Functional and correlative analysis of common endometrial cancer driver mutations
<p>Endometrial cancer is a growing concern with increasing incidence and mortality countering the downward trend observed in many other cancers. Despite recent advances in understanding, much remains unknown about endometrial cancer pathogenesis and the molecular mechanisms that drive its init...
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2022
|
| Subjects: |
| _version_ | 1811139940586618880 |
|---|---|
| author | Brown, MW |
| author2 | Church, D |
| author_facet | Church, D Brown, MW |
| author_sort | Brown, MW |
| collection | OXFORD |
| description | <p>Endometrial cancer is a growing concern with increasing incidence and mortality countering the downward trend observed in many other cancers. Despite recent advances in understanding, much remains unknown about endometrial cancer pathogenesis and the molecular mechanisms that drive its initiation and growth. This has led to worse outcomes for patients due to a lack of effective prediction of disease course and of effective targeted therapeutics, particularly when surgery is not possible or curative. One of the largest advancements in our understanding of endometrial cancer has come from increased mutational profiling of human tumours. These studies have highlighted manygenes exhibiting high rates of mutation as drivers of endometrial cancer, with one suchgene being FBXW7.</p>
<p>In this work, I used genetically engineered mouse models to investigate the role of the Fbxw7(R482Q) mutation as a driver of endometrial cancer, both independently and in combination with other frequent endometrial cancer drivers (Pten loss of function and Trp53 mutation). When expressed alone, heterozygous Fbxw7(R482Q) mutation does not induce any uterine pathology in a PgrCre-driven murine model system. However, when combined with either Pten loss (Pten(∆/∆)) or Trp53(R172H/∆), it significantly accelerated cancer development leading to significantly reduced overall survival.</p>
<p>Examination of the potential mechanism leading to accelerated carcinogenesis in Pten(∆/∆) Fbxw7(R482Q/+) mice highlighted potential dysregulation of Wnt and Hippo pathway transcription factors. Further molecular analysis found an interaction between FBXW7 with LEF1 and TCF7L2. In the case of TCF7L2, interaction could be almost completely disrupted by introduction of common mutations (R465C, R479Q, and R505C) to the WD40 domain of FBXW7. Together, highlighting these Wnt transcription factors as novel FBXW7 substrates.</p>
<p>In conclusion, Fbxw7(R482Q) mutation does not initiate carcinogenesis alone, however, it does promote more aggressive cancer development when combined with other cancer driver mutations. Future work should focus on further characterisation of the mechanisms behind co-operation of <em>Fbxw7</em> mutation with other cancer driver genes and the potential role of FBXW7 mutation as a pre-malignant alteration that may provide a foundation for future malignant transformation.</p> |
| first_indexed | 2024-09-25T04:14:04Z |
| format | Thesis |
| id | oxford-uuid:87a9cc92-98db-49e6-be32-f2c053da60a7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:14:04Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | oxford-uuid:87a9cc92-98db-49e6-be32-f2c053da60a72024-07-15T08:46:02ZFunctional and correlative analysis of common endometrial cancer driver mutationsThesishttp://purl.org/coar/resource_type/c_db06uuid:87a9cc92-98db-49e6-be32-f2c053da60a7CancerEnglishHyrax Deposit2022Brown, MWChurch, D<p>Endometrial cancer is a growing concern with increasing incidence and mortality countering the downward trend observed in many other cancers. Despite recent advances in understanding, much remains unknown about endometrial cancer pathogenesis and the molecular mechanisms that drive its initiation and growth. This has led to worse outcomes for patients due to a lack of effective prediction of disease course and of effective targeted therapeutics, particularly when surgery is not possible or curative. One of the largest advancements in our understanding of endometrial cancer has come from increased mutational profiling of human tumours. These studies have highlighted manygenes exhibiting high rates of mutation as drivers of endometrial cancer, with one suchgene being FBXW7.</p> <p>In this work, I used genetically engineered mouse models to investigate the role of the Fbxw7(R482Q) mutation as a driver of endometrial cancer, both independently and in combination with other frequent endometrial cancer drivers (Pten loss of function and Trp53 mutation). When expressed alone, heterozygous Fbxw7(R482Q) mutation does not induce any uterine pathology in a PgrCre-driven murine model system. However, when combined with either Pten loss (Pten(∆/∆)) or Trp53(R172H/∆), it significantly accelerated cancer development leading to significantly reduced overall survival.</p> <p>Examination of the potential mechanism leading to accelerated carcinogenesis in Pten(∆/∆) Fbxw7(R482Q/+) mice highlighted potential dysregulation of Wnt and Hippo pathway transcription factors. Further molecular analysis found an interaction between FBXW7 with LEF1 and TCF7L2. In the case of TCF7L2, interaction could be almost completely disrupted by introduction of common mutations (R465C, R479Q, and R505C) to the WD40 domain of FBXW7. Together, highlighting these Wnt transcription factors as novel FBXW7 substrates.</p> <p>In conclusion, Fbxw7(R482Q) mutation does not initiate carcinogenesis alone, however, it does promote more aggressive cancer development when combined with other cancer driver mutations. Future work should focus on further characterisation of the mechanisms behind co-operation of <em>Fbxw7</em> mutation with other cancer driver genes and the potential role of FBXW7 mutation as a pre-malignant alteration that may provide a foundation for future malignant transformation.</p> |
| spellingShingle | Cancer Brown, MW Functional and correlative analysis of common endometrial cancer driver mutations |
| title | Functional and correlative analysis of common endometrial cancer driver mutations |
| title_full | Functional and correlative analysis of common endometrial cancer driver mutations |
| title_fullStr | Functional and correlative analysis of common endometrial cancer driver mutations |
| title_full_unstemmed | Functional and correlative analysis of common endometrial cancer driver mutations |
| title_short | Functional and correlative analysis of common endometrial cancer driver mutations |
| title_sort | functional and correlative analysis of common endometrial cancer driver mutations |
| topic | Cancer |
| work_keys_str_mv | AT brownmw functionalandcorrelativeanalysisofcommonendometrialcancerdrivermutations |