Chromoanagenesis Landscape in 10,000 TCGA Patients.

Abstract

Simple SummaryChromoanagenesis is a single catastrophic event in which one or few chromosomes are shattered and disorderly reassembled. Chromoanagenesis is common in many types of cancers. In this study, we utilize data from The Pan-Cancer Analysis of Whole Genome (PCAWG) to build a machine learning algorithm that detects chromoanagenesis with high accuracy. We applied the algorithm on ~10,000 samples from The Cancer Genome Atlas (TCGA), thereby providing, for the first time, chromoanagenesis status labels for the complete data set. An in-depth analysis of somatic and clinical chromoanagenesis features is presented for 20 cancer types. Mutual exclusivity patterns between genes impaired in chromoanagenesis versus non-chromoanagenesis cases might imply at distinct pathways involved in chromoanagenesis-driven tumorigenesis.During the past decade, whole-genome sequencing of tumor biopsies and individuals with congenital disorders highlighted the phenomenon of chromoanagenesis, a single chaotic event of chromosomal rearrangement. Chromoanagenesis was shown to be frequent in many types of cancers, to occur in early stages of cancer development, and significantly impact the tumor’s nature. However, an in-depth, cancer-type dependent analysis has been somewhat incomplete due to the shortage in whole genome sequencing of cancerous samples. In this study, we extracted data from The Pan-Cancer Analysis of Whole Genome (PCAWG) and The Cancer Genome Atlas (TCGA) to construct and test a machine learning algorithm that can detect chromoanagenesis with high accuracy (86%). The algorithm was applied to ~10,000 unlabeled TCGA cancer patients. We utilize the chromoanagenesis assignment results, to analyze cancer-type specific chromoanagenesis characteristics in 20 TCGA cancer types. Our results unveil prominent genes affected in either chromoanagenesis or non-chromoanagenesis tumorigenesis. The analysis reveals a mutual exclusivity relationship between the genes impaired in chromoanagenesis versus non-chromoanagenesis cases. We offer the discovered characteristics as possible targets for cancer diagnostic and therapeutic purposes.