title: Feasibility of novel PPP1R15A and proposed ANXA11 single nucleotide polymorphisms as predictive markers for bevacizumab regimen in metastatic colorectal cancer.
abstract: OBJECTIVE
  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 [(18)F]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). [(18)F]FDG uptake decreased to 75 % in HCT116 xenograft-bearing mice with the G allele, whereas [(18)F]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 [(18)F]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).
  
  
  CONCLUSIONS
  ANXA11 rs1049550 and PPP1R15A rs557806 may improve the identification of mCRC patients sensitive to bevacizumab regimens, and further validation is required in large cohorts.
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.|Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
authors.forename: Seon Ae
authors.initials: SA
authors.lastname: Roh
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.
authors.forename: In Ja
authors.initials: IJ
authors.lastname: Park
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.|Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
authors.forename: Yong Sik
authors.initials: YS
authors.lastname: Yoon
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
authors.forename: Yi Hong
authors.initials: YH
authors.lastname: Kwon
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.
authors.forename: Jin Hwa
authors.initials: JH
authors.lastname: Chung
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Graduate School of East-West Medical Science, Kyung Hee University, Suwon, Gyeonggi-do, Korea.
authors.forename: Dong Hyung
authors.initials: DH
authors.lastname: Cho
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lim
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
authors.forename: Seon Kyu
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
authors.forename: Seon Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea. yongsung@kribb.re.kr.
authors.forename: Yong Sung
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea. jckim@amc.seoul.kr.|Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea. jckim@amc.seoul.kr.|Institute of Innovative Cancer Research, Asan Medical Center, Seoul, Korea. jckim@amc.seoul.kr.
authors.forename: Jin Cheon
authors.initials: JC
authors.lastname: Kim
mesh_terms: D000818:Animals; D017302:Annexins / Q000235:genetics*; D000068258:Bevacizumab / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005240:Feasibility Studies; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide; D054645:Protein Phosphatase 1 / Q000235:genetics*
chemical_list: D017302:Annexins; D000068258:Bevacizumab; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1
keywords: ANXA11; Bevacizumab; Metastatic colorectal cancer; PPP1R15A; Predictive marker