title: Multi-tiered genomic analysis of head and neck cancer ties TP53 mutation to 3p loss.
abstract: Head and neck squamous cell carcinoma (HNSCC) is characterized by aggressive behavior with a propensity for metastasis and recurrence. Here we report a comprehensive analysis of the molecular and clinical features of HNSCC that govern patient survival. We find that TP53 mutation is frequently accompanied by loss of chromosome 3p and that the combination of these events is associated with a surprising decrease in survival time (1.9 years versus >5 years for TP53 mutation alone). The TP53-3p interaction is specific to chromosome 3p and validates in HNSCC and pan-cancer cohorts. In human papillomavirus (HPV)-positive tumors, in which HPV inactivates TP53, 3p deletion is also common and is associated with poor outcomes. The TP53-3p event is modified by mir-548k expression, which decreases survival further, and is mutually exclusive with mutations affecting RAS signaling. Together, the identified markers underscore the molecular heterogeneity of HNSCC and enable a new multi-tiered classification of this disease.
authors.affiliation: Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, California, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Gross
authors.affiliation: Division of Head and Neck Surgery, University of California, San Diego, La Jolla, California, USA.
authors.forename: Ryan K
authors.identifier: 0000000278854327
authors.initials: RK
authors.lastname: Orosco
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Shen
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Egloff
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Carter
authors.affiliation: Department of Computer Science and Engineering, University of California, San Diego, La Jolla, California, USA.
authors.forename: Matan
authors.initials: M
authors.lastname: Hofree
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Choueiri
authors.affiliation: Division of Head and Neck Surgery, University of California, San Diego, La Jolla, California, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Coffey
authors.affiliation: 1] Division of Head and Neck Surgery, University of California, San Diego, La Jolla, California, USA. [2] Department of Medicine, University of California, San Diego, La Jolla, California, USA. [3] Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: D Neil
authors.initials: DN
authors.lastname: Hayes
authors.affiliation: 1] Department of Medicine, University of California, San Diego, La Jolla, California, USA. [2] Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors.forename: Ezra E
authors.initials: EE
authors.lastname: Cohen
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.affiliation: 1] Division of Head and Neck Surgery, University of California, San Diego, La Jolla, California, USA. [2] Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors.forename: Quyen T
authors.initials: QT
authors.lastname: Nguyen
authors.affiliation: 1] Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, California, USA. [2] Department of Medicine, University of California, San Diego, La Jolla, California, USA. [3] Department of Computer Science and Engineering, University of California, San Diego, La Jolla, California, USA. [4] Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002893:Chromosomes, Human, Pair 3; D016158:Genes, p53; D023281:Genomics / Q000379:methods; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D000077195:Squamous Cell Carcinoma of Head and Neck; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
references.citation: PLoS One. 2013;8(2):e56823
references.pmid: 23451093
references.citation: Oncogene. 2012 Jan 26;31(4):446-57
references.pmid: 21725359
references.citation: Cancer Cell. 2004 May;5(5):489-500
references.pmid: 15144956
references.citation: Genome Res. 2010 Sep;20(9):1297-303
references.pmid: 20644199
references.citation: Br J Cancer. 1999 Apr;79(11-12):1821-7
references.pmid: 10206299
references.citation: Lancet Oncol. 2010 Aug;11(8):781-9
references.pmid: 20451455
references.citation: N Engl J Med. 2007 Dec 20;357(25):2552-61
references.pmid: 18094376
references.citation: Cancer Discov. 2013 Jul;3(7):770-81
references.pmid: 23619168
references.citation: Head Neck. 2011 Jun;33(6):817-23
references.pmid: 20737489
references.citation: Genome Res. 2012 Feb;22(2):398-406
references.pmid: 21908773
references.citation: Br J Cancer. 1996 Feb;73(3):366-71
references.pmid: 8562343
references.citation: J Clin Oncol. 2007 Jun 1;25(16):2164-70
references.pmid: 17538160
references.citation: Science. 2011 Aug 26;333(6046):1157-60
references.pmid: 21798893
references.citation: Genome Biol. 2011;12(4):R41
references.pmid: 21527027
references.citation: Cell. 1996 Feb 23;84(4):587-97
references.pmid: 8598045
references.citation: Nat Biotechnol. 2013 Mar;31(3):213-9
references.pmid: 23396013
references.citation: Bioinformatics. 2011 Jun 15;27(12):1739-40
references.pmid: 21546393
references.citation: Cancer. 2013 Aug 15;119(16):3034-42
references.pmid: 23696076
references.citation: Nature. 2014 Jan 23;505(7484):495-501
references.pmid: 24390350
references.citation: Nat Rev Cancer. 2011 Jan;11(1):9-22
references.pmid: 21160525
references.citation: JAMA. 2009 Jul 15;302(3):261-75
references.pmid: 19602686
references.citation: Cancer Discov. 2013 Jul;3(7):761-9
references.pmid: 23619167
references.citation: Oncogene. 1999 Dec 13;18(53):7690-700
references.pmid: 10618709
references.citation: J Clin Oncol. 2010 Jan 1;28(1):15-20
references.pmid: 19933920
references.citation: Nature. 2014 May 1;509(7498):91-5
references.pmid: 24670651
references.citation: Nat Genet. 2013 Oct;45(10):1113-20
references.pmid: 24071849
references.citation: Clin Cancer Res. 2000 Feb;6(2):357-62
references.pmid: 10690511
references.citation: Arch Otolaryngol Head Neck Surg. 1995 Jul;121(7):790-4
references.pmid: 7598859