Studies On Genomic Alterations In HER2 Positive Breast Cancer Focus On Design Synthesis And Evaluation Of Anilinoquinazoline Analogues As Potential HER2 Inhibitors

Abstract

iii newlineABSTRACT newlineStudies on Genomic Alterations in HER2-Positive Breast Cancer Focus on Design, newlineSynthesis and Evaluation of Anilinoquinazoline Analogues as Potential HER2 inhibitors newlineName of student : Heena Singla newlineRegistration number : 15phdhgs02 newlineDegree for which submitted : Ph.D. newlineName of supervisor : Prof. Anjana Munshi newlineName of co-supervisor : Dr. Vinod Kumar newlineName of department : Human Genetics and Molecular Medicine newlineName of school : School of Health Sciences newlineKeywords: HER2-positive breast cancer, overexpression/amplification, trastuzumab newlineresistance, anilinoquinazoline, MTT assay, antiproliferative activity newlineHuman epidermal growth factor receptor 2-positive (HER2-positive) breast cancer is an newlineaggressive breast cancer subtype characterized by HER2 overexpression/amplification. newlineGenomic alterations of HER2 and others have been reported to be associated with, HER2 newlineoverexpression and prediction of trastuzumab-response. The current study was carried out newlineto identify genomic alterations associated with HER2-positive breast cancer and evaluate newlinetheir association with clinical outcome in response to trastuzumab therapy given to HER2- newlinepositive breast cancer patients. Global Sequencing Array (GSA) and polymerase chain newlinereaction-restriction fragment length polymorphism (PCR-RFLP) techniques were used to newlinedetermine alterations in HER2 and other HER2-interacting as well as signaling-related genes newlineimplicated in the disease. In addition, 20 formalin fixed paraffin-embedded (FFPE) tissue newlinesamples were also evaluated by GSA for identifying significant variations associated with the newlinedisease as well as response to trastuzumab therapy. A germline variant in HER2 gene newline(I655V) was found to be significantly associated with the risk of the disease (p lt 0.01). A newlinenonsense mutation in PTPN11 (K99X), a pathogenic CCND1 splice site variant (P241P), a newlinehotspot missense mutation in PIK3CA (E542K) and a hotspot missense mutation in TP53 newline(R249S); were observed in 25%, 75%, 30% and 40% of the HER2-positive breast cancer newlinetissue samples, respectively. Mutant CCN