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Prevalence of RNASEL, ELAC2 and MSR1 Gene Mutations Among Prostate Cancer Patients in Palestine

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Prevalence of RNASEL, ELAC2 and MSR1 Gene Mutations Among Prostate Cancer Patients in Palestine An-Najah National University Faculty of Graduate Studies Prevalence of RNASEL, ELAC2 and MSR1 gene mutations among prostate cancer patients in Palestine By Esra’a Mustafa Mohammed Al Hamad Supervisor Dr. Ashraf Sawafta Co- Supervisor Dr. Majdi Dwikat This Thesis is Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Life Sciences (Biology), Faculty of Graduate Studies, An-Najah National University, Nablus - Palestine. 2014 iii Dedication To the love of my life…my husband To my honor…my father and my lovely mother To the apples of my eyes … Obaidah and Yaman To all of my brothers and my sister To all of my family To all of my friends iv Acknowledgment I would like to thank my supervisors Dr. Ashraf Sawafta and Dr. Majdi Dwikat for their supervision and guidance throughout the work. I would like to thank all technicians in biology labs for their help in work. Many thanks for my uncle Khaleel Al Hamad for his support and encourage. Special thanks to all those patients and their relatives for providing me their blood samples, because this research would not been done without them. vi List of Contents No. Content Page Cover page i Dedication iii Acknowledgment iv Declaration v List of contents vi List of tables viii List of figures ix List of appendixes xi List of abbreviations xii Abstract xiv Chapter One: Introduction 1 1.1 General background 1 1.2 Types of tumors 2 1.3 Genetic pattern of cancer 2 1.4 Prevalence of cancer in west bank 3 1.5 Prostate cancer 7 1.5.1 Etiology of prostate cancer 9 1.5.2 Genetics of prostate cancer 11 1.5.3 Genes associated with hereditary prostate cancer 12 1.5.4 RNASEL/HPC1,ELAC2/HPC2 and MSR1 genes 13 1.6 Objectives 22 Chapter Two: Materials and methods 23 2.1 Sample of the study 23 2.2 Permission and ethical consideration 23 2.3 Blood samples collection 23 2.4 DNA extraction 25 2.5 Qualitative and quantitative DNA check 26 2.6 Mutation screening 26 2.7 Amplification of DNA 26 2.7.1 Primers of PCR 27 2.7.2 PCR master mix and conditions 29 2.7.3 Agarose gel electrophoresis of PCR products 30 2.8 Restriction fragment length polymorphism (RFLP) 31 2.9 Sequencing 35 2.9.1 Purification of PCR products 35 2.9.2 Sanger sequencing 36 2.9.2.1 Mutational analysis of sequencing 37 Chapter three: Results and discussion 40 vii 3.1 Qualitative and quantitative DNA check 40 3.1.1 DNA quality checking by 0.7% agarose 40 3.1.2 Spectrophotometer for DNA concentration 40 3.2 PCR and gel electrophoresis 42 3.3 RFLP results 44 3.3.1 The results of S217L 45 3.3.2 The results of A541T 47 3.3.3 The relationship between S217L and A541T 48 3.4 Sequencing for RNASEL and MSR1 amplicons 51 3.4.1 Checking the purification of the amplicons 52 3.4.2 The results of RNASEL (E265X) 53 3.4.3 The results of MSR1(P275A) 55 3.5 Recommendation 57 References 58 ب الملخص viii List of Tables No. Table Page 1.1 Reported cancer cases by sex and governorate in West 4 Bank in mid-year 2013. 1.2 Distribution of the reported cancer cases by site of the 6 tumor in West Bank in mid-year 2013. 1.3 Family history and prostate cancer risk. 11 2.1 The distribution of the study subjects in the cities of 24 West Bank. 2.2 A list of the mutations of the study. 26 2.3 The sequence of the forward and reverse primers. 28 2.4 The program of touchdown PCR. 30 3.1 The results of spectrophotometer. 41 3.2 The number of patients and healthy carriers of S217L 46 mutation in the study. 3.3 The number of patients and healthy carriers of A541T 48 mutation in the study. 3.4 The results of screening of both mutations of ELAC2 in 49 the same carrier. 3.5 Summary of the results of the first 15 samples. Which 55 include the 4 mutations Ser217Leu, Ala541Thr, E265X and P275A. ix List of Figures No. Figure Page 1.1 Diagram of reported cancer cases by sex and 5 governorate in West Bank in mid-year 2013 1.2 Diagram of reported cancer cases by site of the cancer 6 in West Bank in mid-year 2013 1.3 Zonal predisposition to prostate disease 8 1.4 Stages of prostate cancer. 9 1.5 The location of RNASEL gene 14 1.6 Mechanism of RNASEL activity. 15 1.7 The location of ELAC2 gene. 17 1.8 Model of potential ELAC2 pathomechanism. 18 1.9 The location of MSR1 gene. 20 2.1 The separation of Sigma 50 bp ladder. 31 2.2 The sequence of amplicon containing the S217L 32 mutation. 2.3 The restriction site of TaqαI enzyme on the double 32 strand. 2.4 Diagram of expected results of RFLP analysis of 33 S217L. 2.5 The restriction site of Fnu4HI enzyme on the double 34 strand. 2.6 The sequence of amplicon containing the A541T 34 mutation. 2.7 Diagram of expected results of RFLP analysis of 35 A541T. 2.8 The sequence of RNASEL amplicon. 38 2.9 The sequence of MSR1amplicon. 39 3.1 Representative samples of the extracted genomic 40 DNA. 3.2 Gel of representative samples of ELAC2 (S217L) 42 amplicon. 3.3 Gel of representative samples of ELAC2 (A541T) 43 amplicon. 3.4 Gel of representative samples of RNASEL amplicon. 43 3.5 Gel of representative samples of MSR1amplicon. 44 3.6 3% agarose of representative results of RFLP for 45 (S217L). 3.7 3% agarose of representative results of RFLP for 47 (A541T). x 3.8 Representative bands after purification. 52 3.9 The electropherogram of sample number 6. 52 3.10 The electropherogram of sample number 9. 53 xi List of Appendixes Appendix Name Page A Permission of IRB 74 B Consent form 75 xii List of Abbreviations DNA Deoxyribonucleic acid TN Tumor at stage number N HPV Human papillomavirus EBV Epstein-Barr virus HPC Hereditary prostate cancer HPC1 Loci 1 of Hereditary prostate cancer PCAP Predisposing for prostate cancer CAPB Cancer of the prostate and brain HPC2 Loci 2 of Hereditary prostate cancer HPC20 The loci in chromosome 20 in Hereditary prostate cancer RNASEL Ribonuclease L MSR1 Macrophage scavenger receptor 1 ELAC2 elaC homolog 2 BRCA1/BRCA2 Breast cancer susceptibility gene 1 and 2 G84E Glutamin → Glutamic acid at position 84 a.a HOXB13 Homeobox B PRCA Prostate cancer susceptibility gene RNS4 Ribonuclease gene 4 2-5 A 2’,5’- oligoisoadenylate synthetase- dependent mRNA Messenger ribonucleic acid IFN Interferon ISG43/ISG15 Interferon stimulating gene 43 and 15 PKR Protein kinase R MyoD Myogein regulatory factor G MEFs Mouse embryonic fibroblast M1I Mutation 1 of initiation codon E265X Glutamic acid→ stop codon at position 265 a.a 471∆AAAG Deletion of AAAG at position 471 D541E Aspartic acid→ Glutamic acid at position 541a.a R462Q Arginine → Glutamine at position 462 a.a LDL Low density lipoprotein PolyI/PolyG Polynucliec acid I and G R243X Arginine → stop codon at position 243 a.a IRB Institutional Review Board MOH Ministry of health ml Milliliter EDTA Ethylene diamine tetra acetic acid PCR Polymerase chain reaction μl Microliter RFLP Restriction fragment length polymorphism xiii UCSC University of California Santa Cruz Pmol Pico mole μM Micro molar ddH2O Double distilled water NTC No template control TAE Tris- acetic acid- EDTA buffer bp Base pair kb Kilobyte xiv Prevalence of RNASEL, ELAC2 and MSR1 gene mutations among prostate cancer patients in Palestine By Esra’a Mustafa Mohammed Al Hamad Supervisor Dr. Ashraf Sawafta Co- Supervisor Dr. Majdi Dwikat Abstract Prostate cancer (PC) is considered as a second prevalent cancer type among males in Palestine. Genetic background is the most common leading for PC. A family history with PC increase possibility for offspring to develop this disease for more than three folds. The mean age of diagnosis of PC is 71 ± 6 years, for a male with no family genetic background for PC . However a man who has a family history could be diagnosed before the age of 60. RNASEL, ELAC2 and MSR1 are susceptible genes that play an important role in hereditary prostate cancer (HPC). E265X mutation in RNASEL, (Ser217Leu and Ala541Thr) mutations in ELAC2, and (P275A)in MSR1are founder mutations associated with (HPC). The aim of this study is to investigate the prevalence of these four mutations in Palestinian PC patients and non PC males in order to establish a genetic profile, and to identify healthy people with high risk for PC. Therefore identification and characterization of these genes will be a key step for improving the detection and treatment of prostate cancer. For this purpose 50 blood samples were obtained from 38 PC patients and 12 healthy relatives from different cities of the West Bank. The DNA was xv extracted from each blood sample; and amplified by PCR. The mutational screening were performed by two types of techniques; Restriction fragment length polymorphism (RFLP) which performed for all samples to find the mutations of ELAC2 (Ser217Leu and Ala541Thr), and DNA sequencing was performed for 15 samples (the first 15 samples were collected) to find the mutations of RNASEL (E265X) and MSR1 (P275A). The mutation Ser217Leu was found in 23 subjects out of the 50 tested; 19 of them have heterozygous genotype from both patients and healthy carriers with (38% incidence rate), and 4 patients have homozygous genotype with (8% incidence rate).
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