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Mutational landscapes of tongue carcinoma reveal recurrent mutations in genes of therapeutic and prognostic relevance

 Andre Luiz Vettore  ;  Kalpana Ramnarayanan  ;  Gregory Poore  ;  Kevin Lim  ;  Choon Kiat Ong  ;  Kie Kyon Huang  ;  Hui Sun Leong  ;  Fui Teen Chong  ;  Tony Kiat-Hon Lim  ;  Weng Khong Lim  ;  Ioana Cutcutache  ;  John R. Mcpherson  ;  Yuka Suzuki  ;  Shenli Zhang  ;  Thakshayeni Skanthakumar  ;  Weining Wang  ;  Daniel SW Tan  ;  Byoung Chul Cho  ;  Bin Tean Teh  ;  Steve Rozen  ;  Patrick Tan  ;  N. Gopalakrishna Iyer 
 GENOME MEDICINE, Vol.7 : 98, 2015 
Journal Title
Issue Date
Adult ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group/genetics ; Carcinoma, Squamous Cell/genetics* ; Chromatin/genetics ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Prognosis ; Receptors, Notch/genetics ; Sequence Analysis, DNA ; Singapore ; Tongue Neoplasms/genetics* ; Young Adult
Oral Squamous Cell Carcinoma ; Notch Pathway ; Tongue Cancer ; Oral Tongue ; Germline Variant
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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
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