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Genome Scan Study of Prostate Cancer in Arabs: Identification of Three

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Genome Scan Study of Prostate Cancer in Arabs: Identification of Three Shan et al. Journal of Translational Medicine 2013, 11:121 http://www.translational-medicine.com/content/11/1/121 RESEARCH Open Access Genome scan study of prostate cancer in Arabs: identification of three genomic regions with multiple prostate cancer susceptibility loci in Tunisians Jingxuan Shan1, Khalid Al-Rumaihi2, Danny Rabah3, Issam Al-Bozom4, Dhanya Kizhakayil1, Karim Farhat3, Sami Al-Said2, Hala Kfoury3, Shoba P Dsouza1, Jillian Rowe5, Hanif G Khalak5, Shahzad Jafri5, Idil I Aigha1 and Lotfi Chouchane1* Abstract Background: Large databases focused on genetic susceptibility to prostate cancer have been accumulated from population studies of different ancestries, including Europeans and African-Americans. Arab populations, however, have been only rarely studied. Methods: Using Affymetrix Genome-Wide Human SNP Array 6, we conducted a genome-wide association study (GWAS) in which 534,781 single nucleotide polymorphisms (SNPs) were genotyped in 221 Tunisians (90 prostate cancer patients and 131 age-matched healthy controls). TaqMan® SNP Genotyping Assays on 11 prostate cancer associated SNPs were performed in a distinct cohort of 337 individuals from Arab ancestry living in Qatar and Saudi Arabia (155 prostate cancer patients and 182 age-matched controls). In-silico expression quantitative trait locus (eQTL) analysis along with mRNA quantification of nearby genes was performed to identify loci potentially cis-regulated by the identified SNPs. Results: Three chromosomal regions, encompassing 14 SNPs, are significantly associated with prostate cancer risk in the Tunisian population (P =1×10-4 to P =1×10-5). In addition to SNPs located on chromosome 17q21, previously found associated with prostate cancer in Western populations, two novel chromosomal regions are revealed on chromosome 9p24 and 22q13. eQTL analysis and mRNA quantification indicate that the prostate cancer associated SNPs of chromosome 17 could enhance the expression of STAT5B gene. Conclusion: Our findings, identifying novel GWAS prostate cancer susceptibility loci, indicate that prostate cancer genetic risk factors could be ethnic specific. Keywords: Prostate cancer, GWAS, Arab population Introduction males over 65 years old [3]. In Kuwait, the incidence Prostate cancer (PCa) is the most common malignancy in of prostate cancer rose to 12.3/100,000 men/year in western countries and the second cause of cancer-related 2004 [4]. In 2003, prostate cancer was ranked as the death in Europe and the United States [1]. With lifestyle fourth most diagnosed cancer in Tunisia [5]. In Lebanon, changes, the incidence of the disease has been increasing the age-adjusted standardized incidence was 21.5/100,000 in the Arab populations [2]. From 1991–2006, prostate men/year in 1998 [6]. In Arab populations, the incidence cancer was ranked first among cancers in Qatari of prostate cancer correlates with low prostate volume and testosterone. Despite the low levels of testosterone, * Correspondence: [email protected] the aggressive forms of prostate cancer are found 1Laboratory of Genetic Medicine and Immunology, Weill Cornell Medical frequently in Arab patients, which indicate an increased College in Qatar, Qatar Foundation, Doha, Qatar Full list of author information is available at the end of the article sensitivity of Arab men to this steroid [7]. © 2013 Shan et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Shan et al. Journal of Translational Medicine 2013, 11:121 Page 2 of 8 http://www.translational-medicine.com/content/11/1/121 Prostate cancer is generally considered to be a complex advanced group (T3 − T4N0 M0 and T1 − T4N0–1M1/ disease with several genes underlying onset and severity, T1− T4N1M0–1). Histopathological grade was recorded as and minor susceptibility genes may play a larger role in the Gleason score and was classified into two groups: the prostate cancer risk. Recently, genome-wide association low-grade group (Gleason score < 7) and the high-grade studies (GWAS) have identified dozens of common group (Gleason score⩾7). A detailed description of the variants that confer susceptibility to prostate cancer across clinical-pathological characteristics of this cohort is various ethnicities from European, Asian and African summarized in Table 1. ancestry [8,9]. However, little is known about the prostate The control group consisted of 131 healthy male subjects cancer genetic susceptibility in populations of Arab ancestry. having no evidence of any personal or family history of The genetic susceptibility to prostate cancer is variable cancer. Their PSA levels were within the normal limit among different populations [10]. The difference may (<4 ng/ml) and showed no signs of prostate hyperplasia or highlight the impact of genetic background on disease risk PCa by digital rectal examination. Those who had other between populations. For instance, several SNPs located known malignancies were also excluded. in 8q24 have been implied to a different population There were 155 unrelated PCa patients and 182 susceptibility to prostate cancer [11,12]. These variants, age-matched controls from Arab ancestry living in Qatar located in c-Myc gene, reduced the risk of prostate cancer and Saudi Arabia included in the replication genotyping in Caucasian but not in African Americans, thus protective study. mechanisms that might reduce c-Myc expression in Caucasians do not exist in African Americans. Identification of the genetic variants in different populations may help DNA and RNA extraction us to better understand the genetic and molecular Genomic DNA was extracted from peripheral blood W mechanism of prostate cancer. samples using QIAamp DNA blood Maxi Kit according With the aim to identify genetic variants associated with to the manufacturer’s protocol (Qiagen, Valencia, CA). prostate cancer in Arab populations, we first conducted Thirty-six RNA samples were extracted from archived a GWAS with DNA samples from a Tunisian cohort. formalin-fixed paraffin-embedded non-malignant prostate ™ We further extended the study to evaluate potential tissues using RecoverAll Total Nucleic Acid Isolation associations of 11 SNPs, identified by GWAS, in a cohort Kit (Ambion, Grand Island, NY). from Arab ancestry living in Qatar and Saudi Arabia. Functional significance of the identified prostate cancer associated SNPs was assessed by in-silico analysis and Table 1 Description of the subjects for GWAS study mRNA quantification of certain adjacent genes. Case number 90 Age (mean ± SD) 73.7 ± 8.4a Materials and methods PSA (mean ± SD) 225.5 ± 368.9 Ethics statement Characteristic Number (%) The Institutional Review Boards of Weill Cornell Medical Tumor Stage College in Qatar, the Hamad Medical Corporation, T1-T2 17 (18.9) and King Khalid University Hospital approved the study protocols. All subjects signed informed consent documents T3-T4 44 (48.9) for participation in the study. Data missing 29 (32.2) Lymph node Subjects Negative 52 (57.8) A total of 221 unrelated Tunisian men consisting of 90 Positive 7 (7.8) PCa patients and 131 male age-matched controls were Data missing 31 (34.4) selected from the same population living in the middle coast of Tunisia. PCa patients were recruited from the Metastasis two departments of Urology of Monastir and Sousse Negative 42 (46.7) Hospital, Tunisia, in whom the diagnosis has been Positive 18 (20.0) confirmed histologically. The serum prostate-specific Data missing 25 (33.3) antigen (PSA) values were measured in all the cases before Gleason Score treatment. Clinical characteristics including Gleason grade, GS ≥ 7 44 (48.9) TNM stage, age at diagnosis, and family history were obtained from medical records. The pathological stage at GS < 7 19 (21.1) the time of diagnosis was classified according to TNM Data missing 27 (30.0) system into the localized group (T1− T2N0M0) and the a Age (mean ± SD) for controls: 59.7 ± 12.6. Shan et al. Journal of Translational Medicine 2013, 11:121 Page 3 of 8 http://www.translational-medicine.com/content/11/1/121 Genotyping levels between genotypes were compared using a linear Genome-wide scanning was applied with Affymetrix regression model. To avoid false positive associations Genome-Wide Human SNP Array 6.0 following the due to multiple tests, we set a significance threshold − manufacturer’s protocol. After genotype calling using of P <1.0×10 3 and also assessed significance using the Birdsuite [13], the total SNPs on Affymetrix arrays 10,000-fold permutations (Perm). were subjected to quality control. Nineteen samples were excluded due to low call rate (<95%). SNPs were Gene expression quantification W excluded with low minor allele frequency (<5%), low call Using GoTaq 2-Step RT-qPCR System, total RNA frequency (<95%) and replication error. The final SNP was prepared from 36 non-malignant prostate tissues set included 534,781 SNPs for genome-wide association and reverse transcribed and the mRNA of genes adjacent analysis. to the GWAS prostate cancer SNPs were quantified. Δ The replication study was performed with the Expression values were calculated as 2- Ct using GAPDH W TaqMan SNP genotyping assays on a 7500 Real-Time gene as reference. Primer sequences are listed in the PCR System (Applied Biosystems, Grand Island, NY), Additional file 2 Table S1. The difference in gene expres- with no template as negative controls. The PCR thermal sion between prostate tumors carrying GWAS prostate cycling was as follows: initial denaturing at 95°C for cancer risk alleles and that without was calculated using T 10 min, 40 cycles of 92°C for 15 s and 60°C for 1 min. test with Welch’s correction. Genotype call success rate for cases and for controls was 94.8% and 98.2% respectively. Randomly selected 47 Results samples were verified genotype reproducibility with a Genome Scan analysis of DNA from 90 Tunisian patients coincidence rate 100%.
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