Date of Award

January 2022

Document Type

Open Access Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Xiaomei Ma

Second Advisor

Luisa Fernanda Escobar-Hoyos

Abstract

Cancer patients with similar clinical and pathologic characteristics may have different response to treatments and survival, which may be attributable to distinct molecular properties of their tumor. The most common forms of lung and pancreatic tumors, the adenocarcinomas, often have mutations in the TP53 gene. It is not clear, however, how mutations in this gene may provide prognostic information and/or inform the clinical management of patients with lung adenocarcinoma (LUAD) and pancreatic ductal adenocarcinoma (PDAC). Despite previous studies suggesting that all mutations in TP53 are associated with worse prognosis, it is now known that not all TP53 mutations lead to the same biological function of the protein. This study assessed the potential effect of wild-type, missense and truncating TP53 mutations on the survival of patients with LUAD and PDAC, in two independent prospective clinical cohorts (n = 4,751 LUAD, n = 517 PDAC), using multivariable Cox proportional hazards regression models that adjusted for patient demographic (age at diagnosis, sex, race /ethnicity) and tumor characteristics (presence of distant metastasis at diagnosis). Additionally, we conducted stratified analyses by the status of other mutations in driver oncogenes (e.g., KRAS, EGFR). We found that among LUAD patients, both missense (HR = 1.12, 95% CI: 1.00-1.24; p=0.044) and truncating mutations (hazard ratio [HR] = 1.33, 95% confidence interval [CI]: 1.17-1.51; p<0.001) in TP53 were associated with worse overall survival when compared to wild-type TP53, while the magnitude of association appeared somewhat different. Contrarily, in patients with PDAC, only missense TP53 mutations were associated with a worse survival compared to wild-type TP53 (HR = 1.47, 95% CI: 1.00-2.17; p=0.051). Furthermore, our results indicated that in patients with LUAD, TP53 was associated with a worse survival in the subgroup of patients with co-occurring EGFR mutations, but not among those with co-existing KRAS mutations. These findings suggest that molecular characterization of otherwise indistinguishable tumors may help to break down cancers into distinct entities, each of which ought to be recognized as having separate behaviors and different molecular fingerprints. More importantly, our results indicate that there are innate biological differences among tumors that can impact patients’ survival, and that can be exploited to identify molecular abnormalities for potential targeted therapy.

Comments

This is an Open Access Thesis.

Open Access

This Article is Open Access

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