A subgroup of prostate cancer patients treated with brachytherapy experience radiation-induced injury manifested as either urinary morbidity, proctitis or erectile dysfunction (ED). Results have been obtained from a series of studies suggestive of a genetic basis for clinical radiosensitivity and it has been hypothesized that many patients who exhibit normal tissue radiation toxicity harbor specific single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNPs) associated with a susceptibility for the development of adverse effects resulting from a radiation treatment for prostate cancer. However, the research performed to date has been restricted to genotyping only a limited number of SNPs in a small group of candidate genes. In recognition of our inadequate understanding of the pathways involved in the development of radiation-induced urinary morbidity, proctitis and ED, as well as the incomplete knowledge of the spectrum of genes/proteins involved in the development of these forms of radiation toxicity, it is likely that we have failed to identify many of the SNPs and CNPs that are associated with the development of these manifestations of radiation injury. Therefore, we are proposing a new and innovative strategy to achieve this goal in which a genome wide association study will be performed to discover a more complete spectrum of the SNPs and CNPs (and genes) that are associated with clinical radiosensitivity. This will be a case-control study in which each prostate cancer patient that develops either urinary morbidity, proctitis or ED will be matched on age, race, stage, date of diagnosis and dosimetric parameters, with an appropriate control patient who did not develop that form of radiation injury. There will be 200 cases and 200 controls for each form of radiation injury in this study. Half of the subjects will first be screened for SNPs and CNPs using the Affymetrix 6.0 SNP array. The type I error (a) for rejection of the null hypothesis will be set at 0.0001. Therefore, depending on the minor allele frequency, we will be able to identify SNPs and CNPs whose genome relative risks (GRRs) for the development of each form of radiation induced injury is greater than approximately 2.5. Although this is a relatively modest number of subjects for a genome wide association study, therefore enabling identification of SNPs or CNPs only with relatively high GRRs, it is important to note that only SNPs and CNPs with GRRs greater than roughly 2.5 will likely be of useful predictive value in the actual clinical setting considering the dosimetric uncertainties associated with a standard radiotherapy treatment. A second phase validation study will be performed with a separate replication set comprising the other half of the subjects selected for this project using an a of 0.01, which should eliminate virtually all false positives identified in the initial phase. Finally, we will perform comprehensive SNP screening for all subjects of the DNA region surrounding every SNP that proves positively associated with each form of radiation injury in the replication set of subjects in order to genotype all SNPs in a haplotype block.

Public Health Relevance

This project represents the first study to use the powerful results obtained through the HapMap project and the low cost SNP/CNP genotyping that has become possible with the creation of high density SNP/CNP arrays to perform a genome wide association study to identify SNPs or CNPs associated with the development of radiation injury resulting from treatment for prostate cancer. The results of this project should provide a basis for a predictive screening assay to identify prostate cancer patients who are most likely to develop urinary morbidity, proctitis or ED following radiotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134444-04
Application #
8267125
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Shelburne, Nonniekaye F
Project Start
2009-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$528,676
Indirect Cost
$154,614
Name
Icahn School of Medicine at Mount Sinai
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Rosenstein, Barry S; West, Catharine M; Bentzen, Søren M et al. (2014) Radiogenomics: radiobiology enters the era of big data and team science. Int J Radiat Oncol Biol Phys 89:709-13
Barnett, Gillian C; Thompson, Deborah; Fachal, Laura et al. (2014) A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity. Radiother Oncol 111:178-85
Kerns, Sarah L; Ostrer, Harry; Rosenstein, Barry S (2014) Radiogenomics: using genetics to identify cancer patients at risk for development of adverse effects following radiotherapy. Cancer Discov 4:155-65
Fachal, Laura; Gómez-Caamaño, Antonio; Barnett, Gillian C et al. (2014) A three-stage genome-wide association study identifies a susceptibility locus for late radiotherapy toxicity at 2q24.1. Nat Genet 46:891-4
Kerns, Sarah L; de Ruysscher, Dirk; Andreassen, Christian N et al. (2014) STROGAR - STrengthening the Reporting Of Genetic Association studies in Radiogenomics. Radiother Oncol 110:182-8
Kerns, Sarah L; Stock, Richard; Stone, Nelson et al. (2013) A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of erectile dysfunction following radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys 85:e21-8
Kerns, Sarah L; Stone, Nelson N; Stock, Richard G et al. (2013) A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of urinary symptoms after radiotherapy for prostate cancer. J Urol 190:102-8
Kerns, Sarah L; Stock, Richard G; Stone, Nelson N et al. (2013) Genome-wide association study identifies a region on chromosome 11q14.3 associated with late rectal bleeding following radiation therapy for prostate cancer. Radiother Oncol 107:372-6
West, Catharine M L; Dunning, Alison M; Rosenstein, Barry S (2012) Genome-wide association studies and prediction of normal tissue toxicity. Semin Radiat Oncol 22:91-9
Rosenstein, Barry S (2011) Identification of SNPs associated with susceptibility for development of adverse reactions to radiotherapy. Pharmacogenomics 12:267-75

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