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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

Mutation plot summary of 60 oral tongue squamous cell carcinoma patients showing frequently mutated genes. The top plot shows the key clinical parameters, below which the mutation status of the recurrently mutated genes for each tumor is indicated. Somatic mutations are colored according to functional class according to the legend below the plot. Prevalence is indicated as number of mutations in the graph on the right and mutational frequency is given on the left of the mutation plot
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Fig1: Mutation plot summary of 60 oral tongue squamous cell carcinoma patients showing frequently mutated genes. The top plot shows the key clinical parameters, below which the mutation status of the recurrently mutated genes for each tumor is indicated. Somatic mutations are colored according to functional class according to the legend below the plot. Prevalence is indicated as number of mutations in the graph on the right and mutational frequency is given on the left of the mutation plot

Mentions: After applying the tumor-only filtering protocol to the prevalence set, 380 genes were detected as harboring SNVs or indels. All mutations identified in the prevalence set are shown in Additional file 12. Unsurprisingly, the most prevalent genetic alteration detected in this cohort comprised a broad spectrum of TP53 mutations (38.3 %). Other genes recurrently mutated include DST (26.7 %), RNF213 (16.7 %), USH2A (16.7 %), FAT1 (16.7 %), MLL3/KMT2C (16.7 %), COL6A6 (15.0 %), ZFHX4 (15.0 %), PLEC (15.0 %), and SYNE1 (13.3 %) (Fig. 1). We examined expression levels of these ten genes using HNSCC RNA-seq data from TCGA and our own previously published microarray data [61], both of which confirm that the genes listed here are known to be expressed in OTSCC (data not shown).Fig. 1


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)

Mutation plot summary of 60 oral tongue squamous cell carcinoma patients showing frequently mutated genes. The top plot shows the key clinical parameters, below which the mutation status of the recurrently mutated genes for each tumor is indicated. Somatic mutations are colored according to functional class according to the legend below the plot. Prevalence is indicated as number of mutations in the graph on the right and mutational frequency is given on the left of the mutation plot
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Mutation plot summary of 60 oral tongue squamous cell carcinoma patients showing frequently mutated genes. The top plot shows the key clinical parameters, below which the mutation status of the recurrently mutated genes for each tumor is indicated. Somatic mutations are colored according to functional class according to the legend below the plot. Prevalence is indicated as number of mutations in the graph on the right and mutational frequency is given on the left of the mutation plot
Mentions: After applying the tumor-only filtering protocol to the prevalence set, 380 genes were detected as harboring SNVs or indels. All mutations identified in the prevalence set are shown in Additional file 12. Unsurprisingly, the most prevalent genetic alteration detected in this cohort comprised a broad spectrum of TP53 mutations (38.3 %). Other genes recurrently mutated include DST (26.7 %), RNF213 (16.7 %), USH2A (16.7 %), FAT1 (16.7 %), MLL3/KMT2C (16.7 %), COL6A6 (15.0 %), ZFHX4 (15.0 %), PLEC (15.0 %), and SYNE1 (13.3 %) (Fig. 1). We examined expression levels of these ten genes using HNSCC RNA-seq data from TCGA and our own previously published microarray data [61], both of which confirm that the genes listed here are known to be expressed in OTSCC (data not shown).Fig. 1

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