Feasibility of novel PPP1R15A and proposed ANXA11 single nucleotide polymorphisms as predictive markers for bevacizumab regimen in metastatic colorectal cancer

Cited 10 time in scopus
Metadata Downloads
Title
Feasibility of novel PPP1R15A and proposed ANXA11 single nucleotide polymorphisms as predictive markers for bevacizumab regimen in metastatic colorectal cancer
Author(s)
S A Roh; I J Park; Y S Yoon; Y H Kwon; J H Chung; T W Kim; D H Cho; Byung Ho Lim; Seon-Kyu KimSeon-Young Kim; Yong Sung Kim; J C Kim
Bibliographic Citation
Journal of Cancer Research and Clinical Oncology, vol. 142, pp. 1705-1714
Publication Year
2016
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: PPP1R15Ars557806 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.
Keyword
BevacizumabMetastatic colorectal cancerPPP1R15APredictive markerANXA11
ISSN
0171-5216
Publisher
Springer
DOI
http://dx.doi.org/10.1007/s00432-016-2177-5
Type
Article
Appears in Collections:
Aging Convergence Research Center > 1. Journal Articles
Files in This Item:
  • There are no files associated with this item.


Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.