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Association of DNA Repair and Steroid Metabolism Gene Polymorphisms with Clinical Late Toxicity in Patients Treated with Conformal Radiotherapy for Prostate Cancer

Objective: To explore the possible relationship between single nucleotide polymorphisms (SNP) in candidate genes encoding DNA damage recognition/repair/response and steroid metabolism proteins with respect to clinical radiation toxicity in a retrospective cohort of patients previously treatedwith three-dimensional conformal radiotherapy (3-DCRT) for prostate cancer.
Experimental Design: One hundred twenty-four patients with prostate cancer underwent 3-DCRTat our institutionbetween September1996 andDecember 2000.Of these, 83 consented for follow-up of blood sampling and SNP analysis. Twenty-eight patients were documented as having experienced grade z2 late bladder or rectal toxicity (scoring system of RadiationTherapy Oncology Group) on at least one follow-up visit.We analyzed 49 SNPs in BRCA1, BRCA2, ESR1, XRCC1, XRCC2, XRCC3, NBN, RAD51, RAD52, LIG4, ATM, BCL2,TGFB1, MSH6, ERCC2, XPF, NR3C1, CYP1A1, CYP2C9, CYP2C19, CYP3A5, CYP2D6, CYP11B2, and CYP17A1 genes using the Pyrosequencing technique.
Results: Significant univariate associations with late rectal or bladder toxicity (grade z2) were found for XRCC3 (A>G 5Vuntranslated region NT 4541), LIG4 (T>C Asp568Asp), MLH1 (C>T, Val219Ile), CYP2D6*4( G>A splicing defect), mean rectal andbladder dose, dose to 30% of rectum or bladder, and age < 60 years. On Cox multivariate analysis, significant associations with toxicity were found for LIG4 (T>C, Asp568Asp), ERCC2 (G>A, Asp711Asp), CYP2D6*4 (G>A, splicing defect), mean bladder dose >60 Gy, and dose to 30% of rectal volume >75 Gy.
Conclusions: In this study, we identified SNPs in LIG4, ERCC2, and CYP2D6 genes as putative markers to predict individuals at risk for complications arising from radiation therapy in prostate cancer.

Citation

S. Damaraju, D. Murray, J. Dufour, D. Carandang, R. Myrehaug, G. Fallone, C. Field, R. Greiner, J. Hanson, C. Cass, M. Parliament. "Association of DNA Repair and Steroid Metabolism Gene Polymorphisms with Clinical Late Toxicity in Patients Treated with Conformal Radiotherapy for Prostate Cancer". Clinical Cancer Research (CCR), 12(8), pp 2545-2554, April 2006.

Keywords: PolyomX, SNPs, bioinformatics, cancer, prostate toxicity, machine learning, medical informatics
Category: In Journal

BibTeX

@article{Damaraju+al:CCR06,
  author = {Sambasivarao Damaraju and David Murray and Jennifer Dufour and D.
    Carandang and R. Myrehaug and Gino Fallone and C Field and Russ Greiner and
    J Hanson and Carol Cass and Matthew Parliament},
  title = {Association of DNA Repair and Steroid Metabolism Gene Polymorphisms
    with Clinical Late Toxicity in Patients Treated with Conformal Radiotherapy
    for Prostate Cancer},
  Volume = "12",
  Number = "8",
  Pages = {2545-2554},
  journal = {Clinical Cancer Research (CCR)},
  year = 2006,
}

Last Updated: April 28, 2012
Submitted by Russ Greiner

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