Mutational landscapes of smoking-related cancers in Caucasians and African Americans: Precision oncology perspectives at Wake Forest Baptist comprehensive Cancer Center

Ville Kytola, Umit Topaloglu, Lance D. Miller, Rhonda L. Bitting, Michael M. Goodman, Ralph B. D'Agostino, Rodwige J. Desnoyers, Carol Albright, George Yacoub, Shadi A. Qasem, Barry DeYoung, Vesteinn Thorsson, Ilya Shmulevich, Meng Yang, Anastasia Shcherban, Matthew Pagni, Liang Liu, Matti Nykter, Kexin Chen, Gregory A. HawkinsStefan C. Grant, W. Jeffrey Petty, Angela Alistar, Edward A. Levine, Edgar D. Staren, Carl D. Langefeld, Vincent Miller, Gaurav Singal, Robin M. Petro, Mac Robinson, William Blackstock, Bayard L. Powell, Lynne I. Wagner, Kristie L. Foley, Edward Abraham, Boris Pasche, Wei Zhang

Research output: Contribution to journalArticle

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Abstract

Background: Cancers related to tobacco use and African-American ancestry are under-characterized by genomics. This gap in precision oncology research represents a major challenge in the health disparities in the United States. Methods: The Precision Oncology trial at the Wake Forest Baptist Comprehensive Cancer Center enrolled 431 cancer patients from March 2015 to May 2016. The composition of these patients consists of a high representation of tobacco-related cancers (e.g., lung, colorectal, and bladder) and African-American ancestry (13.5%). Tumors were sequenced to identify mutations to gain insight into genetic alterations associated with smoking and/or African-American ancestry. Results: Tobacco-related cancers exhibit a high mutational load. These tumors are characterized by high-frequency mutations in TP53, DNA damage repair genes (BRCA2 and ATM), and chromatin remodeling genes (the lysine methyltransferases KMT2D or MLL2, and KMT2C or MLL3). These tobacco-related cancers also exhibit augmented tumor heterogeneities. Smoking related genetic mutations were validated by The Cancer Genome Atlas dataset that includes 2,821 cases with known smoking status. The Wake Forest and The Cancer Genome Atlas cohorts (431 and 7,991 cases, respectively) revealed a significantly increased mutation rate in the TP53 gene in the African-American subgroup studied. Both cohorts also revealed 5 genes (e.g. CDK8) significantly amplified in the African-American population. Conclusions: These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer. TP53 mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups.

Original languageEnglish (US)
Pages (from-to)2914-2923
Number of pages10
JournalTheranostics
Volume7
Issue number11
DOIs
StatePublished - Jan 1 2017

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African Americans
Smoking
Neoplasms
Tobacco
Atlases
Mutation Rate
Mutation
Forests
BRCA2 Gene
Genome
Chromatin Assembly and Disassembly
Genomic Instability
p53 Genes
Methyltransferases
Tobacco Use
Genomics
Oncogenes
Ethnic Groups
DNA Repair
Genes

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

Cite this

Kytola, Ville ; Topaloglu, Umit ; Miller, Lance D. ; Bitting, Rhonda L. ; Goodman, Michael M. ; D'Agostino, Ralph B. ; Desnoyers, Rodwige J. ; Albright, Carol ; Yacoub, George ; Qasem, Shadi A. ; DeYoung, Barry ; Thorsson, Vesteinn ; Shmulevich, Ilya ; Yang, Meng ; Shcherban, Anastasia ; Pagni, Matthew ; Liu, Liang ; Nykter, Matti ; Chen, Kexin ; Hawkins, Gregory A. ; Grant, Stefan C. ; Petty, W. Jeffrey ; Alistar, Angela ; Levine, Edward A. ; Staren, Edgar D. ; Langefeld, Carl D. ; Miller, Vincent ; Singal, Gaurav ; Petro, Robin M. ; Robinson, Mac ; Blackstock, William ; Powell, Bayard L. ; Wagner, Lynne I. ; Foley, Kristie L. ; Abraham, Edward ; Pasche, Boris ; Zhang, Wei. / Mutational landscapes of smoking-related cancers in Caucasians and African Americans : Precision oncology perspectives at Wake Forest Baptist comprehensive Cancer Center. In: Theranostics. 2017 ; Vol. 7, No. 11. pp. 2914-2923.
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title = "Mutational landscapes of smoking-related cancers in Caucasians and African Americans: Precision oncology perspectives at Wake Forest Baptist comprehensive Cancer Center",
abstract = "Background: Cancers related to tobacco use and African-American ancestry are under-characterized by genomics. This gap in precision oncology research represents a major challenge in the health disparities in the United States. Methods: The Precision Oncology trial at the Wake Forest Baptist Comprehensive Cancer Center enrolled 431 cancer patients from March 2015 to May 2016. The composition of these patients consists of a high representation of tobacco-related cancers (e.g., lung, colorectal, and bladder) and African-American ancestry (13.5{\%}). Tumors were sequenced to identify mutations to gain insight into genetic alterations associated with smoking and/or African-American ancestry. Results: Tobacco-related cancers exhibit a high mutational load. These tumors are characterized by high-frequency mutations in TP53, DNA damage repair genes (BRCA2 and ATM), and chromatin remodeling genes (the lysine methyltransferases KMT2D or MLL2, and KMT2C or MLL3). These tobacco-related cancers also exhibit augmented tumor heterogeneities. Smoking related genetic mutations were validated by The Cancer Genome Atlas dataset that includes 2,821 cases with known smoking status. The Wake Forest and The Cancer Genome Atlas cohorts (431 and 7,991 cases, respectively) revealed a significantly increased mutation rate in the TP53 gene in the African-American subgroup studied. Both cohorts also revealed 5 genes (e.g. CDK8) significantly amplified in the African-American population. Conclusions: These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer. TP53 mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups.",
author = "Ville Kytola and Umit Topaloglu and Miller, {Lance D.} and Bitting, {Rhonda L.} and Goodman, {Michael M.} and D'Agostino, {Ralph B.} and Desnoyers, {Rodwige J.} and Carol Albright and George Yacoub and Qasem, {Shadi A.} and Barry DeYoung and Vesteinn Thorsson and Ilya Shmulevich and Meng Yang and Anastasia Shcherban and Matthew Pagni and Liang Liu and Matti Nykter and Kexin Chen and Hawkins, {Gregory A.} and Grant, {Stefan C.} and Petty, {W. Jeffrey} and Angela Alistar and Levine, {Edward A.} and Staren, {Edgar D.} and Langefeld, {Carl D.} and Vincent Miller and Gaurav Singal and Petro, {Robin M.} and Mac Robinson and William Blackstock and Powell, {Bayard L.} and Wagner, {Lynne I.} and Foley, {Kristie L.} and Edward Abraham and Boris Pasche and Wei Zhang",
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Kytola, V, Topaloglu, U, Miller, LD, Bitting, RL, Goodman, MM, D'Agostino, RB, Desnoyers, RJ, Albright, C, Yacoub, G, Qasem, SA, DeYoung, B, Thorsson, V, Shmulevich, I, Yang, M, Shcherban, A, Pagni, M, Liu, L, Nykter, M, Chen, K, Hawkins, GA, Grant, SC, Petty, WJ, Alistar, A, Levine, EA, Staren, ED, Langefeld, CD, Miller, V, Singal, G, Petro, RM, Robinson, M, Blackstock, W, Powell, BL, Wagner, LI, Foley, KL, Abraham, E, Pasche, B & Zhang, W 2017, 'Mutational landscapes of smoking-related cancers in Caucasians and African Americans: Precision oncology perspectives at Wake Forest Baptist comprehensive Cancer Center', Theranostics, vol. 7, no. 11, pp. 2914-2923. https://doi.org/10.7150/thno.20355

Mutational landscapes of smoking-related cancers in Caucasians and African Americans : Precision oncology perspectives at Wake Forest Baptist comprehensive Cancer Center. / Kytola, Ville; Topaloglu, Umit; Miller, Lance D.; Bitting, Rhonda L.; Goodman, Michael M.; D'Agostino, Ralph B.; Desnoyers, Rodwige J.; Albright, Carol; Yacoub, George; Qasem, Shadi A.; DeYoung, Barry; Thorsson, Vesteinn; Shmulevich, Ilya; Yang, Meng; Shcherban, Anastasia; Pagni, Matthew; Liu, Liang; Nykter, Matti; Chen, Kexin; Hawkins, Gregory A.; Grant, Stefan C.; Petty, W. Jeffrey; Alistar, Angela; Levine, Edward A.; Staren, Edgar D.; Langefeld, Carl D.; Miller, Vincent; Singal, Gaurav; Petro, Robin M.; Robinson, Mac; Blackstock, William; Powell, Bayard L.; Wagner, Lynne I.; Foley, Kristie L.; Abraham, Edward; Pasche, Boris; Zhang, Wei.

In: Theranostics, Vol. 7, No. 11, 01.01.2017, p. 2914-2923.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutational landscapes of smoking-related cancers in Caucasians and African Americans

T2 - Precision oncology perspectives at Wake Forest Baptist comprehensive Cancer Center

AU - Kytola, Ville

AU - Topaloglu, Umit

AU - Miller, Lance D.

AU - Bitting, Rhonda L.

AU - Goodman, Michael M.

AU - D'Agostino, Ralph B.

AU - Desnoyers, Rodwige J.

AU - Albright, Carol

AU - Yacoub, George

AU - Qasem, Shadi A.

AU - DeYoung, Barry

AU - Thorsson, Vesteinn

AU - Shmulevich, Ilya

AU - Yang, Meng

AU - Shcherban, Anastasia

AU - Pagni, Matthew

AU - Liu, Liang

AU - Nykter, Matti

AU - Chen, Kexin

AU - Hawkins, Gregory A.

AU - Grant, Stefan C.

AU - Petty, W. Jeffrey

AU - Alistar, Angela

AU - Levine, Edward A.

AU - Staren, Edgar D.

AU - Langefeld, Carl D.

AU - Miller, Vincent

AU - Singal, Gaurav

AU - Petro, Robin M.

AU - Robinson, Mac

AU - Blackstock, William

AU - Powell, Bayard L.

AU - Wagner, Lynne I.

AU - Foley, Kristie L.

AU - Abraham, Edward

AU - Pasche, Boris

AU - Zhang, Wei

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background: Cancers related to tobacco use and African-American ancestry are under-characterized by genomics. This gap in precision oncology research represents a major challenge in the health disparities in the United States. Methods: The Precision Oncology trial at the Wake Forest Baptist Comprehensive Cancer Center enrolled 431 cancer patients from March 2015 to May 2016. The composition of these patients consists of a high representation of tobacco-related cancers (e.g., lung, colorectal, and bladder) and African-American ancestry (13.5%). Tumors were sequenced to identify mutations to gain insight into genetic alterations associated with smoking and/or African-American ancestry. Results: Tobacco-related cancers exhibit a high mutational load. These tumors are characterized by high-frequency mutations in TP53, DNA damage repair genes (BRCA2 and ATM), and chromatin remodeling genes (the lysine methyltransferases KMT2D or MLL2, and KMT2C or MLL3). These tobacco-related cancers also exhibit augmented tumor heterogeneities. Smoking related genetic mutations were validated by The Cancer Genome Atlas dataset that includes 2,821 cases with known smoking status. The Wake Forest and The Cancer Genome Atlas cohorts (431 and 7,991 cases, respectively) revealed a significantly increased mutation rate in the TP53 gene in the African-American subgroup studied. Both cohorts also revealed 5 genes (e.g. CDK8) significantly amplified in the African-American population. Conclusions: These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer. TP53 mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups.

AB - Background: Cancers related to tobacco use and African-American ancestry are under-characterized by genomics. This gap in precision oncology research represents a major challenge in the health disparities in the United States. Methods: The Precision Oncology trial at the Wake Forest Baptist Comprehensive Cancer Center enrolled 431 cancer patients from March 2015 to May 2016. The composition of these patients consists of a high representation of tobacco-related cancers (e.g., lung, colorectal, and bladder) and African-American ancestry (13.5%). Tumors were sequenced to identify mutations to gain insight into genetic alterations associated with smoking and/or African-American ancestry. Results: Tobacco-related cancers exhibit a high mutational load. These tumors are characterized by high-frequency mutations in TP53, DNA damage repair genes (BRCA2 and ATM), and chromatin remodeling genes (the lysine methyltransferases KMT2D or MLL2, and KMT2C or MLL3). These tobacco-related cancers also exhibit augmented tumor heterogeneities. Smoking related genetic mutations were validated by The Cancer Genome Atlas dataset that includes 2,821 cases with known smoking status. The Wake Forest and The Cancer Genome Atlas cohorts (431 and 7,991 cases, respectively) revealed a significantly increased mutation rate in the TP53 gene in the African-American subgroup studied. Both cohorts also revealed 5 genes (e.g. CDK8) significantly amplified in the African-American population. Conclusions: These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer. TP53 mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups.

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DO - 10.7150/thno.20355

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