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Target Cell Pre-enrichment and Whole Genome Amplification for Single Cell Downstream Characterization
Published on: May 15, 2018
Copy Number Alterations in Tumor Genomes Deleting Antineoplastic Drug Targets Partially Compensated by Complementary
Ha Vu Tran1,2, Alexandra K Kiemer3, Volkhard Helms4
1Saarland University, Center for Bioinformatics, Saarbruecken, Germany.
Background/Aim:
Genomic DNA copy number alterations (CNAs) are frequent in tumors and have been catalogued by The Cancer Genome Atlas project. Emergence of chemoresistance frequently renders drug therapies ineffective.
Materials And Methods:
We analyzed how CNAs recurrently found in the genomes of TCGA patients of thirty-one tumor types affect protein targets of antineoplastic (AN) agents.
Results:
CNA deletions more frequently affected the targets of AN agents than CNA amplifications. Interestingly, in seven tumors we observed signs of compensatory CNAs. For example, in glioblastoma multiforme, two target genes (FLT1, FLT3) of the experimental drug sorafenib were recurrently deleted, whereas another target (KDR) of sorafenib was recurrently amplified. In renal clear cell carcinoma, the target FLT1 of pazopanib, sunitinib, sorafenib, and axitinib was recurrently deleted, whereas FLT4 bound by the same drugs, was recurrently amplified.
Conclusion:
Deletions of AN target proteins can be compensated by amplification of alternative targets.
Insights
Genomic copy number alterations (CNAs) in tumors frequently delete antineoplastic (AN) drug targets. However, amplifications of alternative targets can compensate for these deletions, impacting treatment effectiveness.
Area of Science:
- Genomics
- Cancer Biology
- Pharmacology
Background:
- Genomic DNA copy number alterations (CNAs) are common in tumors.
- The Cancer Genome Atlas (TCGA) project has cataloged these alterations.
- Chemoresistance is a major challenge in cancer drug therapies.
Purpose of the Study:
- To investigate the impact of recurrent CNAs on protein targets of antineoplastic (AN) agents.
- To analyze CNA patterns across 31 tumor types from TCGA.
- To understand how CNAs contribute to drug resistance.
Main Methods:
- Analysis of CNA data from The Cancer Genome Atlas (TCGA) project.
- Identification of recurrent CNAs in 31 different tumor types.
- Assessment of the effect of CNAs on protein targets of antineoplastic agents.
Main Results:
- CNA deletions were observed more frequently than amplifications affecting AN agent targets.
- Evidence of compensatory CNAs was found in seven tumor types.
- Examples include deletions and amplifications of sorafenib targets in glioblastoma multiforme and pazopanib/sunitinib targets in renal clear cell carcinoma.
Conclusions:
- Deletions of antineoplastic (AN) drug target proteins can be counteracted by the amplification of alternative targets.
- This compensatory mechanism may influence the efficacy of cancer therapies.
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