Theranostics 2017; 7(11):2914-2923. doi:10.7150/thno.20355

Research Paper

Mutational Landscapes of Smoking-Related Cancers in Caucasians and African Americans: Precision Oncology Perspectives at Wake Forest Baptist Comprehensive Cancer Center

Ville Kytola1, 2, 10*, Umit Topaloglu1, 2*, Lance D. Miller1, 2*, Rhonda L. Bitting1, 3, Michael M. Goodman1, 3, Ralph B. D`Agostino Jr1, 4, Rodwige J. Desnoyers1, 3, Carol Albright1, 3, George Yacoub1, 3, Shadi A. Qasem1, 5, Barry DeYoung1, 5, Vesteinn Thorsson11, Ilya Shmulevich11, Meng Yang1, 2, 12, Anastasia Shcherban1, 2, 10, Matthew Pagni1, 7, Liang Liu1, Matti Nykter10, Kexin Chen12, Gregory A. Hawkins1, 15, Stefan C. Grant1, 3, W. Jeffrey Petty1, 3, Angela Tatiana Alistar1, 3, Edward A. Levine1, 6, Edgar D. Staren1, 6, Carl D. Langefeld4, Vincent Miller13, Gaurav Singal13, Robin M. Petro1, 3, Mac Robinson1, William Blackstock1, 8, Bayard L. Powell1, 3, Lynne I. Wagner1, 9, Kristie L. Foley1, 9, Edward Abraham14, Boris Pasche1, 2, 3✉, Wei Zhang1, 2, 15✉

1. Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston Salem, NC, USA 27157;
2. Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC, USA 27157;
3. Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston Salem, NC, USA 27157;
4. Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston Salem, NC, USA 27157;
5. Department of Laboratory Medicine and Pathology, Wake Forest School of Medicine, Winston Salem, NC, USA 27157;
6. Department of General Surgery-Section of Surgical Oncology, Wake Forest School of Medicine, Winston Salem, NC, USA 27157;
7. Department of Radiology, Wake Forest School of Medicine, Winston Salem, NC, USA 27157;
8. Department of Radiation Oncology, Wake Forest School of Medicine, Winston Salem, NC, USA 27157;
9. Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Winston Salem, NC, USA 27157;
10. Institute for Biosciences and Medical Technology, University of Tampere, Tampere, Finland 33520;
11. Institute for Systems Biology, Seattle, WA, USA 98109;
12. Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China 300060;
13. Foundation Medicine, Cambridge, MA, USA 02141;
14. Wake Forest School of Medicine, Winston Salem, NC, USA 27157;
15. Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston Salem, NC, USA 27157.
* Equal contributions

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.

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How to cite this article:
Kytola V, Topaloglu U, Miller LD, Bitting RL, Goodman MM, D`Agostino RB Jr, 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 AT, 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. Mutational Landscapes of Smoking-Related Cancers in Caucasians and African Americans: Precision Oncology Perspectives at Wake Forest Baptist Comprehensive Cancer Center. Theranostics 2017; 7(11):2914-2923. doi:10.7150/thno.20355. Available from http://www.thno.org/v07p2914.htm