A mutational signature associated with alcohol consumption and prognostically significantly mutated driver genes in esophageal squamous cell carcinoma

X. C. Li; M. Y. Wang; M. Yang; H. J. Dai; B. F. Zhang; W. Wang; X. L. Chu; X. Wang; H. Zheng; R. F. Niu; W. Zhang; Kexin X. Chen

doi:10.1093/annonc/mdy011

A mutational signature associated with alcohol consumption and prognostically significantly mutated driver genes in esophageal squamous cell carcinoma

X. C. Li, M. Y. Wang, M. Yang, H. J. Dai, B. F. Zhang, W. Wang, X. L. Chu, X. Wang, H. Zheng, R. F. Niu, W. Zhang, Kexin X. Chen

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69 Scopus citations

Abstract

Background: Esophageal squamous cell carcinoma (ESCC) is often diagnosed at an advanced and incurable stage. Information on driver genes and prognosticators in ESCC remains incomplete. The objective was to elucidate significantly mutated genes (SMGs), mutational signatures, and prognosticators in ESCC. Patients and methods: Three MutSig algorithms (i.e. MutSigCV, MutSigCL and MutSigFN) and '20/20+' ratio-metric were employed to identify SMGs. Nonnegative matrix factorization was used to decipher mutational signatures. Kaplan-Meier survival analysis, multivariate Cox and logistic regression models were applied to analyze association between mutational features and clinical parameters. Results: We identified 26 SMGs, including 8 novel (NAV3, TENM3, PTCH1, TGFBR2, RIPK4, PBRM1, USP8 and BAP1) and 18 that have been previously reported. Three mutational signatures were identified to be prevalent in ESCC including clocklike C > T at CpG, APOBEC overactive C > T at TpCp[A/T], and a signature featured by T > C substitution. The T > C mutational signature was significantly correlated with alcohol consumption (OR: 3.59; 95% CI: 2.30-5.67; P < 0.001). This alcohol consumption signature was also observed in liver cancer and head and neck squamous cell carcinoma, and its mutational activity was substantially higher in samples with mutations in TP53. Survival analysis revealed that TENM3 mutations (HR: 5.54; CI: 2.68-11.45; P < 0.001) and TP53 hotspot mutation p.R213* (HR: 3.37; CI: 1.73-8.06; P < 0.001) were significantly associated with shortened survival outcome. The association remained statistically significant after controlling for age, gender, TNM stage and tumor grade. Conclusions: We have uncovered several new SMGs in ESCC and defined an alcohol consumption related mutational signature. TENM3 mutations and the TP53 hotspot mutation p.R213* are independent prognosticators for poor survival in ESCC.

Original language	English (US)
Pages (from-to)	938-944
Number of pages	7
Journal	Annals of Oncology
Volume	29
Issue number	4
DOIs	https://doi.org/10.1093/annonc/mdy011
State	Published - Apr 1 2018

Keywords

Driver genes
Esophagus
Mutational signature
Prognosticator

ASJC Scopus subject areas

Hematology
Oncology

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10.1093/annonc/mdy011

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Li, X. C., Wang, M. Y., Yang, M., Dai, H. J., Zhang, B. F., Wang, W., Chu, X. L., Wang, X., Zheng, H., Niu, R. F., Zhang, W., & Chen, K. X. (2018). A mutational signature associated with alcohol consumption and prognostically significantly mutated driver genes in esophageal squamous cell carcinoma. Annals of Oncology, 29(4), 938-944. https://doi.org/10.1093/annonc/mdy011

@article{a00dc3b65b4441d2afb6b7823359b393,

title = "A mutational signature associated with alcohol consumption and prognostically significantly mutated driver genes in esophageal squamous cell carcinoma",

abstract = "Background: Esophageal squamous cell carcinoma (ESCC) is often diagnosed at an advanced and incurable stage. Information on driver genes and prognosticators in ESCC remains incomplete. The objective was to elucidate significantly mutated genes (SMGs), mutational signatures, and prognosticators in ESCC. Patients and methods: Three MutSig algorithms (i.e. MutSigCV, MutSigCL and MutSigFN) and '20/20+' ratio-metric were employed to identify SMGs. Nonnegative matrix factorization was used to decipher mutational signatures. Kaplan-Meier survival analysis, multivariate Cox and logistic regression models were applied to analyze association between mutational features and clinical parameters. Results: We identified 26 SMGs, including 8 novel (NAV3, TENM3, PTCH1, TGFBR2, RIPK4, PBRM1, USP8 and BAP1) and 18 that have been previously reported. Three mutational signatures were identified to be prevalent in ESCC including clocklike C > T at CpG, APOBEC overactive C > T at TpCp[A/T], and a signature featured by T > C substitution. The T > C mutational signature was significantly correlated with alcohol consumption (OR: 3.59; 95% CI: 2.30-5.67; P < 0.001). This alcohol consumption signature was also observed in liver cancer and head and neck squamous cell carcinoma, and its mutational activity was substantially higher in samples with mutations in TP53. Survival analysis revealed that TENM3 mutations (HR: 5.54; CI: 2.68-11.45; P < 0.001) and TP53 hotspot mutation p.R213* (HR: 3.37; CI: 1.73-8.06; P < 0.001) were significantly associated with shortened survival outcome. The association remained statistically significant after controlling for age, gender, TNM stage and tumor grade. Conclusions: We have uncovered several new SMGs in ESCC and defined an alcohol consumption related mutational signature. TENM3 mutations and the TP53 hotspot mutation p.R213* are independent prognosticators for poor survival in ESCC.",

keywords = "Driver genes, Esophagus, Mutational signature, Prognosticator",

author = "Li, {X. C.} and Wang, {M. Y.} and M. Yang and Dai, {H. J.} and Zhang, {B. F.} and W. Wang and Chu, {X. L.} and X. Wang and H. Zheng and Niu, {R. F.} and W. Zhang and Chen, {Kexin X.}",

note = "Funding Information: This work was partially supported by the Program for Changjiang Scholars and Innovative Research Team in University in China (IRT_14R40 to KC), and the Tianjin Municipal Education Commission (11601501-2016KJ0148 to DH). WZ is supported by a Fellowship from the National Foundation for Cancer Research, an Endowed Hanes and Willis Family Professor in Cancer at the Wake Forest Baptist Comprehensive Cancer Center, and the Cancer Center Support Grant from the National Cancer Institute to the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (P30 CA012197). Funding Information: We thank Dr Mac Robinson at Wake Forest Baptist Comprehensive Cancer Center for editing the manuscript.This work was partially supported by the Program for Changjiang Scholars and Innovative Research Team in University in China (IRT_14R40 to KC), and the Tianjin Municipal Education Commission (11601501-2016KJ0148 to DH). WZ is supported by a Fellowship from the National Foundation for Cancer Research, an Endowed Hanes and Willis Family Professor in Cancer at the Wake Forest Baptist Comprehensive Cancer Center, and the Cancer Center Support Grant from the National Cancer Institute to the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (P30 CA012197) Publisher Copyright: {\textcopyright} The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.",

year = "2018",

month = apr,

day = "1",

doi = "10.1093/annonc/mdy011",

language = "English (US)",

volume = "29",

pages = "938--944",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Oxford University Press",

number = "4",

}

TY - JOUR

T1 - A mutational signature associated with alcohol consumption and prognostically significantly mutated driver genes in esophageal squamous cell carcinoma

AU - Li, X. C.

AU - Wang, M. Y.

AU - Yang, M.

AU - Dai, H. J.

AU - Zhang, B. F.

AU - Wang, W.

AU - Chu, X. L.

AU - Wang, X.

AU - Zheng, H.

AU - Niu, R. F.

AU - Zhang, W.

AU - Chen, Kexin X.

N1 - Funding Information: This work was partially supported by the Program for Changjiang Scholars and Innovative Research Team in University in China (IRT_14R40 to KC), and the Tianjin Municipal Education Commission (11601501-2016KJ0148 to DH). WZ is supported by a Fellowship from the National Foundation for Cancer Research, an Endowed Hanes and Willis Family Professor in Cancer at the Wake Forest Baptist Comprehensive Cancer Center, and the Cancer Center Support Grant from the National Cancer Institute to the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (P30 CA012197). Funding Information: We thank Dr Mac Robinson at Wake Forest Baptist Comprehensive Cancer Center for editing the manuscript.This work was partially supported by the Program for Changjiang Scholars and Innovative Research Team in University in China (IRT_14R40 to KC), and the Tianjin Municipal Education Commission (11601501-2016KJ0148 to DH). WZ is supported by a Fellowship from the National Foundation for Cancer Research, an Endowed Hanes and Willis Family Professor in Cancer at the Wake Forest Baptist Comprehensive Cancer Center, and the Cancer Center Support Grant from the National Cancer Institute to the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (P30 CA012197) Publisher Copyright: © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Background: Esophageal squamous cell carcinoma (ESCC) is often diagnosed at an advanced and incurable stage. Information on driver genes and prognosticators in ESCC remains incomplete. The objective was to elucidate significantly mutated genes (SMGs), mutational signatures, and prognosticators in ESCC. Patients and methods: Three MutSig algorithms (i.e. MutSigCV, MutSigCL and MutSigFN) and '20/20+' ratio-metric were employed to identify SMGs. Nonnegative matrix factorization was used to decipher mutational signatures. Kaplan-Meier survival analysis, multivariate Cox and logistic regression models were applied to analyze association between mutational features and clinical parameters. Results: We identified 26 SMGs, including 8 novel (NAV3, TENM3, PTCH1, TGFBR2, RIPK4, PBRM1, USP8 and BAP1) and 18 that have been previously reported. Three mutational signatures were identified to be prevalent in ESCC including clocklike C > T at CpG, APOBEC overactive C > T at TpCp[A/T], and a signature featured by T > C substitution. The T > C mutational signature was significantly correlated with alcohol consumption (OR: 3.59; 95% CI: 2.30-5.67; P < 0.001). This alcohol consumption signature was also observed in liver cancer and head and neck squamous cell carcinoma, and its mutational activity was substantially higher in samples with mutations in TP53. Survival analysis revealed that TENM3 mutations (HR: 5.54; CI: 2.68-11.45; P < 0.001) and TP53 hotspot mutation p.R213* (HR: 3.37; CI: 1.73-8.06; P < 0.001) were significantly associated with shortened survival outcome. The association remained statistically significant after controlling for age, gender, TNM stage and tumor grade. Conclusions: We have uncovered several new SMGs in ESCC and defined an alcohol consumption related mutational signature. TENM3 mutations and the TP53 hotspot mutation p.R213* are independent prognosticators for poor survival in ESCC.

AB - Background: Esophageal squamous cell carcinoma (ESCC) is often diagnosed at an advanced and incurable stage. Information on driver genes and prognosticators in ESCC remains incomplete. The objective was to elucidate significantly mutated genes (SMGs), mutational signatures, and prognosticators in ESCC. Patients and methods: Three MutSig algorithms (i.e. MutSigCV, MutSigCL and MutSigFN) and '20/20+' ratio-metric were employed to identify SMGs. Nonnegative matrix factorization was used to decipher mutational signatures. Kaplan-Meier survival analysis, multivariate Cox and logistic regression models were applied to analyze association between mutational features and clinical parameters. Results: We identified 26 SMGs, including 8 novel (NAV3, TENM3, PTCH1, TGFBR2, RIPK4, PBRM1, USP8 and BAP1) and 18 that have been previously reported. Three mutational signatures were identified to be prevalent in ESCC including clocklike C > T at CpG, APOBEC overactive C > T at TpCp[A/T], and a signature featured by T > C substitution. The T > C mutational signature was significantly correlated with alcohol consumption (OR: 3.59; 95% CI: 2.30-5.67; P < 0.001). This alcohol consumption signature was also observed in liver cancer and head and neck squamous cell carcinoma, and its mutational activity was substantially higher in samples with mutations in TP53. Survival analysis revealed that TENM3 mutations (HR: 5.54; CI: 2.68-11.45; P < 0.001) and TP53 hotspot mutation p.R213* (HR: 3.37; CI: 1.73-8.06; P < 0.001) were significantly associated with shortened survival outcome. The association remained statistically significant after controlling for age, gender, TNM stage and tumor grade. Conclusions: We have uncovered several new SMGs in ESCC and defined an alcohol consumption related mutational signature. TENM3 mutations and the TP53 hotspot mutation p.R213* are independent prognosticators for poor survival in ESCC.

KW - Driver genes

KW - Esophagus

KW - Mutational signature

KW - Prognosticator

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U2 - 10.1093/annonc/mdy011

DO - 10.1093/annonc/mdy011

M3 - Article

C2 - 29351612

AN - SCOPUS:85046682133

SN - 0923-7534

VL - 29

SP - 938

EP - 944

JO - Annals of Oncology

JF - Annals of Oncology

IS - 4

ER -

A mutational signature associated with alcohol consumption and prognostically significantly mutated driver genes in esophageal squamous cell carcinoma

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