Germline Genetic Determination of Cancer Outcome

Author

Benjamin N. Ostendorf

Date of Award

2020

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Tavazoie Laboratory

Abstract

Immunotherapy has transformed the treatment of melanoma patients. However, despite the enormous promise of immunotherapy, a major fraction of patients with advanced melanoma still succumb to this deadly disease. In addition, systemic immunotherapy can lead to relevant toxicities. Therefore, it is an unmet need to identify the factors that modulate the outcome and response to therapy of melanoma patients. One major factor accounting for individual differences in the host response to cancer is the genetic makeup of the germline. A thorough assessment of the role of germline genetics in melanoma outcome is lacking, partly because of the difficulty in assessing the vast number of genetic variants present in the human population. In this thesis, I describe the discovery of the impact of three highly prevalent variants of the Apolipoprotein E (APOE) gene on melanoma progression and outcome. Using transgenic human APOE mice, we found that mice expressing the APOE4 variant exhibit slower melanoma progression and metastasis than APOE2 mice. The impact of APOE genotype on melanoma progression was mediated by modulation of anti-melanoma immunity. APOE4 mice showed enhanced activation of anti-tumor immunity relative to APOE2 mice, and T cell depletion abrogated the impact of APOE genotype on melanoma progression. Importantly, analysis of large-scale human melanoma data validated the impact of APOE genotype on melanoma progression in humans. Amongst melanoma patients at high risk of melanoma-associated death, carriers of the APOE2 variant showed worse survival outcomes relative to APOE3 homozygotes and APOE4 carriers in two independent studies. APOE genotype also impacted melanoma outcome in the context of anti-PD1 immunotherapy in both mice and humans. Additionally, APOE4 mice derived robust benefit of pharmacologic activation of liver-X-receptors, a class of transcription factors inducing APOE expression. In contrast, APOE2 showed no treatment benefit, indicating that APOE genotype may serve as a biomarker for response to LXR-agonistic immunotherapy. Overall, our data describe the first example of highly common germline variants that modulate the outcome of a common cancer type. These findings suggest APOE to be a potential biomarker for outcome and therapy response in melanoma. More generally, our findings suggest that common variants of the germline genetic makeup substantially modulate cancer outcome and will likely be a cornerstone of precision cancer management.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Recommended Citation

Ostendorf, Benjamin N., "Germline Genetic Determination of Cancer Outcome" (2020). Student Theses and Dissertations. 591.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/591