Access Type

Open Access Dissertation

Date of Award

January 2020

Degree Type


Degree Name



Molecular Biology and Genetics

First Advisor

Michael A. Tainsky


A quarter of all cases of ovarian cancer (OVCA) cases are due to inherited factors. However, much of the genetic risk remains unknown. We have previously established the importance of whole exome sequencing to answer the question for missing heritability. We identified clinically actionable and novel risk loci in the DNA repair and cell cycle regulation pathways by assessing a cohort of women diagnosed with OVCA, wildtype for BRCA1/BRCA2 and suspected to be hereditary due to family history of breast cancer/OVCA. Equally as important was the exploration and discovery of novel risk loci in the apoptosis pathway. A total of 13 truncating mutations in apoptosis genes were found in over 35% of our patient cohort. The TP53I3-S252* premature stop gain was identified in two unrelated patients, one of whom also had a clinically actionable truncating variant in FANCM. The intriguing proposed function of TP53I3 is its ability to maintain DNA damage response and being transcriptionally activated by p53 to cause ROS induced apoptosis. It has been hypothesized as a key gene that connects DNA repair mechanisms with downstream apoptosis as a quinine oxidoreductase. Additionally two mutations in TP53AIP1 and two in BCLAF1 were identified in multiple individuals. Therefore, this study highlights the importance of the often overlooked pathway of apoptosis. The importance of genetic assessment of the apoptosis pathway was further strengthen back the observation that TP53I3-S252* significantly decreases homologous recombination repair (HRR) and significantly resists response to chemotherapy drugs bleomycin, mitomycin c (MMC) and etoposide. Additionally, in the presence of oxidative stress from hydrogen peroxide and/or etoposide there was a reduction in the formation of reactive oxygen species, which is an important precursor to apoptosis.

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