The repeated inflammation caused by monthly ovulation exposes the fallopian tube epithelium to oxidative stress, leading to transcription-associated mutations in the TP53 gene. This is believed to be the first step in the development of high grade serous ovarian carcinoma (HGSC). Estrogen and inflammatory cytokines generated during ovulation cause DNA damage in the fallopian tube cells through reactive oxygen species. Mutation of the TP53 gene prevents the cells from undergoing apoptosis in response to this damage, allowing genetic changes to accumulate and cancer to develop.

1. Transcription-Associated Mutation of
TP53 as the Cause of High Grade
Serous Ovarian Carcinoma
Zachariah Tritz, Caitlin Van Lith, Zachary WareJoncas, Charlotte Elwell

2. Sporadic Transformation of FTE to HGSC
The repeated inflammation caused by ovulation exposes the
upregulated TP53 gene to a highly oxidative environment leading to a
transcription-associated mutation of TP53 as the first step in the
genesis of High Grade Serous Ovarian Carcinoma.

3. Estrogen and Ovulation
Follicular Fluid and Inflammation
Fallopian Tube Epithelium (FTE)
High Grade Serous Carcinoma (HGSC)
Transcription-Associated Mutation
Interleukin-1β (IL-1β), ROS, and SOD2
Functional and Mutated TP53 Gene

4. High Grade Serous Carcinoma Other Ovarian Cancers
Percent of Cases Approximately 70%1 Approximately 30%1
Average Stage of
Diagnosis
III or IV2 III3
5 Year Survival Rate 5% - 27%4 20% - 99%4
● 90% are sporadic in origin [2]
● Consistent biological marker : TP53 mutation [1]
1. Seidman JD, et al 2004 2. Risch HA, et al. 2001 3.Rossing MA, et al 2010 4. Seiden, Michael V. 2012
High Grade Serous Carcinoma (HGSC)

5. Estrogen and Ovulation
Follicular Fluid and Inflammation
Fallopian Tube Epithelium (FTE)
High Grade Serous Carcinoma (HGSC)
Transcription-Associated Mutation
Interleukin-1β (IL-1β), ROS, and SOD2
Functional and Mutated TP53 Gene

6. Functional and Mutated TP53 Gene
Based on a figure by Theirry Soussi 2007
DNA Damage
Oxidative Stress
p53
Apoptosis
Cell Death
Cell Cycle Arrest
DNA Repair
Cellular/Genetic Stability
TP53

7. Cell cannot regulate repair
and undergo apoptosis
HGSC
Functional and Mutated TP53 Gene
DNA Damage
Oxidative Stress
p53
Apoptosis
Cell Death
Cell Cycle Arrest
DNA Repair
Cellular/Genetic Stability
TP53
Based on a figure by Theirry Soussi 2007

8. Estrogen and Ovulation
Follicular Fluid and Inflammation
Fallopian Tube Epithelium (FTE)
High Grade Serous Carcinoma (HGSC)
Transcription-Associated Mutation
Interleukin-1β (IL-1β), ROS, and SOD2
Functional and Mutated TP53 Gene

9. Ovary
Distal
Fallopian
Tube
Tumor
https://bionews-tx.com/news/2014/07/17/new-route-for-ovarian-cancer-
spread-uncovered-by-md-anderson-researchers/
Ovary
Fallopian Tube Epithelium (FTE)

10. Estrogen and Ovulation
Follicular Fluid and Inflammation
Fallopian Tube Epithelium (FTE)
High Grade Serous Carcinoma (HGSC)
Transcription-Associated Mutation
Interleukin-1β (IL-1β), ROS, and SOD2
Functional and Mutated TP53 Gene

11. Estrogen and Ovulation
Emori, M.M., and R. Drapkin. 2014.
● Estrogen and LH levels peak shortly before
ovulation [5]
● Rupture in ovary needs to be repaired
○ Recruits inflammatory response [2]
HORMONES
MONTHLY MENSTRUAL CYCLE

12. Estrogen and Ovulation
Follicular Fluid and Inflammation
Fallopian Tube Epithelium (FTE)
High Grade Serous Carcinoma (HGSC)
Transcription-Associated Mutation
Interleukin-1β (IL-1β), ROS, and SOD2
Functional and Mutated TP53 Gene

13. ROS
Follicular Fluid and Inflammation
Leukocyte
OvumOvary

14. Estrogen and Ovulation
Follicular Fluid and Inflammation
Fallopian Tube Epithelium (FTE)
High Grade Serous Carcinoma (HGSC)
Transcription-Associated Mutation
Interleukin-1β (IL-1β), ROS, and SOD2
Functional and Mutated TP53 Gene

15. Fallopian Tube
Epithelium
Interleukin-1β (IL-1β), ROS, and SOD2
Leukocyte
Estrogen
IL-1β
TP53
SOD2Human Follicular Fluid
Lau 2014 Roy 2007

16. Estrogen and Ovulation
Follicular Fluid and Inflammation
Fallopian Tube Epithelium (FTE)
High Grade Serous Carcinoma (HGSC)
Transcription-Associated Mutation
Interleukin-1β (IL-1β), ROS, and SOD2
Functional and Mutated TP53 Gene

17. Transcription-Associated Mutation
www.personal.psu.edu/chromatinFiber.jpg

18. Inflammation
High IL-1β
High ROS
Low SOD2
Exposed to
Mutation
TP53
Upregulated
& Unwound
Known to
cause DNA
damage
Shown to
increase
mutation rate
in yeast
Summary
Implicated
in other
cancers
TP53
mutation
associated
with cancer

19. Experimental Proposal
iPSCs FTE
Meyer 2016

20. Significance
• Ovulation is controllable
• Research on inflammation inhibitors
• Aspirin reduces rates of ovarian cancer [14]
• Prolong the time it takes for mutations
to accumulate
• Reduce the prevalence of ovarian cancer
in society

21. Acknowledgements
We would like to thank the Mayo Clinic IMPACT
Competition, our faculty advisor, Dr. Kim Kandl, and St.
Olaf College for offering us help and support
throughout this process.

22. Sources
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