Pan-cancer analysis of intratumor heterogeneity as a prognostic determinant of survival

// Luc G.T. Morris 1,2,* , Nadeem Riaz 1,3* , Alexis Desrichard 1 , Yasin Şenbabaoğlu 4 , A. Ari Hakimi 2 , Vladimir Makarov 1 , Jorge S. Reis-Filho 1,5 and Timothy A. Chan 1,3 1 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA 2 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA 3 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 4 Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA 5 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA * These authors have contributed equally to this work Correspondence to: Luc G.T. Morris, email: // Timothy A. Chan, email: // Keywords : heterogeneity, evolution, survival, cancer, immune surveillance Received : January 14, 2016 Accepted : January 21, 2016 Published : January 28, 2016 Abstract As tumors accumulate genetic alterations, an evolutionary process occurs in which genetically distinct subclonal populations of cells co-exist, resulting in intratumor genetic heterogeneity (ITH). The clinical implications of ITH remain poorly defined. Data are limited with respect to whether ITH is an independent determinant of patient survival outcomes, across different cancer types. Here, we report the results of a pan-cancer analysis of over 3300 tumors, showing a varied landscape of ITH across 9 cancer types. While some gene mutations are subclonal, the majority of driver gene mutations are clonal events, present in nearly all cancer cells. Strikingly, high levels of ITH are associated with poorer survival across diverse types of cancer. The adverse impact of high ITH is independent of other clinical, pathologic and molecular factors. High ITH tends to be associated with lower levels of tumor-infiltrating immune cells, but this association is not able to explain the observed survival differences. Together, these data show that ITH is a prognostic marker in multiple cancers. These results illuminate the natural history of cancer evolution, indicating that tumor heterogeneity represents a significant obstacle to cancer control.