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

Vettore AL, Ramnarayanan K, Poore G, Lim K, Ong CK, Huang KK, Leong HS, Chong FT, Lim TK, Lim WK, Cutcutache I, Mcpherson JR, Suzuki Y, Zhang S, Skanthakumar T, Wang W, Tan DS, Cho BC, Teh BT, Rozen S, Tan P, Iyer NG - Genome Med (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. andre.vettore@gmail.com.

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.

No MeSH data available.


Related in: MedlinePlus

a Co-mutation map showing alterations in genes involved in the Notch pathway in 19 (32 %) oral tongue squamous cell carcinoma (OTSCC) samples. Gene names and mutation rates are as indicated on either side of the plot, while the type of mutation follows the legend below. b, c Comparison between OTSCC, oral cavity cohort from TCGA (OC-TCGA) and entire head and neck cohort of TCGA (HN-TCGA) for NOTCH1 mutation frequency and alterations in the entire Notch pathway (11 genes), respectively. P value based on t-test as indicated if significant or NS if not significant. d Kaplan-Meier plot showing DFS estimates according to the mutational status of the Notch pathway. P value is based on log-rank test. e Results of multivariate analysis of selected prognostic factors for DFS in OTSCC by Cox proportional hazards model. HR hazard ratio
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Fig4: a Co-mutation map showing alterations in genes involved in the Notch pathway in 19 (32 %) oral tongue squamous cell carcinoma (OTSCC) samples. Gene names and mutation rates are as indicated on either side of the plot, while the type of mutation follows the legend below. b, c Comparison between OTSCC, oral cavity cohort from TCGA (OC-TCGA) and entire head and neck cohort of TCGA (HN-TCGA) for NOTCH1 mutation frequency and alterations in the entire Notch pathway (11 genes), respectively. P value based on t-test as indicated if significant or NS if not significant. d Kaplan-Meier plot showing DFS estimates according to the mutational status of the Notch pathway. P value is based on log-rank test. e Results of multivariate analysis of selected prognostic factors for DFS in OTSCC by Cox proportional hazards model. HR hazard ratio

Mentions: As stated above, we found the Notch pathway to be altered in a high proportion of the Asian OTSCCs. However, classical single-gene NOTCH1 mutations, previously reported in other studies, were notably absent from our cohort (only three cases have NOTCH1 mutations). Nevertheless, pathway analyses demonstrated that the Notch signaling pathway was altered in OTSCC in the same proportion as previously reported for HNSCC [14] or detected in oral cavity tumors and HNSCC by TCGA (Fig. 4). Genes recurrently altered in this pathway include AR, ARNT, EP300, CREBBP, JAK2, JAK3 NCOA1, NOTCH2, NOTCH3, and PARP1. In total, the Notch signaling pathway was altered in 32 % (19/60) of the OTSCC cases, with all somatic events following a mutually exclusive pattern (Fig. 4).Fig. 4


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

Vettore AL, Ramnarayanan K, Poore G, Lim K, Ong CK, Huang KK, Leong HS, Chong FT, Lim TK, Lim WK, Cutcutache I, Mcpherson JR, Suzuki Y, Zhang S, Skanthakumar T, Wang W, Tan DS, Cho BC, Teh BT, Rozen S, Tan P, Iyer NG - Genome Med (2015)

a Co-mutation map showing alterations in genes involved in the Notch pathway in 19 (32 %) oral tongue squamous cell carcinoma (OTSCC) samples. Gene names and mutation rates are as indicated on either side of the plot, while the type of mutation follows the legend below. b, c Comparison between OTSCC, oral cavity cohort from TCGA (OC-TCGA) and entire head and neck cohort of TCGA (HN-TCGA) for NOTCH1 mutation frequency and alterations in the entire Notch pathway (11 genes), respectively. P value based on t-test as indicated if significant or NS if not significant. d Kaplan-Meier plot showing DFS estimates according to the mutational status of the Notch pathway. P value is based on log-rank test. e Results of multivariate analysis of selected prognostic factors for DFS in OTSCC by Cox proportional hazards model. HR hazard ratio
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4580363&req=5

Fig4: a Co-mutation map showing alterations in genes involved in the Notch pathway in 19 (32 %) oral tongue squamous cell carcinoma (OTSCC) samples. Gene names and mutation rates are as indicated on either side of the plot, while the type of mutation follows the legend below. b, c Comparison between OTSCC, oral cavity cohort from TCGA (OC-TCGA) and entire head and neck cohort of TCGA (HN-TCGA) for NOTCH1 mutation frequency and alterations in the entire Notch pathway (11 genes), respectively. P value based on t-test as indicated if significant or NS if not significant. d Kaplan-Meier plot showing DFS estimates according to the mutational status of the Notch pathway. P value is based on log-rank test. e Results of multivariate analysis of selected prognostic factors for DFS in OTSCC by Cox proportional hazards model. HR hazard ratio
Mentions: As stated above, we found the Notch pathway to be altered in a high proportion of the Asian OTSCCs. However, classical single-gene NOTCH1 mutations, previously reported in other studies, were notably absent from our cohort (only three cases have NOTCH1 mutations). Nevertheless, pathway analyses demonstrated that the Notch signaling pathway was altered in OTSCC in the same proportion as previously reported for HNSCC [14] or detected in oral cavity tumors and HNSCC by TCGA (Fig. 4). Genes recurrently altered in this pathway include AR, ARNT, EP300, CREBBP, JAK2, JAK3 NCOA1, NOTCH2, NOTCH3, and PARP1. In total, the Notch signaling pathway was altered in 32 % (19/60) of the OTSCC cases, with all somatic events following a mutually exclusive pattern (Fig. 4).Fig. 4

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singaore. andre.vettore@gmail.com.

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.

No MeSH data available.


Related in: MedlinePlus