title: Pan-cancer analysis of intratumor heterogeneity as a prognostic determinant of survival.
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.
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Luc G T
authors: LG
authors: Morris
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Nadeem
authors: N
authors: Riaz
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Alexis
authors: A
authors: Desrichard
authors: Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Yasin
authors: Y
authors: Şenbabaoğlu
authors: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: A Ari
authors: AA
authors: Hakimi
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Vladimir
authors: V
authors: Makarov
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Jorge S
authors: JS
authors: Reis-Filho
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Timothy A
authors: TA
authors: Chan
mesh_terms: D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D015999:Multivariate Analysis; D009154:Mutation; D009369:Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016019:Survival Analysis
keywords: cancer; evolution; heterogeneity; immune surveillance; survival