway analysis further linked DEGs to cellular senescence, platinum drug resistance, homologous recombination, p53 signaling, and the cell cycle, underscoring ATM’s multifaceted role in HNSCC.</abstract><keywords/></article-meta></front><body/><back><ref-list><ref id="B1" content-type="article"><label>1</label><element-citation publication-type="journal"><p>Mody MD, Rocco JW, Yom SS, et al., 2021, Head and Neck Cancer. Lancet, 398(10318): 2289–2299. https://doi.org/10.1016/S0140-6736(21)01550-6</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B2" content-type="article"><label>2</label><element-citation publication-type="journal"><p>Antra, Parashar P, Hungyo H, et al., 2022, Unraveling Molecular Mechanisms of Head and Neck Cancer. Crit Rev Oncol Hematol, 178: 103778. https://doi.org/10.1016/j.critrevonc.2022.103778</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B3" content-type="article"><label>3</label><element-citation publication-type="journal"><p>Pulte D, Brenner H, 2010, Changes in Survival in Head and Neck Cancers in the Late 20th and Early 21st Century: A Period Analysis. Oncologist, 15(9): 994–1001. https://doi.org/10.1634/theoncologist.2009-0289</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B4" content-type="article"><label>4</label><element-citation publication-type="journal"><p>Barnes JM, Graboyes EM, Adjei Boakye E, et al., 2023, The Affordable Care Act and suicide incidence among adults with cancer. J Cancer Surviv, 17(2): 449–459. https://doi.org/10.1007/s11764-022-01205-z</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B5" content-type="article"><label>5</label><element-citation publication-type="journal"><p>Sung H, Ferlay J, Siegel RL, et al., 2021, Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 71(3): 209–249. https://doi.org/10.3322/caac.21660</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B6" content-type="article"><label>6</label><element-citation publication-type="journal"><p>Reis Ferreira M, Pasto A, Ng T, et al., 2022, The Microbiota and Radiotherapy for Head and Neck Cancer: What Should Clinical Oncologists Know? Cancer Treat Rev, 109: 102442. https://doi.org/10.1016/j.ctrv.2022.102442</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B7" content-type="article"><label>7</label><element-citation publication-type="journal"><p>Rothenberg SM, Ellisen LW, 2012, The Molecular Pathogenesis of Head and Neck Squamous Cell Carcinoma. J Clin Invest, 122(6): 1951–1957. https://doi.org/10.1172/jci59889</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B8" content-type="article"><label>8</label><element-citation publication-type="journal"><p>Yin J, He X, Qin F, et al., 2022, m6A-Related lncRNA Signature for Predicting Prognosis and Immune Response in Head and Neck Squamous Cell Carcinoma. Am J Transl Res, 14(11): 7653–7669.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B9" content-type="article"><label>9</label><element-citation publication-type="journal"><p>Moslemi M, Moradi Y, Dehghanbanadaki H, et al., 2021, The Association Between ATM Variants and Risk of Breast Cancer: A Systematic Review and Meta-Analysis. BMC Cancer, 21(1): 27. https://doi.org/10.1186/s12885-020-07749-6</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B10" content-type="article"><label>10</label><element-citation publication-type="journal"><p>Dork T, Bendix R, Bremer M, et al., 2001, Spectrum of ATM Gene Mutations in a Hospital-Based Series of Unselected Breast Cancer Patients. Cancer Res, 61(20): 7608–7615.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B11" content-type="article"><label>11</label><element-citation publication-type="journal"><p>Fernandes N, Sun Y, Chen S, et al., 2005, DNA Damage-Induced Association of ATM with Its Target Proteins Requires a Protein Interaction Domain in the N Terminus of ATM. J Biol Chem, 280(15): 15158–15164. https://doi.org/10.1074/jbc.M412065200</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B12" content-type="article"><label>12</label><element-citation publication-type="journal"><p>Andrade MA, Petosa C, O'Donoghue SI, et al., 2001, Comparison of ARM and HEAT Protein Repeats. J Mol Biol, 309(1): 1–18. https://doi.org/10.1006/jmbi.2001.4624</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B13" content-type="article"><label>13</label><element-citation publication-type="journal"><p>Piazza I, Rutkowska A, Ori A, et al., 2014, Association of Condensin with Chromosomes Depends on DNA Binding by Its HEAT-Repeat Subunits. Nat Struct Mol Biol, 21(6): 560–568. https://doi.org/10.1038/nsmb.2831</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B14" content-type="article"><label>14</label><element-citation publication-type="journal"><p>Rubinson EH, Gowda AS, Spratt TE, et al., 2010, An Unprecedented Nucleic Acid Capture Mechanism for Excision of DNA Damage. Nature, 468(7322): 406–411. https://doi.org/10.1038/nature09428</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B15" content-type="article"><label>15</label><element-citation publication-type="journal"><p>Lee JH, Paull TT, 2005, ATM Activation by DNA Double-Strand Breaks Through the Mre11-Rad50-Nbs1 Complex. Science, 308(5721): 551–554. https://doi.org/10.1126/science.1108297</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B16" content-type="article"><label>16</label><element-citation publication-type="journal"><p>Lee JH, Paull TT, 2004, Direct Activation of the ATM Protein Kinase by the Mre11/Rad50/Nbs1 Complex. Science, 304(5667): 93–6. https://doi.org/10.1126/science.1091496</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B17" content-type="article"><label>17</label><element-citation publication-type="journal"><p>Uziel T, Lerenthal Y, Moyal L, et al., 2003, Requirement of the MRN Complex for ATM Activation by DNA Damage. EMBO J, 22(20): 5612–5621. https://doi.org/10.1093/emboj/cdg541</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B18" content-type="article"><label>18</label><element-citation publication-type="journal"><p>Shiloh Y, Ziv Y, 2013, The ATM Protein Kinase: Regulating the Cellular Response to Genotoxic Stress, and More. Nat Rev Mol Cell Biol, 14(4): 197–210. https://doi.org/10.1038/nrm3546</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B19" content-type="article"><label>19</label><element-citation publication-type="journal"><p>Swift M, Morrell D, Cromartie E, et al., 1986, The Incidence and Gene Frequency of Ataxia-Telangiectasia in the United States. Am J Hum Genet, 39(5): 573–583.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B20" content-type="article"><label>20</label><element-citation publication-type="journal"><p>Cremona CA, Behrens A, 2014, ATM Signalling and Cancer. Oncogene, 33(26): 3351–3360. https://doi.org/10.1038/onc.2013.275</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B21" content-type="article"><label>21</label><element-citation publication-type="journal"><p>Song L, Lin C, Wu Z, et al., 2011, miR-18a Impairs DNA Damage Response Through Downregulation of Ataxia Telangiectasia Mutated (ATM) Kinase. PLoS One, 6(9): e25454. https://doi.org/10.1371/journal.pone.0025454</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B22" content-type="article"><label>22</label><element-citation publication-type="journal"><p>Rezaeian AH, Khanbabaei H, Calin GA, 2020, Therapeutic Potential of the miRNA-ATM Axis in the Management of Tumor Radioresistance. Cancer Res, 80(2): 139–150. https://doi.org/10.1158/0008-5472.CAN-19-1807</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B23" content-type="article"><label>23</label><element-citation publication-type="journal"><p>Matsuoka S, Ballif BA, Smogorzewska A, et al., 2007, ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage. Science, 316(5828): 1160–1166. https://doi.org/10.1126/science.1140321</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B24" content-type="article"><label>24</label><element-citation publication-type="journal"><p>Thompson D, Duedal S, Kirner J, et al., 2005, Cancer Risks and Mortality in Heterozygous ATM Mutation Carriers. J Natl Cancer Inst, 97(11): 813–822. https://doi.org/10.1093/jnci/dji141</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B25" content-type="article"><label>25</label><element-citation publication-type="journal"><p>Goldgar DE, Healey S, Dowty JG, et al., 2011, Rare Variants in the ATM Gene and Risk of Breast Cancer. Breast Cancer Res, 13(4): R73. https://doi.org/10.1186/bcr2919</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B26" content-type="article"><label>26</label><element-citation publication-type="journal"><p>Angele S, Hall J, 2000, The ATM Gene and Breast Cancer: Is It Really A Risk Factor? Mutat Res, 462(2–3): 167–178. https://doi.org/10.1016/s1383-5742(00)00034-x</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B27" content-type="article"><label>27</label><element-citation publication-type="journal"><p>Chandrashekar DS, Bashel B, Balasubramanya SAH, et al., 2017, UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia, 19(8): 649–658. https://doi.org/10.1016/j.neo.2017.05.002</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B28" content-type="article"><label>28</label><element-citation publication-type="journal"><p>Tang Z, Kang B, Li C, et al., 2019, GEPIA2: An Enhanced Web Server for Large-Scale Expression Profiling and Interactive Analysis. Nucleic Acids Res, 47(W1): W556–W560. https://doi.org/10.1093/nar/gkz430</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B29" content-type="article"><label>29</label><element-citation publication-type="journal"><p>Maciejczyk A, Szelachowska J, Czapiga B, et al., 2013, Elevated BUBR1 Expression is Associated with Poor Survival in Early Breast Cancer Patients: 15-Year Follow-Up Analysis. J Histochem Cytochem, 61(5): 330–339. https://doi.org/10.1369/0022155413480148</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B30" content-type="article"><label>30</label><element-citation publication-type="journal"><p>Cerami E, Gao J, Dogrusoz U, et al., 2012, The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discov, 2(5): 401–404. https://doi.org/10.1158/2159-8290.CD-12-0095</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B31" content-type="article"><label>31</label><element-citation publication-type="journal"><p>von Mering C, Huynen M, Jaeggi D, et al., 2003, STRING: A Database of Predicted Functional Associations Between Proteins. Nucleic Acids Res, 31(1): 258–261. https://doi.org/10.1093/nar/gkg034</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B32" content-type="article"><label>32</label><element-citation publication-type="journal"><p>Szklarczyk D, Morris JH, Cook H, et al., 2017, The STRING Database in 2017: Quality-Controlled Protein-Protein Association Networks, Made Broadly Accessible. Nucleic Acids Res, 45(D1): D362–D368. https://doi.org/10.1093/nar/gkw937</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B33" content-type="article"><label>33</label><element-citation publication-type="journal"><p>Franceschini A, Szklarczyk D, Frankild S, et al., 2013, STRING v9.1: Protein-Protein Interaction Networks, With Increased Coverage and Integration. Nucleic Acids Res, 41(Database issue): D808–815. https://doi.org/10.1093/nar/gks1094</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B34" content-type="article"><label>34</label><element-citation publication-type="journal"><p>von Mering C, Jensen LJ, Snel B, et al., 2005, STRING: Known and Predicted Protein-Protein Associations, Integrated and Transferred Across Organisms. Nucleic Acids Res, 33(Database issue): D433–D437. https://doi.org/10.1093/nar/gki005</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B35" content-type="article"><label>35</label><element-citation publication-type="journal"><p>Huang DW, Sherman BT, Lempicki RA, 2009, Systematic and Integrative Analysis of Large Gene Lists Using DAVID Bioinformatics Resources. Nat Protoc, 4(1): 44–57. https://doi.org/10.1038/nprot.2008.211</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B36" content-type="article"><label>36</label><element-citation publication-type="journal"><p>Denny JC, Collins FS, 2021, Precision Medicine in 2030 – Seven Ways to Transform Healthcare. Cell, 184(6): 1415–1419. https://doi.org/10.1016/j.cell.2021.01.015</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B37" content-type="article"><label>37</label><element-citation publication-type="journal"><p>Krzyszczyk P, Acevedo A, Davidoff EJ, et al., 2018, The Growing Role of Precision and Personalized Medicine for Cancer Treatment. Technology (Singap World Sci), 6(3–4): 79–100. https://doi.org/10.1142/S2339547818300020</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B38" content-type="article"><label>38</label><element-citation publication-type="journal"><p>Chi H, Xie X, Yan Y, et al., 2022, Natural Killer Cell-Related Prognosis Signature Characterizes Immune Landscape and Predicts Prognosis of HNSCC. Front Immunol, 13: 1018685. https://doi.org/10.3389/fimmu.2022.1018685</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B39" content-type="article"><label>39</label><element-citation publication-type="journal"><p>Li Z, Zheng C, Liu H, et al., 2023, A Novel Oxidative Stress-Related Gene Signature as An Indicator of Prognosis and Immunotherapy Responses in HNSCC. Aging (Albany NY), 15(24): 14957–14984. https://doi.org/10.18632/aging.205323</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B40" content-type="article"><label>40</label><element-citation publication-type="journal"><p>Nan Z, Dou Y, Chen A, et al., 2023, Identification and Validation of A Prognostic Signature of Autophagy, Apoptosis and Pyroptosis-Related Genes for Head and Neck Squamous Cell Carcinoma: To Imply Therapeutic Choices of HPV Negative Patients. Front Immunol, 13: 1100417. https://doi.org/10.3389/fimmu.2022.1100417</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B41" content-type="article"><label>41</label><element-citation publication-type="journal"><p>Lugano R, Ramachandran M, Dimberg A, 2020, Tumor Angiogenesis: Causes, Consequences, Challenges and Opportunities. Cell Mol Life Sci, 77(9): 1745–1770. https://doi.org/10.1007/s00018-019-03351-7</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B42" content-type="article"><label>42</label><element-citation publication-type="journal"><p>Stine ZE, Schug ZT, Salvino JM, et al., 2022, Targeting Cancer Metabolism in the Era of Precision Oncology. Nat Rev Drug Discov, 21(2): 141–162. https://doi.org/10.1038/s41573-021-00339-6</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B43" content-type="article"><label>43</label><element-citation publication-type="journal"><p>Onkar SS, Carleton NM, Lucas PC, et al., 2023, The Great Immune Escape: Understanding the Divergent Immune Response in Breast Cancer Subtypes. Cancer Discov, 13(1): 23–40. https://doi.org/10.1158/2159-8290.CD-22-0475</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B44" content-type="article"><label>44</label><element-citation publication-type="journal"><p>Rotman G, Shiloh Y, 1998, ATM: From Gene To Function. Hum Mol Genet, 7(10): 1555–1563. https://doi.org/10.1093/hmg/7.10.1555. PMID: 9735376.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B45" content-type="article"><label>45</label><element-citation publication-type="journal"><p>Broeks A, Urbanus JH, Floore AN, et al., 2000, ATM-Heterozygous Germline Mutations Contribute to Breast Cancer-Susceptibility. Am J Hum Genet, 66(2): 494–500. https://doi.org/10.1086/302746</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B46" content-type="article"><label>46</label><element-citation publication-type="journal"><p>Fletcher O, Johnson N, dos Santos Silva I, et al., 2010, Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls. Cancer Epidemiol Biomarkers Prev, 19(9): 2143–2151. https://doi.org/10.1158/1055-9965.EPI-10-0374</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B47" content-type="article"><label>47</label><element-citation publication-type="journal"><p>Thorstenson YR, Roxas A, Kroiss R, et al., 2003, Contributions of ATM Mutations to Familial Breast and Ovarian Cancer. Cancer Res, 63(12): 3325–3333.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B48" content-type="article"><label>48</label><element-citation publication-type="journal"><p>Abraham RT, 2004, PI 3-Kinase Related Kinases: ‘Big’ Players in Stress-Induced Signaling Pathways. DNA Repair (Amst), 3(8–9): 883–887. https://doi.org/10.1016/j.dnarep.2004.04.002</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B49" content-type="article"><label>49</label><element-citation publication-type="journal"><p>Hall MJ, Bernhisel R, Hughes E, et al., 2021, Germline Pathogenic Variants in the Ataxia Telangiectasia Mutated (ATM) Gene are Associated with High and Moderate Risks for Multiple Cancers. Cancer Prev Res (Phila), 14(4): 433–440. https://doi.org/10.1158/1940-6207.CAPR-20-0448</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B50" content-type="article"><label>50</label><element-citation publication-type="journal"><p>Breast Cancer Association Consortium, Dorling L, Carvalho S, et al., 2021, Breast Cancer Risk Genes – Association Analysis in More than 113,000 Women. N Engl J Med, 384(5): 428–439. https://doi.org/10.1056/NEJMoa1913948</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B51" content-type="article"><label>51</label><element-citation publication-type="journal"><p>Meng ZH, Ben Y, Li Z, et al., 2004, Aberrations of Breast Cancer Susceptibility Genes Occur Early in Sporadic Breast Tumors and In Acquisition of Breast Epithelial Immortalization. Genes Chromosomes Cancer, 41(3): 214–222. https://doi.org/10.1002/gcc.20089</p><pub-id pub-id-type="doi"/></element-citation></ref></ref-list></back></article>
