Punctuated evolution of canonical genomic aberrations in uveal melanoma

Matthew G Field,Christina L Decatur,Anne M Bowcock,Stefan Kurtenbach,Hima Anbunathan,Michael A Durante,Louis Z Cai,J William Harbour

doi:10.1038/s41467-017-02428-w

Matthew G Field, Christina L Decatur + Show 6 more

Open Access

https://doi.org/10.1038/s41467-017-02428-w

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Abstract

Cancer is thought to arise through the accumulation of genomic aberrations evolving under Darwinian selection. However, it remains unclear when the aberrations associated with metastasis emerge during tumor evolution. Uveal melanoma (UM) is the most common primary eye cancer and frequently leads to metastatic death, which is strongly linked to BAP1 mutations. Accordingly, UM is ideally suited for studying the clonal evolution of metastatic competence. Here we analyze sequencing data from 151 primary UM samples using a customized bioinformatic pipeline, to improve detection of BAP1 mutations and infer the clonal relationships among genomic aberrations. Strikingly, we find BAP1 mutations and other canonical genomic aberrations usually arise in an early punctuated burst, followed by neutral evolution extending to the time of clinical detection. This implies that the metastatic proclivity of UM is “set in stone” early in tumor evolution and may explain why advances in primary treatment have not improved survival.

Highlights

Cancer is thought to arise through the accumulation of genomic aberrations evolving under Darwinian selection
gene expression profile (GEP) classification data were available for all JWH samples and was estimated using RNA sequencing (RNAseq) data for The Cancer Genome Atlas (TCGA) samples[16]
To enhance our ability to detect such a wide range of inactivating mutations, we developed a robust pipeline of complementary bioinformatic tools to improve read alignments, manage low read counts, and identify large genomic alterations (Supplementary Fig. 1)

Summary

Introduction

Cancer is thought to arise through the accumulation of genomic aberrations evolving under Darwinian selection. We find BAP1 mutations and other canonical genomic aberrations usually arise in an early punctuated burst, followed by neutral evolution extending to the time of clinical detection This implies that the metastatic proclivity of UM is “set in stone” early in tumor evolution and may explain why advances in primary treatment have not improved survival. We analyze generation sequencing (NGS) data from 151 primary UMs using a wide range of bioinformatic tools and techniques to optimize our detection of BAP1 and other mutations and CNAs, to explore their clonal relationships This approach reveals many previously undetected BAP1 and spliceosome mutations, and uncovers strong evidence that the canonical genomic aberrations in UM usually arise in an early, punctuated burst followed by clonal stasis. These findings underscore the striking differences in genomic structure and evolution between UM and cutaneous melanoma, and they have profound implications for treatment and survival in UM

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