<p> RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE,</p><p>KARNATAKA</p><p>PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION</p><p>1. NAME OF THE CANDIDATE: Dr. Christine Mary Jane</p><p>ADDRESS: Department of Medicine St. John’s Medical College Hospital</p><p>John Nagar, Sarjapur Road</p><p>Koramangala</p><p>Bangalore – 560034</p><p>Tel. No. 080-22065834</p><p>2. NAME OF THE INSTITUTION: St. John’s Medical College</p><p>Bangalore</p><p>3. COURSE OF STUDY AND SUBJECT: MD, General Medicine</p><p>4. DATE OF ADMISSION TO THE COURSE: 01-06-2013</p><p>5. TITLE: STUDY OF CNVs COPY NUMBER VARIANTS) AS A PROGNOSTIC MARKER IN CHRONIC MYELOID LEUKEMIA. STUDY OF CNVs (copy number variants) AS A PROGNOSTIC MARKER IN CHRONIC MYELOID LEUKEMIA DR CHRISTINE MARY JANE GUIDE: DR CECIL ROSS MD PROFESSOR.</p><p>6. Introduction  CML is a clonal, haematologic malignant disease characterised by the acquisition of the BCR/ABL fusion gene generated by a cytogenetically balanced philadelphia chromosome translocation.  The product of the gene, the bcr/abl protein is a constitutively active protein tyrosine kinase, which plays a central role in the pathogenesis of CML(1). </p><p> There is variability in drug sensitivity, resistance and response to treatment in the three disease phenotypes of CML- chronic phase, accelerated phase and blast phase.</p><p>6.1Study agent/procedure  The development of drug resistance is multi factorial.  It can include mechanisms such as BCR/ABL gene amplification, development of multidrug resistance or mutation of the BCR/ABL kinase domain.  But not all treatment failures can be accounted for by these changes. </p><p>6.2 CNV (COPY NUMBER VARIATION)  CNV (Copy Number Variation) can be defined as a DNA segment that is 1 kbp or larger and present at variable copy number in comparison with a reference genome.  Deletions, insertions, duplications and complex multi-site variants are included under CNVs.  A CNV can be simple in structure, such as tandem duplication, or may involve complex gains or losses of homologous sequences at multiple sites in the genome.  CNVs influence gene expression, phenotypic variation and adaptation by disrupting and altering gene and can cause diseases (2). 6.3 Objective: To assess prognostic significance of known CNVs in CML patients on Tyrosine kinase inhibitor therapy (TKI) therapy.</p><p>Inclusion criteria : BCR-ABL positive CML patients in chronic/ accelerated phase/ blast crisis who have been on TKI therapy for a minimum of 3 months</p><p>Exclusion criteria  Clinical evidence of heart failure.  Concurrent serious hepatic disorder or renal disorder.  On irregular treatment.</p><p>7.STUDY DESIGN- A cross sectional study. All patients with CML on TKI’s (tyrosine kinase inhibitors) for at least 3 months on follow up in St. John’s Medical college  Duration of study: One year from october 2013 to october 2014.  Sample size: 30  Sampling technique: Convenience sampling. </p><p>7.1 Criteria for Cytogenetic, Hematologic & Molecular Response :  This is based on clinical analysis, cytogenetic study and hybridization techniques. 7.2MATERIALS AND METHODS :  Patients who have been on TKI for a minimum of 3 months will be assessed by RQ-Polymerase chain reaction for determining CNVs.  Comparison will be made between CNV in patients among the following groups: 1. With complete haematological response (CHR) and depth of molecular remission. 2. Without CHR 3. Blast crises and accelerated phase </p><p>Statistical analysis:  The relative copy number of target sequences in DNA samples can be determined using a comparative CT (Δ CT) method. This method calculates a relative value both to the normal control DNA (the callibrator) and to the endogenous control reference sequence. </p><p>7.3 Data analysis procedure: Descriptive measure  The change in a particular gene is a numerical variable. Drug response is a dichotomous variable- Yes/No.  Hence a student T test will be done for each gene studied. </p><p>FUNDING: Intramural funds.</p><p>8.References: 1.Markovic VD, Bouman D, Bayani J, Al-Maghrabi J, Kamel-Reid S,Squire JA.;Lack of BCR/ABL reciprocal fusion in variant Philadelphia chromosome translocations: a use of double fusion signalFISH and spectral karyotyping, Leukemia 14(2000) 1157–1160. 2. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H,Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, González JR,Gratacòs M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J,Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME. Global variation in copy number in the human genome. Nature. 2006 Nov 23;444(7118):444-54. </p><p>3. Braude I, Vukovic B, Prasad M, Marrano P, Turley S, Barber D, Zielenska M, Squire JA. Large scale copy number variation (CNV) at 14q12 is associated with the presence of genomic abnormalities in neoplasia. BMC Genomics. 2006 Jun 6;7:138. PubMed PMID: 16756668; PubMed Central PMCID: PMC1550726.</p><p>4. Branford S, Hughes T. Diagnosis and monitoring of chronic myeloid leukemia by qualitative and quantitative RT-PCR. Methods Mol Med. 2006;125:69-92. 5. Kolomietz E, Al-Maghrabi J, Brennan S, Karaskova J, Minkin S, Lipton J, Squire JA. Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis. Blood. 2001 Jun 1;97(11):3581-8. </p><p>6.Kolomietz E, Marrano P, Yee K, Thai, Braude I, Kolomietz A, K Chun, S Minkin1, Kamel-Reid S,Minden1 M and Squire JA; Quantitative PCR identifies a minimal deleted region of 120 kb extending from the Philadelphia chromosome ABL translocation breakpoint in chronic myeloid leukemia with poor outcome. Leukemia. 2003 Jul;17(7):1313-23.</p><p>7.Guan M, Liu L, Zhao X,Wu Q,Yu B, Shao Y, Yang H, Fu X,Wan J, Zhang W; Copy Number Variations of EphA3 Are Associated With Multiple Types of Hematologic Malignancies, Clinical Lymphoma, Myeloma & Leukemia.</p><p>Clin Lymphoma Myeloma Leuk. 2011 Feb;11(1):50-3. 9. SIGNATURE OF THE CANDIDATE</p><p>10. REMARKS OF THE GUIDE</p><p>11. NAME AND DESIGNATION OF</p><p>11.1 GUIDE: DR. CECIL ROSS</p><p>PROFFESSOR OF MEDICINE</p><p>11.2 SIGNATURE:</p><p>11.3 HEAD OF DEPARTMENT: DR.G.D.RAVINDRAN</p><p>PROFESSOR & HEAD</p><p>11.4. SIGNATURE:</p><p>11.5. REMARKS OF CHAIRMAN AND DEAN: DR.</p><p>11.6. SIGNATURE:</p>