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The hypothesis that forms the basis for this research is that patients who possess certain SNPs or CNPs are at a greater risk for developing severe urinary morbidity or erectile dysfunction (ED) resulting from radiotherapy for prostate cancer. The specific aim of this project was to identify through a genome wide association study the SNPs and CNPs associated with the development of these adverse effects resulting from the use of radiation to treat prostate cancer. We have performed a two-stage genome-wide association study and identified and validated loci associated with each of these primary outcomes. It is expected that the results of this work will provide the basis for a clinically relevant predictive test to identify patients at increased risk for development of adverse events following radiotherapy. It is anticipated that such a tool will be used to aid clinicians in personalizing treatment to improve the therapeutic outcome for men diagnosed with prostate cancer., The original document contains color images.

The hypothesis that forms the basis for this research is that patients who possess certain SNPs or CNPs are at a greater risk for developing severe urinary morbidity or ED resulting from radiotherapy for prostate cancer. The specific aim of this project is to identify through a genome wide association study the SNPs and CNPs associated with the development of severe urinary morbidity and ED resulting from the use of radiation to treat prostate cancer. It should be noted that we may also identify SNPs or CNPs that are associated with protection against the development of these forms of radiation injury. The main accomplishment of the third year was substantial progress on the validation phase of the project. Specifically, we selected approximately 5,000 SNPs from the discovery phase of the GWAS and have begun to genotype the 600 samples that comprise the validation cohort.

The hypothesis that forms the basis for this research is that patients who possess certain SNPs or CNPs are at a greater risk for developing severe urinary morbidity or ED resulting from radiotherapy for prostate cancer. The specific aim of this project is to identify through a genome wide association study the SNPs and CNPs associated with the development of severe urinary morbidity and ED resulting from the use of radiation to treat prostate cancer. It should be noted that we may also identify SNPs or CNPs that are associated with protection against the development of these forms of radiation injury. Through the end of the project at the NYUMC site, substantial progress was made on the validation phase of the project. This included selection of approximately 5,000 SNPs and CNPs from the discovery phase of the GWAS for genotyping of the 600 samples that comprise the validation cohort. The genotyping and analysis are now being completed through a no-cost extension of the project at the Mount Sinai site.

The hypothesis that forms the basis for this research is that patients who possess certain SNPs or CNPs are at a greater risk for developing severe urinary morbidity, proctitis or ED resulting from radiotherapy for prostate cancer. The specific aim of this project is to identify through a genome wide association study the SNPs and CNPs associated with the development of severe urinary morbidity and ED resulting from the use of radiation to treat prostate cancer. It should be noted that we may also identify SNPs or CNPs that are associated with protection against the development of these forms of radiation injury. The main accomplishment of the second year was the completion of the discovery phase of the project. Specifically, case and control samples for each of the outcomes were run on Affymetrix SNP6.0 arrays, checked with quality control steps, and analyzed for association of genetic variants. We identified approximately 700 SNPs associated with one or more of the outcomes that we will investigate in the validation cohort., The original document contains color images.

BackgroundIonizing radiation is a known mutagen and an established breast carcinogen. The ATM gene is a key regulator of cellular responses to the DNA damage induced by ionizing radiation. We investigated whether genetic variants in ATM play a clinically significant role in radiation-induced contralateral breast cancer in women.MethodsThe Women's Environmental, Cancer, and Radiation Epidemiology Study is an international population-based case-control study nested within a cohort of 52,536 survivors of unilateral breast cancer diagnosed between 1985 and 2000. The 708 case subjects were women with contralateral breast cancer, and the 1397 control subjects were women with unilateral breast cancer matched to the case subjects on age, follow-up time, registry reporting region, and race and/or ethnicity. All women were interviewed and underwent full mutation screening of the entire ATM gene. Complete medical treatment history information was collected, and for all women who received radiotherapy, the radiation dose to the contralateral breast was reconstructed using radiotherapy records and radiation measurements. Rate ratios (RRs) and corresponding 95% confidence intervals (CIs) were estimated by using multivariable conditional logistic regression. All P values are two-sided.ResultsAmong women who carried a rare ATM missense variant (ie, one carried by <1% of the study participants) that was predicted to be deleterious, those who were exposed to radiation (mean radiation exposure = 1.2 Gy, SD = 0.7) had a statistically significantly higher risk of contralateral breast cancer compared with unexposed women who carried the wild-type genotype (0.01-0.99 Gy: RR = 2.8, 95% CI = 1.2 to 6.5; > or =1.0 Gy: RR = 3.3, 95% CI = 1.4 to 8.0) or compared with unexposed women who carried the same predicted deleterious missense variant (0.01-0.99 Gy: RR = 5.3, 95% CI = 1.6 to 17.3; > or =1.0 Gy: RR = 5.8, 95% CI = 1.8 to 19.0; P(trend) = .044).ConclusionsWomen who carry rare del

The hypothesis that forms the basis for this research is that patients who possess certain SNPs or CNPs are at a greater risk for developing severe urinary morbidity or ED resulting from radiotherapy for prostate cancer. The specific aim of this project is to identify through a genome wide association study the SNPs and CNPs associated with the development of severe urinary morbidity and ED resulting from the use of radiation to treat prostate cancer. It should be noted that we may also identify SNPs or CNPs that are associated with protection against the development of these forms of radiation injury. The main accomplishment of the first year of the project was the performance of a rigorous review of the subjects to be genotyped in this study to insure that all criteria were met for their designation as cases and controls. In addition, all technical issues were resolved to enable performance of genome wide genotyping with Affymetrix 6.0 arrays as well as establishment of the assays for SNP and CNP genotyping that will be performed with a replication set of subjects.

The hypothesis being tested in this project is that a greater proportion of patients who develop radiation-induced subcutaneous late tissue morbidity possess a variant allele in the ATM gene compared with patients who do not suffer these complications. An additional objective is to determine the functional impact upon the protein encoded by the ATM gene for each genetic alteration identified and subsequent cellular radiosensitivity. The specific aims of this project are to (1) screen 50 breast cancer patients for ATM genetic alterations who developed radiation induced late subcutaneous tissue morbidity, (2) establish a control group and screen 100 patients without evidence of this late radiation reaction, and (3) perform functional studies using cells from patients identified as ATM carriers to determine to what extent each ATM variant identified affects radiosensitivity and normal activity of the protein produced by the ATM gene. The main accomplishment during the second year of this study was to accrue a total of 104 patients into this study and complete a full DHPLC screening of the ATM gene in each of these subjects. In addition, functional studies were performed with a series of wild type, AT and ATM heterozygote cell lines to measure the ATM kinase activity in these cells.

The hypothesis being tested in this project is that a greater proportion of African-Americans with breast cancer harbor specific germline genetic alteration in the ATM gene or possess a particular ATM haplotype, compared to African-American women without breast cancer. An additional objective is to determine the functional impact upon the protein encoded by the ATM gene for each mutation identified. Specific Aims: The specific aims of this project are to (1) screen 100 African-American breast cancer patients and 100 African-American women without breast cancer and (2) perform functional studies using cells from patients identified as ATM carriers to determine whether each ATM genetic variant identified affects radiosensitivity and levels of the protein encoded by the ATM gene for each mutation examined. The main accomplishment during this past year was to accrue into the study and complete the DHPLC sequencing of 188 subjects. As a result, specific ATM variants were identified in 117 subjects. In addition, functional assays were accomplished to measure ATM kinase activity in a series of wild type cells as well as cells obtained from ATM patients, obligate ATM heterozygotes and cell lines generated from subjects accrued into this study.

IntroductionDeficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation can cause cluster damage and double-strand breaks (DSBs) that pose problems for cellular repair processes. Three genes (ATM, BRCA1, and BRCA2) encode products that are essential for the normal cellular response to DSBs, but predispose to breast cancer when mutated.DesignTo examine the joint roles of radiation exposure and genetic susceptibility in the etiology of breast cancer, we designed a case-control study nested within five population-based cancer registries. We hypothesized that a woman carrying a mutant allele in one of these genes is more susceptible to radiation-induced breast cancer than is a non-carrier. In our study, 700 women with asynchronous bilateral breast cancer were individually matched to 1400 controls with unilateral breast cancer on date and age at diagnosis of the first breast cancer, race, and registry region, and counter-matched on radiation therapy. Each triplet comprised two women who received radiation therapy and one woman who did not. Radiation absorbed dose to the contralateral breast after initial treatment was estimated with a comprehensive dose reconstruction approach that included experimental measurements in anthropomorphic and water phantoms applying patient treatment parameters. Blood samples were collected from all participants for genetic analyses.ConclusionsOur study design improves the potential for detecting gene-environment interactions for diseases when both gene mutations and the environmental exposures of interest are rare in the general population. This is particularly applicable to the study of bilateral breast cancer because both radiation dose and genetic susceptibility have important etiologic roles, possibly by interactive mechanisms. By using counter-matching, we optimized the informativeness of the collected dosimetry data by increasing the variability of radiation dose within the case-control sets and enhan

The hypothesis being tested in this project is that a greater proportion of patients who develop radiation-induced RTOG/EORTC grade 3/4 subcutaneous late tissue morbidity possess a mutated ATM gene compared with patients who do not suffer these complications. An additional objective is to determine the functional impact upon the protein encoded both in the ATM gene for each mutation identified and subsequent cellular radiosensitivity, The specific aims of this project are to (1) screen 50 breast cancer patients for a ATM mutations who developed radiation-induced grade 3/4 late subcutaneous tissue morbidity as defined by the RTOG/EORTC scoring scheme, (2) establish control group and screen 100 patients without evidence of this late radiation reaction, and (3) perform functional studies using cells from patients identified as ATM carriers to determine to what extent each ATM mutation identified affect radiosensitivity and normal activity of the protein produced by the ATM gene.

The hypothesis being tested in this project is that a greater proportion of African-Americans with breast cancer harbor germline mutation in the ATM gene compared to African-American women without breast cancer. An additional objective is to determine the functional impact upon the protein encoded by the ATM gene for each mutation identified. Specific Aims: The specific aims of this project are to (1) screen 100 African-American breast cancer patients and 100 African-American women without breast cancer and (2) perform functional studies using cells from patients identified as ATM carriers to determine whether each ATM mutation identified affect radiosensitivity and levels of the protein encoded by the ATM gene for each mutation identified. The main accomplishment during the first year of this study was to establish and optimize all of the assays and technique that will be used in this project.

The purpose of this project was to screen women who developed either unilateral or bilateral breast cancer for mutations and polymorphisms in the ATM gene. To accomplish this, during the first three years of this project, DNA samples were isolated from breast cancer patients and screened using a Non-radioisotopic RNase Cleavage- based Assay (NIRCA). However, not a single mutation was discovered from any of these patients which raised a concern as to the sensitivity of this assay. To address this concern, the P of this project purchased an instrument for the performance of denaturing high performance liquid chromatography (DHPLC). This is a high throughput technique in which large numbers of DNA samples can be rapidly screened with a high degree of sensitivity and accuracy. During the fourth year of this study, representing a no-cost extension of this project, it was possible to re- screen all of the DNA samples obtained from the unilateral breast cancer patients for ATM mutations using DHPLC. Through this work, we identified 6 breast cancer patients possessing a total of 8 different germline mutations and 43 patients harboring a total of 141 DNA sequence variations representing 21 different common polymorphisms and rare variants., Original contains color plates: All DTIC reproductions will be in black and white.

The purpose of this project is to determine whether women who developed bilateral breast cancer following radiotherapy for an initial breast cancer had a higher incidence of heterozygosity for a mutation in the ATM gene than either breast cancer patients who did not develop a second breast cancer or bilateral breast cancer patients who did not receive radiotherapy. To accomplish this, during the first three years of this project, DNA samples were isolated from unilateral and bilateral breast cancer patients and screened for ATM mutations using a Non-radioisotopic RNase Cleavage-based Assay (NIRCA). However, not a single mutation was discovered from any of these patients which raised a concern as to the sensitivity of this assay. To address this concern, the PI of this project recently purchased an instrument for the performance of denaturing high performance liquid chromatography (DHPLC). This is a high throughput technique in which large numbers of DNA samples can be rapidly screened with a high degree of sensitivity and accuracy. During the fourth year of this study, representing a no-cost extension of this project, all of the DNA samples obtained from the unilateral and bilateral breast cancer patients will be re-screened for ATM mutations using DHPLC. We have begun this process with screening eight ATM exons and have already found eight patients possessing base sequence alterations that had previously gone undetected using NIRCA.