RNA-seq Based Transcription Characterization of Fusion Breakpoints as a Potential Estimator for Its Oncogenic Potential.

Jian-Lei Gu,Shi-Yi Liu,Morris Chukhman,Cong Liu,Hui Lu,Yao Lu

doi:10.1155/2017/9829175

Jian-Lei Gu, Shi-Yi Liu + Show 4 more

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https://doi.org/10.1155/2017/9829175

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Abstract

Based on high-throughput sequencing technology, the detection of gene fusions is no longer a big challenge but estimating the oncogenic potential of fusion genes remains challenging. Recent studies successfully applied machine learning methods and gene structural and functional features of fusion mutation to predict their oncogenic potentials. However, the transcription characterizations features of fusion genes have not yet been studied. In this study, based on the clonal evolution theory, we hypothesized that a fusion gene is more likely to be an oncogenic genomic alteration, if the neoplastic cells harboring this fusion mutation have larger clonal size than other neoplastic cells in a tumor. We proposed a novel method, called iFCR (internal Fusion Clone Ratio), given an estimation of oncogenic potential for fusion mutations. We have evaluated the iFCR method in three public cancer transcriptome sequencing datasets; the results demonstrated that the fusion mutations occurring in tumor samples have higher internal fusion clone ratio than normal samples. And the most frequent prostate cancer fusion mutation, TMPRSS2-ERG, appears to have a remarkably higher iFCR value in all three independent patients. The preliminary results suggest that the internal fusion clone ratio might potentially advantage current fusion mutation oncogenic potential prediction methods.

Highlights

Chromosomal rearrangement events often lead to gene fusion mutation and result in a hybrid fusion gene, consisting of two separate fusion parents [1, 2]
A large number of important fusion mutations have been recognized [3], including the first identified “Philadelphia chromosome” BCR-ABL gene fusion in chronic myelogenous leukemia [4], the important biomarker of synovial sarcomas, SYT–SSX gene fusion [5], and the most studied fusion TMPRSS2-ERG in prostate cancer [6]
In order to estimate the subclone structure based on transcriptome sequencing data, we make a simple assumption that fusion genes and their parent genes have similar expression level among neoplastic cells in the same sample

Summary

Introduction

Chromosomal rearrangement events often lead to gene fusion mutation and result in a hybrid fusion gene, consisting of two separate fusion parents (genes) [1, 2]. Distinguishing oncogenic fusion mutations, whose functions are critical for cancer initiation, progression, and metastasis, remains a big challenge. A fusion event is considered as an oncogenic mutation if it occurs more frequently in cancer patients (i.e., high recurrent rate) [2, 7]. This strategy is expensive and time-consuming to conduct experiments for many patients. This method has limited power to predict the oncogenic potential of novel and rare fusion mutations for a certain patient, and its application in the era of precise medicine is limited

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