All ETDs from UAB

Advisory Committee Chair

Sadeep Shrestha

Advisory Committee Members

Xiangqin Cui

Andres Forerro

Ryan Irvin

Upender Manne

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) School of Public Health

Abstract

This research analyzes the underlying genomic features of breast tumors during immune response, with the overall goal of discovering markers of how tumor immunity and the known features of disease pathology relate. We aimed to 1) identify and validate somatic copy number variation and RNA expression associated with nodal metastasis; 2) construct an array-based measure of tumor infiltrating immune cells and determine its prominent clinical and transcriptional features; and 3) examine the relationship between somatic mutations within p53 and tumor immune cell infiltration status. In two sets of data, gene-level copy number variation (CNV) and RNA expression from the primary tumors of 650 and 772 women were analyzed for association with nodal metastasis (NM). We found that approximately 10% of CNV changes altered RNA in a meaningful way for NM, yet these CNVs were low prevalence with no strong peaks of amplified expression. Novel CNV-to-RNA gains were observed in CTAGE5, NDUFC2, EIF4EBP1, and PSCA. An additional dataset of 947 women was added to aim 2 to further improve validation. Genes with the strongest difference in expression between immune-high and immune-low tumors were CCL19 and CXCL9; molecular subtype had minor influence on this relationship. Gains in expression of CD52 and LYZ were found to be consistent with immune-rich status, while SCUBE2 and GRIA2 were linked to immune-poor tumors. Aim 3 built from the immune signature in the previous aim to analyze how somatic mutations in the p53 tumor suppressor gene partner with immune-rich and immune-poor status of tumors. In a set of 601 participants, women with any somatic mutation in p53 had 2.5 times higher odds of also having immune-rich tumors (95% CI, 1.8-3.7, FDR <0.001). A single mutation, p.R175H was shown to be present in a much higher frequency in immune-rich tumors. In conclusion, markers of immunophenotype in breast cancer in this dissertation have shown nodal metastasis as unlikely to be rooted in CNV-to-RNA driven expression in primary tumors. We have identified RNA expression elements in immune-rich tumors, while few distinct features were found in immune-poor tumors. Somatic mutations in p53 were confirmed as having immunogenic importance, with individual mutations warranting further investigation. These findings underscore the rich potential of genomic biomarkers of immunophenotype in breast cancer epidemiology.

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