Multi Omic Characterization and Study of Treatment Associated Clonal Evolution in Mantle Cell Lymphoma and Lung Adenocarcinoma

Ghosh, Saindhabi (2025) Multi Omic Characterization and Study of Treatment Associated Clonal Evolution in Mantle Cell Lymphoma and Lung Adenocarcinoma. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS Dissertation of Saindhabi Ghosh (20MS083)) 20MS083_Thesis_file.pdf - Submitted Version Restricted to Repository staff only Download (4MB)

Abstract

The project focuses on the approaches of performing a multi-omic study on therapy-associated cancer where two different models were used for Mantle Cell Lymphoma (MCL) and Lung Adenocarcinoma. MCL is primarily characterized by the malignant transformation of B lymphocytes within the mantle zone, the outermost layer of lymphoid follicles. A hallmark of MCL is a reciprocal chromosomal translocation t(11;14)(q13;q32) that drives overexpression of Cyclin D1. Despite advancements in therapeutic strategies, MCL remains challenging to study due to its high relapse rates post-treatment and has the tendency to become progressively more aggressive. To elucidate the genetic basis of MCL relapse, we conducted a comprehensive analysis of whole exome sequencing (WES) data from a large patient cohort (n=322). Sample groups such as baseline samples (collected at initial diagnosis) versus treatment-relapsed (n=282) samples, high-risk versus low-risk (n=200), and nodal versus extranodal tissue samples (n=252) were analyzed. This in-depth analysis enabled the identification of key mutations and copy number variations associated with MCL progression and relapse. These findings provide a comprehensive genomic landscape distinguishing clinically relevant patient subgroups. Additionally, the numerical chromosomal instability was found to increase with treatment administration. These insights contribute to the understanding of the genetic mechanisms driving MCL progression and resistance, potentially guiding future therapeutic strategies and risk stratification. In the second part of this study, RNAseq data of Ubqln1 and Ubqln4 overexpressing mice models were analyzed to study Ubqln1/4 overexpression in lung adenocarcinoma. Using a Kras-Trp53 mutant (KP) mouse model, we observed an increased sensitivity to PARP inhibitor (Olaparib) and anti-PD1 treatment in Ubqln1/4 overexpression (KPU1/KPU4) as compared to KP mouse. In line with this we observed downregulation of homologous recombination (HR) genes with overexpression of Ubqln1/4. However, under the treatment we observed enrichment of MAPK pathways (Olaprib) and downregulation of antigen processing and presentation (anti-PD1). Our findings suggest differential roles for Ubqln1 and Ubqln4 in therapy resistance. We observed the response of immunotherapy and PARP inhibition in KPU4 and KPU1 mice as compared to KP mice (s. above) highlighting that overexpression of Ubqln1 and Ubqln4 could serve as potential biomarkers for tailoring PARP inhibitor and immunotherapy strategies in lung adenocarcinoma. In line with this our detection of the downregulation of HR genes with Ubqln1/4 overexpression suggests a potential mechanisms of cancer aggressiveness.

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