Clinical Investigation
Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms (SNPs) Associated With the Development of Erectile Dysfunction in African-American Men After Radiotherapy for Prostate Cancer

https://doi.org/10.1016/j.ijrobp.2010.07.036Get rights and content

Purpose

To identify single nucleotide polymorphisms (SNPs) associated with erectile dysfunction (ED) among African-American prostate cancer patients treated with external beam radiation therapy.

Methods and Materials

A cohort of African-American prostate cancer patients treated with external beam radiation therapy was observed for the development of ED by use of the five-item Sexual Health Inventory for Men (SHIM) questionnaire. Final analysis included 27 cases (post-treatment SHIM score ≤7) and 52 control subjects (post-treatment SHIM score ≥16). A genome-wide association study was performed using approximately 909,000 SNPs genotyped on Affymetrix 6.0 arrays (Affymetrix, Santa Clara, CA).

Results

We identified SNP rs2268363, located in the follicle-stimulating hormone receptor (FSHR) gene, as significantly associated with ED after correcting for multiple comparisons (unadjusted p = 5.46 × 10−8, Bonferroni p = 0.028). We identified four additional SNPs that tended toward a significant association with an unadjusted p value < 10−6. Inference of population substructure showed that cases had a higher proportion of African ancestry than control subjects (77% vs. 60%, p = 0.005). A multivariate logistic regression model that incorporated estimated ancestry and four of the top-ranked SNPs was a more accurate classifier of ED than a model that included only clinical variables.

Conclusions

To our knowledge, this is the first genome-wide association study to identify SNPs associated with adverse effects resulting from radiotherapy. It is important to note that the SNP that proved to be significantly associated with ED is located within a gene whose encoded product plays a role in male gonad development and function. Another key finding of this project is that the four SNPs most strongly associated with ED were specific to persons of African ancestry and would therefore not have been identified had a cohort of European ancestry been screened. This study demonstrates the feasibility of a genome-wide approach to investigate genetic predisposition to radiation injury.

Introduction

Radiotherapy can provide a sustainable cure for prostate cancer and is accepted as a standard treatment option. However, side effects develop in many men after radiotherapy, including urinary morbidity, proctitis, and erectile dysfunction (ED), which have a substantial effect on quality of life. Acute symptoms resolve in most patients after a few months, but a subset of patients have long-term morbidity 1, 2. A method to predict which patients are at greatest risk for permanent side effects would assist both clinicians and patients in weighing the benefits of radiotherapy vs. other options of treating localized prostate cancer. Cohort studies have found that some clinical factors such as treatment type, radiation dose, pretreatment symptoms, age, and comorbidities, such as diabetes and vascular disease, are associated with the development of side effects, but these clinical factors do not fully explain the variability in outcome 1, 2, 3, 4.

Research on radiation-induced injury in prostate and breast cancer patients suggests that much of the variation in normal tissue damage can be attributed to patient-specific, possibly genetic, variation rather than treatment differences or random effects. An initial study examining the development of skin telangiectasia among breast cancer patients treated with radiation therapy estimates that 81% to 90% of variation in normal tissue damage is the result of patient-specific characteristics (5). Studies among prostate cancer patients have identified single nucleotide polymorphisms (SNPs) in candidate genes, including ATM, LIG4, ERCC2, SOD2, TGFB1, XRCC1, XRCC3, and CYP2D6, among others, that are associated with the development of late toxicity in response to radiation therapy 6, 7, 8, 9, 10. Single nucleotide polymorphisms in several of these genes have also been associated with adverse effects in breast cancer patients 5, 11, 12, 13, 14.

To date, research attempting to identify genetic variants associated with radiotherapy side effects has taken a candidate-gene approach, mostly screening genes involved in the DNA damage response. However, conflicting results have been obtained in these studies, and no single SNP or group of SNPs has proven to exhibit a consistent association with the development of a normal tissue toxicity after radiotherapy 15, 16. For this project, we took a broader approach and performed a genome-wide association study with ED as a measure of normal tissue damage experienced by prostate cancer patients treated with external beam radiation therapy. This study was also designed to address a health disparity in radiogenomics research in that subjects with primarily European ancestry have constituted the majority of individuals included in these studies. There is growing recognition that the results obtained from one ethnic/racial group are not necessarily applicable to individuals whose ancestry is primarily from a different ethnic/racial group. Thus the findings in this field of research may not benefit other racial groups if the research is performed primarily with subjects of European background. The research reported in this article focused on African-American men with the goal to identify the genetic variants specific to this population that may be associated with the development of radiation-induced ED. This study identifies several potentially predictive genetic variants and supports the feasibility of using a genome-wide approach to investigate the genetic predisposition to radiation injury.

Section snippets

Study population and case definition

A cohort of 138 African-American men with adenocarcinoma of the prostate were recruited for this study from the Department of Radiation Oncology of the Elmhurst and Queens Hospital Center affiliated with Mount Sinai School of Medicine between 2001 and 2006. Patients were treated with three-dimensional conformal radiotherapy or intensity-modulated radiotherapy and received 39 to 42 fractions of 1.8 Gy. Treatments were delivered with 6- or 18-MV photons via a Varian 21 EX linear accelerator

Patient characteristics

Information on demographic, clinical, and lifestyle factors that may be related to the outcome was compared between cases and control subjects (Table 1). A greater proportion of cases reported hypothyroidism compared with control subjects (11.1% vs. 0, p = 0.014). Cases had on average a slightly higher pretreatment SHIM score than control subjects (21 vs. 20, p < 0.001). This trend is opposite that commonly seen among prostate cancer radiotherapy patients but is likely an artifact of the way

Discussion

To our knowledge, this is the first study to use a genome-wide approach to identify genetic variants associated with the development of long-term side effects of radiation therapy. Among 512,497 SNPs, we have identified rs2268363, located in the FSHR gene, which is significantly associated with the development of ED after using Bonferroni correction for multiple testing. The FSHR is expressed in Sertoli cells of the testis and is involved in testis development and function. Severe disruption of

References (35)

  • G. Montana et al.

    Statistical tests for admixture mapping with case-control and cases-only data

    Am J Hum Genet

    (2004)
  • R.A. White et al.

    Positional cloning of the Ttc7 gene required for normal iron homeostasis and mutated in hea and fsn anemia mice

    Genomics

    (2005)
  • M. Negishi et al.

    Prostanoid receptors and their biological actions

    Prog Lipid Res

    (1993)
  • J.A. Talcott et al.

    Time course and predictors of symptoms after primary prostate cancer therapy

    J Clin Oncol

    (2003)
  • M. Pinkawa et al.

    Impact of age and comorbidities on health-related quality of life for patients with prostate cancer: Evaluation before a curative treatment

    BMC Cancer

    (2009)
  • T.J. Wilt et al.

    Systematic review: Comparative effectiveness and harms of treatments for clinically localized prostate cancer

    Ann Intern Med

    (2008)
  • S. Damaraju et al.

    Association of DNA repair and steroid metabolism gene polymorphisms with clinical late toxicity in patients treated with conformal radiotherapy for prostate cancer

    Clin Cancer Res

    (2006)
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    Note—An online CME test for this article can be taken at http://asro.astro.org under Continuing Education.

    This research was supported by Grants RSGT-05-200-01-CCE from the American Cancer Society, PC074201 from the Department of Defense Prostate Cancer Research Program, and 1R01CA134444 from the National Institutes of Health.

    Conflict of interest: none.

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