Deletions in metastatic colorectal cancer with chromothripsis

Abstract

Aim: In our previously reported study, we found a correlation between DNA massive fragmentation and increased progression free survival (PFS) in metastatic colorectal cancer (mCRC), but not overall survival. The aim of this study is to find overlapping deleted genome regions in selected mCRC patients with chromothripsis and detect possible cause of increased PFS, and find new genes or combinations, involved in colorectal cancer oncogenesis. Materials and Methods: 10 mCRC patients with chromothripsis receiving 5-fluorouracil, oxaliplatin, leucovorin (FOLFOX) first-line palliative chemotherapy between August, 2011 and October, 2012 were selected for this study. Microarray analysis was performed using the Infinium HumanOmniExpress-12 v1.0 formalin-fixed paraffin-embedded (FFPE) BeadChip kit (Illumina). BeadChip was scaned on HiScan (Illumina). Analysis was performed by GenomeStudio software (Illumina) and R version 3.1.2. Copy number variation and breakpoints on the chromosomes were analyzed using the DNA copy package. Results: Eight deleted tumor suppressor genes (ROBO2, CADM2, FAT4, PCDH10, PCDH18, CDH18, TSG1, CTNNA3) and four deleted oncogenes (CDH12, GPM6A, ADAM29, COL11A1) were identified in more than half of patients. In 70% patients' deletion in COL11A1 was detected. Deletion of MIR1269, MIR4465, MIR1261 and MIR4490 in patients with longer time to progression was observed. Four patients (40%) with PFS over 14 months, presented with NRG3 deletion (oncogene, еpidermal growth factor receptor (EGFR) ligand) what could possibly decrease proliferation of cancer cells via decreasing EGFR activation. Conclusions: Multiple chromosomal deletions (MIR1269, NRG3, ADK) in mCRC patients with chromothripsis are associated with better response to first line palliative FOLFOX-type chemotherapy and increased PFS.