RT Journal Article SR Electronic T1 Further genetic diversification in multiple tumors and an evolutionary perspective on therapeutics JF bioRxiv FD Cold Spring Harbor Laboratory SP 025429 DO 10.1101/025429 A1 Yong Tao A1 Zheng Hu A1 Shaoping Ling A1 Shiou-Hwie Yeh A1 Weiwei Zhai A1 Ke Chen A1 Chunyan Li A1 Yu Wang A1 Kaile Wang A1 Hurng-Yi Wang A1 Eric A. Hungate A1 Kenan Onel A1 Jiang Liu A1 Changqing Zeng A1 Richard R. Hudson A1 Pei-Jer Chen A1 Xuemei Lu A1 Chung-I Wu YR 2015 UL http://biorxiv.org/content/early/2015/08/25/025429.abstract AB The genetic diversity within a single tumor can be extremely large, possibly with mutations at all coding sites (Ling et al. 2015). In this study, we analyzed 12 cases of multiple hepatocellular carcinoma (HCC) tumors by sequencing and genotyping several samples from each case. In 10 cases, tumors are clonally related by a process of cell migration and colonization. They permit a detailed analysis of the evolutionary forces (mutation, migration, drift and natural selection) that influence the genetic diversity both within and between tumors. In 23 inter-tumor comparisons, the descendant tumor usually shows a higher growth rate than the parent tumor. In contrast, neutral diversity dominates within-tumor observations such that adaptively growing clones are rarely found. The apparent adaptive evolution between tumors can be explained by the inherent bias for detecting larger tumors that have a growth advantage. Beyond these tumors are a far larger number of clones which, growing at a neutral rate and too small to see, can nevertheless be verified by molecular means. Given that the estimated genetic diversity is often very large, therapeutic strategies need to take into account the pre-existence of many drug-resistance mutations. Importantly, these mutations are expected to be in the very low frequency range in the primary tumors (and become frequent in the relapses, as is indeed reported (1-3). In conclusion, tumors may often harbor a very large number of mutations in the very low frequency range. This duality provides both a challenge and an opportunity for designing strategies against drug resistance (4-8).One Sentence Summary The total genetic diversity across all tumors of a single patient, with large number of low frequency mutations driven by neutral and adaptive forces, presents both a challenge and an opportunity for new cancer therapeutics.