The mutational landscape of early- and typical-onset oral tongue squamous cell carcinoma

Benjamin R. Campbell; Zhishan Chen; Daniel L. Faden; Nishant Agrawal; Ryan J. Li; Glenn J. Hanna; N. Gopalakrishna Iyer; Arnoud Boot; Steven G. Rozen; Andre L. Vettore; Binay Panda; Neeraja M. Krishnan; Curtis R. Pickering; Jeffrey N. Myers; Xingyi Guo; Krystle A. Lang Kuhs

doi:10.1002/cncr.33309

The mutational landscape of early- and typical-onset oral tongue squamous cell carcinoma

Benjamin R. Campbell, Zhishan Chen, Daniel L. Faden, Nishant Agrawal, Ryan J. Li, Glenn J. Hanna, N. Gopalakrishna Iyer, Arnoud Boot, Steven G. Rozen, Andre L. Vettore, Binay Panda, Neeraja M. Krishnan, Curtis R. Pickering, Jeffrey N. Myers, Xingyi Guo, Krystle A. Lang Kuhs

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

Background: The incidence of oral tongue squamous cell carcinoma (OTSCC) is increasing among younger birth cohorts. The etiology of early-onset OTSCC (diagnosed before the age of 50 years) and cancer driver genes remain largely unknown. Methods: The Sequencing Consortium of Oral Tongue Cancer was established through the pooling of somatic mutation data of oral tongue cancer specimens (n = 227 [107 early-onset cases]) from 7 studies and The Cancer Genome Atlas. Somatic mutations at microsatellite loci and Catalog of Somatic Mutations in Cancer mutation signatures were identified. Cancer driver genes were identified with the MutSigCV and WITER algorithms. Mutation comparisons between early- and typical-onset OTSCC were evaluated via linear regression with adjustments for patient-related factors. Results: Two novel driver genes (ATXN1 and CDC42EP1) and 5 previously reported driver genes (TP53, CDKN2A, CASP8, NOTCH1, and FAT1) were identified. Six recurrent mutations were identified, with 4 occurring in TP53. Early-onset OTSCC had significantly fewer nonsilent mutations even after adjustments for tobacco use. No associations of microsatellite locus mutations and mutation signatures with the age of OTSCC onset were observed. Conclusions: This international, multicenter consortium is the largest study to characterize the somatic mutational landscape of OTSCC and the first to suggest differences by age of onset. This study validates multiple previously identified OTSCC driver genes and proposes 2 novel cancer driver genes. In analyses by age, early-onset OTSCC had a significantly smaller somatic mutational burden that was not explained by differences in tobacco use. Lay Summary: This study identifies 7 specific areas in the human genetic code that could be responsible for promoting the development of tongue cancer. Tongue cancer in young patients (under the age of 50 years) has fewer overall changes to the genetic code in comparison with tongue cancer in older patients, but the authors do not think that this is due to differences in smoking rates between the 2 groups. The cause of increasing cases of tongue cancer in young patients remains unclear.

Original language	English
Pages (from-to)	544-553
Number of pages	10
Journal	Cancer
Volume	127
Issue number	4
DOIs	https://doi.org/10.1002/cncr.33309
State	Published - Feb 15 2021

Bibliographical note

Publisher Copyright:
© 2020 American Cancer Society

Funding

Ryan J. Li reports personal fees and other from Intuitive Surgical outside the submitted work. Glenn J. Hanna reports grants from Bristol‐Myers Squibb, GlaxoSmithKline, NantKwest/Altor Bioscience, Kite, Kartos, Elevar, the ASCO Conquer Cancer Foundation, the V Foundation, and Gateway for Cancer Research; grants and personal fees from Exicure, Regeneron, Sanofi Genzyme, and Bicara; and personal fees from Bio‐Rad, Kura, Maverick, Prelude, and Merck outside the submitted work. The other authors made no disclosures. This work was supported by the National Cancer Institute (K07CA218247; principal investigator Krystle A. Lang Kuhs). Curtis R. Pickering reports grants from the National Institute of Dental and Craniofacial Research during the conduct of the study. The University of Texas MD Anderson Cancer Center is supported by the National Institutes of Health (grant P30 CA016672).

Funders	Funder number
National Institutes of Health (NIH)	P30 CA016672
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	K07CA218247
National Childhood Cancer Registry – National Cancer Institute
National Institute of Dental and Craniofacial Research
Conquer Cancer Foundation
Gateway for Cancer Research
GlaxoSmithKline

Keywords

NOTCH1
TP53
age of onset
oral tongue cancer
tobacco

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/cncr.33309

Cite this

Campbell, B. R., Chen, Z., Faden, D. L., Agrawal, N., Li, R. J., Hanna, G. J., Iyer, N. G., Boot, A., Rozen, S. G., Vettore, A. L., Panda, B., Krishnan, N. M., Pickering, C. R., Myers, J. N., Guo, X., & Lang Kuhs, K. A. (2021). The mutational landscape of early- and typical-onset oral tongue squamous cell carcinoma. Cancer, 127(4), 544-553. https://doi.org/10.1002/cncr.33309

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title = "The mutational landscape of early- and typical-onset oral tongue squamous cell carcinoma",

abstract = "Background: The incidence of oral tongue squamous cell carcinoma (OTSCC) is increasing among younger birth cohorts. The etiology of early-onset OTSCC (diagnosed before the age of 50 years) and cancer driver genes remain largely unknown. Methods: The Sequencing Consortium of Oral Tongue Cancer was established through the pooling of somatic mutation data of oral tongue cancer specimens (n = 227 [107 early-onset cases]) from 7 studies and The Cancer Genome Atlas. Somatic mutations at microsatellite loci and Catalog of Somatic Mutations in Cancer mutation signatures were identified. Cancer driver genes were identified with the MutSigCV and WITER algorithms. Mutation comparisons between early- and typical-onset OTSCC were evaluated via linear regression with adjustments for patient-related factors. Results: Two novel driver genes (ATXN1 and CDC42EP1) and 5 previously reported driver genes (TP53, CDKN2A, CASP8, NOTCH1, and FAT1) were identified. Six recurrent mutations were identified, with 4 occurring in TP53. Early-onset OTSCC had significantly fewer nonsilent mutations even after adjustments for tobacco use. No associations of microsatellite locus mutations and mutation signatures with the age of OTSCC onset were observed. Conclusions: This international, multicenter consortium is the largest study to characterize the somatic mutational landscape of OTSCC and the first to suggest differences by age of onset. This study validates multiple previously identified OTSCC driver genes and proposes 2 novel cancer driver genes. In analyses by age, early-onset OTSCC had a significantly smaller somatic mutational burden that was not explained by differences in tobacco use. Lay Summary: This study identifies 7 specific areas in the human genetic code that could be responsible for promoting the development of tongue cancer. Tongue cancer in young patients (under the age of 50 years) has fewer overall changes to the genetic code in comparison with tongue cancer in older patients, but the authors do not think that this is due to differences in smoking rates between the 2 groups. The cause of increasing cases of tongue cancer in young patients remains unclear.",

keywords = "NOTCH1, TP53, age of onset, oral tongue cancer, tobacco",

author = "Campbell, {Benjamin R.} and Zhishan Chen and Faden, {Daniel L.} and Nishant Agrawal and Li, {Ryan J.} and Hanna, {Glenn J.} and Iyer, {N. Gopalakrishna} and Arnoud Boot and Rozen, {Steven G.} and Vettore, {Andre L.} and Binay Panda and Krishnan, {Neeraja M.} and Pickering, {Curtis R.} and Myers, {Jeffrey N.} and Xingyi Guo and {Lang Kuhs}, {Krystle A.}",

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doi = "10.1002/cncr.33309",

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AU - Chen, Zhishan

AU - Faden, Daniel L.

AU - Agrawal, Nishant

AU - Li, Ryan J.

AU - Hanna, Glenn J.

AU - Iyer, N. Gopalakrishna

AU - Boot, Arnoud

AU - Rozen, Steven G.

AU - Vettore, Andre L.

AU - Panda, Binay

AU - Krishnan, Neeraja M.

AU - Pickering, Curtis R.

AU - Myers, Jeffrey N.

AU - Guo, Xingyi

AU - Lang Kuhs, Krystle A.

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N2 - Background: The incidence of oral tongue squamous cell carcinoma (OTSCC) is increasing among younger birth cohorts. The etiology of early-onset OTSCC (diagnosed before the age of 50 years) and cancer driver genes remain largely unknown. Methods: The Sequencing Consortium of Oral Tongue Cancer was established through the pooling of somatic mutation data of oral tongue cancer specimens (n = 227 [107 early-onset cases]) from 7 studies and The Cancer Genome Atlas. Somatic mutations at microsatellite loci and Catalog of Somatic Mutations in Cancer mutation signatures were identified. Cancer driver genes were identified with the MutSigCV and WITER algorithms. Mutation comparisons between early- and typical-onset OTSCC were evaluated via linear regression with adjustments for patient-related factors. Results: Two novel driver genes (ATXN1 and CDC42EP1) and 5 previously reported driver genes (TP53, CDKN2A, CASP8, NOTCH1, and FAT1) were identified. Six recurrent mutations were identified, with 4 occurring in TP53. Early-onset OTSCC had significantly fewer nonsilent mutations even after adjustments for tobacco use. No associations of microsatellite locus mutations and mutation signatures with the age of OTSCC onset were observed. Conclusions: This international, multicenter consortium is the largest study to characterize the somatic mutational landscape of OTSCC and the first to suggest differences by age of onset. This study validates multiple previously identified OTSCC driver genes and proposes 2 novel cancer driver genes. In analyses by age, early-onset OTSCC had a significantly smaller somatic mutational burden that was not explained by differences in tobacco use. Lay Summary: This study identifies 7 specific areas in the human genetic code that could be responsible for promoting the development of tongue cancer. Tongue cancer in young patients (under the age of 50 years) has fewer overall changes to the genetic code in comparison with tongue cancer in older patients, but the authors do not think that this is due to differences in smoking rates between the 2 groups. The cause of increasing cases of tongue cancer in young patients remains unclear.

AB - Background: The incidence of oral tongue squamous cell carcinoma (OTSCC) is increasing among younger birth cohorts. The etiology of early-onset OTSCC (diagnosed before the age of 50 years) and cancer driver genes remain largely unknown. Methods: The Sequencing Consortium of Oral Tongue Cancer was established through the pooling of somatic mutation data of oral tongue cancer specimens (n = 227 [107 early-onset cases]) from 7 studies and The Cancer Genome Atlas. Somatic mutations at microsatellite loci and Catalog of Somatic Mutations in Cancer mutation signatures were identified. Cancer driver genes were identified with the MutSigCV and WITER algorithms. Mutation comparisons between early- and typical-onset OTSCC were evaluated via linear regression with adjustments for patient-related factors. Results: Two novel driver genes (ATXN1 and CDC42EP1) and 5 previously reported driver genes (TP53, CDKN2A, CASP8, NOTCH1, and FAT1) were identified. Six recurrent mutations were identified, with 4 occurring in TP53. Early-onset OTSCC had significantly fewer nonsilent mutations even after adjustments for tobacco use. No associations of microsatellite locus mutations and mutation signatures with the age of OTSCC onset were observed. Conclusions: This international, multicenter consortium is the largest study to characterize the somatic mutational landscape of OTSCC and the first to suggest differences by age of onset. This study validates multiple previously identified OTSCC driver genes and proposes 2 novel cancer driver genes. In analyses by age, early-onset OTSCC had a significantly smaller somatic mutational burden that was not explained by differences in tobacco use. Lay Summary: This study identifies 7 specific areas in the human genetic code that could be responsible for promoting the development of tongue cancer. Tongue cancer in young patients (under the age of 50 years) has fewer overall changes to the genetic code in comparison with tongue cancer in older patients, but the authors do not think that this is due to differences in smoking rates between the 2 groups. The cause of increasing cases of tongue cancer in young patients remains unclear.

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The mutational landscape of early- and typical-onset oral tongue squamous cell carcinoma

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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