Modeling Genomic Instability and Selection Pressure in a Mouse Model of Melanoma

Lawrence N Kwong,Lihua Zou,Sharmeen Chagani,Chandra Sekhar Pedamallu,Mingguang Liu,Shan Jiang,Alexei Protopopov,Jianhua Zhang,Gad Getz,Lynda Chin

doi:10.1016/j.celrep.2017.04.065

Abstract

Tumor evolution is an iterative process of selection for pro-oncogenic aberrations. This process can beaccelerated by genomic instability, but how itinteracts with different selection bottlenecks to shape the evolving genomic landscape remains understudied. Here, we assessed tumor initiation and therapy resistance bottlenecks in mouse models of melanoma, with or without genomic instability. At the initiation bottleneck, whole-exome sequencing revealed that drug-naive tumors were genomically silent, and this was surprisingly unaffected when genomic instability was introduced via telomerase inactivation. We hypothesize that the strong engineered alleles created low selection pressure. At the therapy resistance bottleneck, strong selective pressure was applied using a BRAF inhibitor. In the absence of genomic instability, tumors acquired a non-genomic drug resistance mechanism. By contrast, telomerase-deficient, drug-resistant melanomas acquired highly recurrent copy number gains. These proof-of-principle experiments demonstrate how different selection pressures can interact with genomic instability to impact tumor evolution.

Highlights

Tumor evolution is shaped by different forces, including genomic instability, which increases the rate of genetic aberrations and selection pressures that create bottlenecks, together enhancing the enrichment for tumor cells harboring pro-oncogenic aberrations
As a prime example of iterative, pro-tumorigenic selection, high counts of somatic copy number aberrations (SCNAs) and mutations are a hallmark of late-stage melanoma (The Cancer Genome Atlas Network, 2015; Kabbarah et al, 2010)
We describe whole-exome sequencing (WES) results that address how selection pressure strengths can interact with genomic instability to shape tumor genomic evolution

Summary

Introduction

Tumor evolution is shaped by different forces, including genomic instability, which increases the rate of genetic aberrations and selection pressures that create bottlenecks, together enhancing the enrichment for tumor cells harboring pro-oncogenic aberrations. TERT gain, as well as frequently observed TERTpromoter-activating mutations (Horn et al, 2013; Huang et al, 2013), which are further boosted by BRAF signaling (Li et al, 2016), mark the reactivation of telomerase as a common early event in human melanoma (Shain et al, 2015) The reason this can be critical for tumor progression is that, in humans, while telomerase is widely active during fetal development and in some adult stem cells, it is non-expressed in most cells after birth (Blackburn et al, 2015). This may allow for accumulated telomerase-deficiency-driven genomic aberrations to provide pro-oncogenic substrates for further evolutionary selection

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