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 S.W. Tan, Byoung Chul Cho, Bin Tean Teh, Steve RozenPatrick Tan, N. Gopalakrishna Iyer

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Article number98
JournalGenome Medicine
Volume7
Issue number1
DOIs
Publication statusPublished - 2015 Sep 23

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Tongue
Carcinoma
Mutation
Genes
Exome
Therapeutics
High-Throughput Nucleotide Sequencing
Neoplasms
Inborn Genetic Diseases
Chromatin Assembly and Disassembly
Pharmaceutical Preparations
Mouth
Carcinogenesis
Neck
Multivariate Analysis
Head
Recurrence
Survival
Incidence

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Vettore, A. L., Ramnarayanan, K., Poore, G., Lim, K., Ong, C. K., Huang, K. K., ... Iyer, N. G. (2015). Mutational landscapes of tongue carcinoma reveal recurrent mutations in genes of therapeutic and prognostic relevance. Genome Medicine, 7(1), [98]. https://doi.org/10.1186/s13073-015-0219-2
Vettore, Andre Luiz ; Ramnarayanan, Kalpana ; Poore, Gregory ; Lim, Kevin ; Ong, Choon Kiat ; Huang, Kie Kyon ; Leong, Hui Sun ; Chong, Fui Teen ; Lim, Tony Kiat Hon ; Lim, Weng Khong ; Cutcutache, Ioana ; Mcpherson, John R. ; Suzuki, Yuka ; Zhang, Shenli ; Skanthakumar, Thakshayeni ; Wang, Weining ; Tan, Daniel S.W. ; Cho, Byoung Chul ; Teh, Bin Tean ; Rozen, Steve ; Tan, Patrick ; Iyer, N. Gopalakrishna. / Mutational landscapes of tongue carcinoma reveal recurrent mutations in genes of therapeutic and prognostic relevance. In: Genome Medicine. 2015 ; Vol. 7, No. 1.
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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.",
author = "Vettore, {Andre Luiz} and Kalpana Ramnarayanan and Gregory Poore and Kevin Lim and Ong, {Choon Kiat} and Huang, {Kie Kyon} and Leong, {Hui Sun} and Chong, {Fui Teen} and Lim, {Tony Kiat Hon} and Lim, {Weng Khong} and Ioana Cutcutache and Mcpherson, {John R.} and Yuka Suzuki and Shenli Zhang and Thakshayeni Skanthakumar and Weining Wang and Tan, {Daniel S.W.} and Cho, {Byoung Chul} and Teh, {Bin Tean} and Steve Rozen and Patrick Tan and Iyer, {N. Gopalakrishna}",
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Vettore, AL, Ramnarayanan, K, Poore, G, Lim, K, Ong, CK, Huang, KK, Leong, HS, Chong, FT, Lim, TKH, Lim, WK, Cutcutache, I, Mcpherson, JR, Suzuki, Y, Zhang, S, Skanthakumar, T, Wang, W, Tan, DSW, Cho, BC, Teh, BT, Rozen, S, Tan, P & Iyer, NG 2015, 'Mutational landscapes of tongue carcinoma reveal recurrent mutations in genes of therapeutic and prognostic relevance', Genome Medicine, vol. 7, no. 1, 98. https://doi.org/10.1186/s13073-015-0219-2

Mutational landscapes of tongue carcinoma reveal recurrent mutations in genes of therapeutic and prognostic relevance. / Vettore, Andre Luiz; Ramnarayanan, Kalpana; Poore, Gregory; Lim, Kevin; Ong, Choon Kiat; Huang, Kie Kyon; Leong, Hui Sun; Chong, Fui Teen; Lim, Tony Kiat Hon; Lim, Weng Khong; Cutcutache, Ioana; Mcpherson, John R.; Suzuki, Yuka; Zhang, Shenli; Skanthakumar, Thakshayeni; Wang, Weining; Tan, Daniel S.W.; Cho, Byoung Chul; Teh, Bin Tean; Rozen, Steve; Tan, Patrick; Iyer, N. Gopalakrishna.

In: Genome Medicine, Vol. 7, No. 1, 98, 23.09.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutational landscapes of tongue carcinoma reveal recurrent mutations in genes of therapeutic and prognostic relevance

AU - Vettore, Andre Luiz

AU - Ramnarayanan, Kalpana

AU - Poore, Gregory

AU - Lim, Kevin

AU - Ong, Choon Kiat

AU - Huang, Kie Kyon

AU - Leong, Hui Sun

AU - Chong, Fui Teen

AU - Lim, Tony Kiat Hon

AU - Lim, Weng Khong

AU - Cutcutache, Ioana

AU - Mcpherson, John R.

AU - Suzuki, Yuka

AU - Zhang, Shenli

AU - Skanthakumar, Thakshayeni

AU - Wang, Weining

AU - Tan, Daniel S.W.

AU - Cho, Byoung Chul

AU - Teh, Bin Tean

AU - Rozen, Steve

AU - Tan, Patrick

AU - Iyer, N. Gopalakrishna

PY - 2015/9/23

Y1 - 2015/9/23

N2 - 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.

AB - 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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U2 - 10.1186/s13073-015-0219-2

DO - 10.1186/s13073-015-0219-2

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VL - 7

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JF - Genome Medicine

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