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Published on: March 21, 2018
Deletions in metastatic colorectal cancer with chromothripsis
E Skuja1, D Butane2, M Nakazawa-Miklasevica2
1Clinic of Oncology, P. Stradins Clinical University Hospital, Riga LV-1002, Latvia.
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.
Insights
Chromosomal deletions in metastatic colorectal cancer (mCRC) patients with chromothripsis correlate with improved progression-free survival (PFS) after FOLFOX chemotherapy. Specific deletions may influence cancer cell proliferation and treatment response.
Area of Science:
- Genomics
- Oncology
- Cancer Research
Background:
- Previous studies linked massive DNA fragmentation to increased progression-free survival (PFS) in metastatic colorectal cancer (mCRC).
- Chromothripsis, a complex genomic rearrangement, is observed in various cancers, including mCRC.
Purpose of the Study:
- To identify overlapping deleted genome regions in mCRC patients with chromothripsis.
- To investigate the potential causes of increased PFS in these patients.
- To discover novel genes or combinations involved in colorectal cancer oncogenesis.
Main Methods:
- Analysis of 10 mCRC patients with chromothripsis who received first-line FOLFOX chemotherapy.
- Microarray analysis using Illumina Infinium HumanOmniExpress-12 v1.0 BeadChip kit on FFPE samples.
- Copy number variation and breakpoint analysis using R software and the DNA copy package.
Main Results:
- Identified eight deleted tumor suppressor genes (e.g., ROBO2, FAT4) and four deleted oncogenes (e.g., COL11A1, NRG3).
- Deletion in COL11A1 was detected in 70% of patients.
- Deletions of MIR1269, MIR4465, MIR1261, and MIR4490 were associated with longer time to progression.
- NRG3 deletion was observed in 40% of patients with PFS > 14 months, potentially reducing cancer cell proliferation via decreased EGFR activation.
Conclusions:
- Multiple chromosomal deletions (MIR1269, NRG3, ADK) in mCRC patients with chromothripsis are linked to better response to FOLFOX chemotherapy.
- These deletions are associated with increased PFS in mCRC patients.
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