title: Mutational landscapes of tongue carcinoma reveal recurrent mutations in genes of therapeutic and prognostic relevance.
abstract: BACKGROUND
  Carcinoma of the oral tongue (OTSCC) is the most common malignancy of the oral cavity, characterized by frequent recurrence and poor survival. The last three decades has witnessed a change in the OTSCC epidemiological profile, with increasing incidence in younger patients, females and never-smokers. Here, we sought to characterize the OTSCC genomic landscape and to determine factors that may delineate the genetic basis of this disease, inform prognosis and identify targets for therapeutic intervention.
  
  
  METHODS
  Seventy-eight cases were subjected to whole-exome (n = 18) and targeted deep sequencing (n = 60).
  
  
  RESULTS
  While the most common mutation was in TP53, the OTSCC genetic landscape differed from previously described cohorts of patients with head and neck tumors: OTSCCs demonstrated frequent mutations in DST and RNF213, while alterations in CDKN2A and NOTCH1 were significantly less frequent. Despite a lack of previously reported NOTCH1 mutations, integrated analysis showed enrichments of alterations affecting Notch signaling in OTSCC. Importantly, these Notch pathway alterations were prognostic on multivariate analyses. A high proportion of OTSCCs also presented with alterations in drug targetable and chromatin remodeling genes. Patients harboring mutations in actionable pathways were more likely to succumb from recurrent disease compared with those who did not, suggesting that the former should be considered for treatment with targeted compounds in future trials.
  
  
  CONCLUSIONS
  Our study defines the Asian OTSCC mutational landscape, highlighting the key role of Notch signaling in oral tongue tumorigenesis. We also observed somatic mutations in multiple therapeutically relevant genes, which may represent candidate drug targets in this highly lethal tumor type.
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. andre.vettore@gmail.com.|Laboratory of Cancer Molecular Biology, Department of Biological Sciences, Federal University of São Paulo, Rua Pedro de Toledo 669, São Paulo, 04039-032, Brazil. andre.vettore@gmail.com.
authors.forename: Andre Luiz
authors.initials: AL
authors.lastname: Vettore
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. kalpana.ramnarayanan@duke-nus.edu.sg.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Ramnarayanan
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. gregory.poore@duke.edu.
authors.forename: Gregory
authors.initials: G
authors.lastname: Poore
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. kevin.lim@duke-nus.edu.sg.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lim
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. cmrock@nccs.com.sg.|Laboratory of Cancer Molecular Biology, Department of Biological Sciences, Federal University of São Paulo, Rua Pedro de Toledo 669, São Paulo, 04039-032, Brazil. cmrock@nccs.com.sg.
authors.forename: Choon Kiat
authors.initials: CK
authors.lastname: Ong
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. kiekyon.huang@gmail.com.
authors.forename: Kie Kyon
authors.initials: KK
authors.lastname: Huang
authors.affiliation: Cancer Therapeutics Research Laboratory, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore. hui.sun.leong@nccs.com.sg.
authors.forename: Hui Sun
authors.initials: HS
authors.lastname: Leong
authors.affiliation: Cancer Therapeutics Research Laboratory, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore. Chong.F.T@nccs.com.sg.
authors.forename: Fui Teen
authors.initials: FT
authors.lastname: Chong
authors.affiliation: Department of Pathology, Singapore General Hospital, Outram Road, Singapore, 169608, Singapore. lim.kiat.hon@sgh.com.sg.
authors.forename: Tony Kiat-Hon
authors.initials: TK
authors.lastname: Lim
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. wengkhong.lim@duke-nus.edu.sg.|Laboratory of Cancer Epigenome, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore. wengkhong.lim@duke-nus.edu.sg.
authors.forename: Weng Khong
authors.initials: WK
authors.lastname: Lim
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. ioana.cutcutache@duke-nus.edu.sg.
authors.forename: Ioana
authors.initials: I
authors.lastname: Cutcutache
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. john.mcpherson@duke-nus.edu.sg.
authors.forename: John R
authors.initials: JR
authors.lastname: Mcpherson
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. yuka.suzuki@duke-nus.edu.sg.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. shenli.zhang@duke-nus.edu.sg.
authors.forename: Shenli
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Surgical Oncology, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore. thakshayeni@nccs.com.sg.
authors.forename: Thakshayeni
authors.initials: T
authors.lastname: Skanthakumar
authors.affiliation: Department of Surgical Oncology, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore. wang.weining.88@gmail.com.
authors.forename: Weining
authors.initials: W
authors.lastname: Wang
authors.affiliation: Cancer Therapeutics Research Laboratory, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore. Daniel.Tan.S.W@nccs.com.sg.
authors.forename: Daniel S W
authors.initials: DS
authors.lastname: Tan
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. cbc1971@yuhs.ac.|Division of Medical Oncology, Yonsei Cancer Center, Yonsei Unversity College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, South Korea. cbc1971@yuhs.ac.
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Cho
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. teh.bin.tean@singhealth.com.sg.|Laboratory of Cancer Epigenome, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore. teh.bin.tean@singhealth.com.sg.|Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore, 117599, Singapore. teh.bin.tean@singhealth.com.sg.
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. steve.rozen@duke-nus.edu.sg.|Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, 27710, USA. steve.rozen@duke-nus.edu.sg.
authors.forename: Steve
authors.initials: S
authors.lastname: Rozen
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. gmstanp@duke-nus.edu.sg.|Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore, 117599, Singapore. gmstanp@duke-nus.edu.sg.|Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore, 138672, Singapore. gmstanp@duke-nus.edu.sg.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. gopaliyer@nccs.com.sg.|Cancer Therapeutics Research Laboratory, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore. gopaliyer@nccs.com.sg.|Department of Surgical Oncology, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore. gopaliyer@nccs.com.sg.
authors.forename: N Gopalakrishna
authors.initials: NG
authors.lastname: Iyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002843:Chromatin / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D051880:Receptors, Notch / Q000235:genetics; D017422:Sequence Analysis, DNA; D012846:Singapore; D014062:Tongue Neoplasms / Q000235:genetics*; D055815:Young Adult
chemical_list: D002843:Chromatin; D051880:Receptors, Notch