High RAD54B expression: an independent predictor of postoperative distant recurrence in colorectal cancer patients

We recently reported a specific mechanism that RAD54B, an important factor in homologous recombination, promotes genomic instability via the degradation of p53 protein in vitro. However, clinical significance of RAD54Bin colorectal cancer (CRC) remains unclear. Thus we analyzed RAD54B geneexpression in CRC patients. Using the training set (n = 123), the optimal cut-off value for stratification was determined, and validated in another cohort (n = 89). Kaplan–Meier plots showed that distant recurrence free survival was significantly lesser in high RAD54B expression group compared with that of low expression group in both training (P = 0.0013) and validation (P = 0.024) set. Multivariate analysis using Cox proportional-hazards model showed that high RAD54B expression was an independent predictor in both training (hazard ratio, 4.31; 95% CI, 1.53–13.1; P = 0.0060) and validation (hazard ratio, 3.63; 95% CI, 1.23–10.7; P = 0.021) set. In addition, a negative significant correlation between RAD54B and CDKN1A, a target gene of p53, was partially confirmed, suggesting that RAD54B functions via the degradation of p53 protein even in clinical samples. This study first demonstrated RAD54B expression has potential to serve as a novel prognostic biomarker, particularly for distant recurrence in CRC patients.

[1]  K. Miyagawa,et al.  Rad54B serves as a scaffold in the DNA damage response that limits checkpoint strength , 2014, Nature Communications.

[2]  J. Tabernero,et al.  Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. , 2013, The New England journal of medicine.

[3]  G. Sauter,et al.  RAD51 overexpression is a negative prognostic marker for colorectal adenocarcinoma , 2013, International journal of cancer.

[4]  Xiaolan Zhao,et al.  Homologous recombination and its regulation , 2012, Nucleic acids research.

[5]  W. Jia,et al.  Elevated expression of Rad51 is correlated with decreased survival in resectable esophageal squamous cell carcinoma , 2011, Journal of surgical oncology.

[6]  W. Heyer,et al.  Functions of the Snf2/Swi2 family Rad54 motor protein in homologous recombination. , 2011, Biochimica et biophysica acta.

[7]  M. Copetti,et al.  High RAD51 mRNA expression characterize estrogen receptor‐positive/progesteron receptor‐negative breast cancer and is associated with patient's outcome , 2011, International journal of cancer.

[8]  J. Barrett,et al.  Patterns of Expression of DNA Repair Genes and Relapse From Melanoma , 2010, Clinical Cancer Research.

[9]  T. Helleday.  Homologous recombination in cancer development, treatment and development of drug resistance. , 2010, Carcinogenesis.

[10]  Alan Cantor,et al.  Rationally Designed Pharmacogenomic Treatment Using Concurrent Capecitabine and Radiotherapy for Glioblastoma; Gene Expression Profiles Associated with Outcome , 2010, Clinical Cancer Research.

[11]  J. Welsh,et al.  Rad51 protein expression and survival in patients with glioblastoma multiforme. , 2009, International journal of radiation oncology, biology, physics.

[12]  K. Miyagawa,et al.  Biochemical analysis of the N-terminal domain of human RAD54B , 2008, Nucleic acids research.

[13]  Daniel J. Freeman,et al.  Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  Joseph G Ibrahim,et al.  UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. , 2007, Journal of the National Cancer Institute.

[15]  L. Skoog,et al.  The BRCA1/BRCA2/Rad51 complex is a prognostic and predictive factor in early breast cancer. , 2007, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[16]  Wolf-Dietrich Heyer,et al.  Rad54: the Swiss Army knife of homologous recombination? , 2006, Nucleic acids research.

[17]  R. Weichselbaum,et al.  Pilot study examining tumor expression of RAD51 and clinical outcomes in human head cancers. , 2006, International journal of oncology.

[18]  S. Kato,et al.  Meta-analysis of the p53 Mutation Database for Mutant p53 Biological Activity Reveals a Methodologic Bias in Mutation Detection , 2006, Clinical Cancer Research.

[19]  W. Zhong,et al.  High-level expression of Rad51 is an independent prognostic marker of survival in non-small-cell lung cancer patients , 2005, British Journal of Cancer.

[20]  R. Houlston,et al.  Systematic review of microsatellite instability and colorectal cancer prognosis. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  T. Helleday,et al.  The role of RAD51 in etoposide (VP16) resistance in small cell lung cancer , 2003, International journal of cancer.

[22]  M. Murphy,et al.  The codon 72 polymorphic variants of p53 have markedly different apoptotic potential , 2003, Nature Genetics.

[23]  L. Symington.  Role of RAD52 Epistasis Group Genes in Homologous Recombination and Double-Strand Break Repair , 2002, Microbiology and Molecular Biology Reviews.

[24]  K. Miyagawa,et al.  Human Rad54B is a double-stranded DNA-dependent ATPase and has biochemical properties different from its structural homolog in yeast, Tid1/Rdh54. , 2002, Nucleic acids research.

[25]  K. Miyagawa,et al.  A role for RAD54B in homologous recombination in human cells , 2002, The EMBO journal.

[26]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[27]  R. Fishel,et al.  BCR/ABL regulates mammalian RecA homologs, resulting in drug resistance. , 2001, Molecular cell.

[28]  D. Schild,et al.  Homologous recombinational repair of DNA ensures mammalian chromosome stability. , 2001, Mutation research.

[29]  R. Fotedar,et al.  The functions of the cdk-cyclin kinase inhibitor p21WAF1. , 2000, Pathologie-biologie.

[30]  Hiroki Inui,et al.  Mutations of a novel human RAD54 homologue, RAD54B, in primary cancer , 1999, Oncogene.

[31]  S. Vispé,et al.  Overexpression of Rad51 protein stimulates homologous recombination and increases resistance of mammalian cells to ionizing radiation. , 1998, Nucleic acids research.

[32]  P. Baumann,et al.  Synergistic actions of Rad51 and Rad52 in recombination and DNA repair , 1998, Nature.

[33]  L. Cox.  Multiple pathways control cell growth and transformation: overlapping and independent activities of p53 and p21Cip1/WAF1/Sdi1 , 1997, The Journal of pathology.

[34]  C. Pabo,et al.  The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spots. , 1993, Genes & development.

[35]  J. Hardcastle,et al.  Colorectal cancer , 1993, Europe Against Cancer European Commission Series for General Practitioners.