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

Abstract

<b><i>Background:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> Tobacco-related cancers exhibit a high mutational load. These tumors are characterized by high-frequency mutations in <i>TP53</i>, DNA damage repair genes (<i>BRCA2</i> and <i>ATM),</i> and chromatin remodeling genes (the lysine methyltransferases <i>KMT2D</i> or <i>MLL2</i>, and <i>KMT2C</i> or <i>MLL3)</i>. 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 <i>TP53</i> gene in the African-American subgroup studied. Both cohorts also revealed 5 genes (e.g. <i>CDK8</i>) significantly amplified in the African-American population. <b><i>Conclusions:</i></b> These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer. <i>TP53</i> mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups.