Abstract
Purpose
Bevacizumab improves survival in patients with metastatic colorectal cancer (mCRC) under chemotherapy, but few predictive markers have been identified.
Methods
To investigate chemosensitive single nucleotide polymorphisms (SNPs) of mCRC, we performed exome sequencing and RNA sequencing in 19 patients. A clinical association analysis was performed with the other 116 patients who had received chemotherapy to bevacizumab regimens. In vivo biodistribution studies and [18F]FDG-PET imaging were performed on mice bearing human colorectal cancer (HCT116 and SW480) xenografts after injection of bevacizumab with 5-FU, leucovorin, and irinotecan (FOLFIRI).
Results
PPP1R15A rs557806 showed the most significant association with FRB-driven tumor IR in exome sequencing and the highest correlation (r = 0.74) with drug responses in RNA sequencing. Patients homozygous for the reference alleles (GG) of PPP1R15A rs557806 exhibited greater disease control rate and a tendency toward greater objective response rate (ORR) than those with homozygous or heterozygous substitution alleles (GC and CC; P = 0.027 and 0.073, respectively). In xenografted mice, HCT116 clones transfected with the G allele at PPP1R15A rs557806 were more sensitive to bevacizumab regimens than those with the C allele. Tumor volume of xenografts with the G allele was significantly lower than that of xenografts with the C allele (P = 0.004, day 13). [18F]FDG uptake decreased to 75 % in HCT116 xenograft-bearing mice with the G allele, whereas [18F]FDG uptake was 42 % in mice xenografts with the C allele (P = 0.032). ANXA11 rs1049550, a predictive biomarker of SNP described in our previous study, was validated using the xenograft model. Tumor volume and [18F]FDG uptake analyses showed that tumors in the SW480 xenografts expressing the substitution allele (T) at ANXA11 rs1049550 were more susceptible to FOLFIRI plus bevacizumab-induced suppression than those expressing the reference allele (C) (P = 0.001 and 0.026, respectively).
Conclusion
ANXA11 rs1049550 and PPP1R15A rs557806 may improve the identification of mCRC patients sensitive to bevacizumab regimens, and further validation is required in large cohorts.
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Acknowledgments
This work was supported in part by Grants (to J.C. Kim) from the Korea Research Foundation (2013R1A2A1A03070986), Ministry of Science, ICT, and Future Planning, and the Korea Health 21 R&D Project (HI06C0868 and HI13C1750), Ministry of Health, Welfare, and Family Affairs, Republic of Korea.
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The study protocol was approved by the Institutional Review Board for Human Genetic and Genomic Research (Registration No. 2014-0150). All participants provided their written informed consent. This study was also reviewed and approved by the Institutional Animal Care and Use Committee of the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea (Registration No. 2014-03-038).
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Roh, S.A., Park, I.J., Yoon, Y.S. et al. Feasibility of novel PPP1R15A and proposed ANXA11 single nucleotide polymorphisms as predictive markers for bevacizumab regimen in metastatic colorectal cancer. J Cancer Res Clin Oncol 142, 1705–1714 (2016). https://doi.org/10.1007/s00432-016-2177-5
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DOI: https://doi.org/10.1007/s00432-016-2177-5