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Investigating the Effects of Exon 3 CTNNB1 Mutations in Endometrioid Endometrial Cancers
Investigating the Effects of Exon 3 CTNNB1 Mutations in Endometrioid Endometrial Cancers
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202104722
- ISBN
- 9798291555125
- DDC
- 616.07
- 서명/저자
- Investigating the Effects of Exon 3 CTNNB1 Mutations in Endometrioid Endometrial Cancers
- 발행사항
- [Sl] : The University of North Carolina at Chapel Hill, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 104 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-02, Section: B.
- 주기사항
- Advisor: Broaddus, Russell;Gladden, Andrew.
- 학위논문주기
- Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2025.
- 초록/해제
- 요약Endometrial cancer is the most common gynecological malignancy in the Western world, with steadily increasing annual incidence and mortality rates. CTNNB1 exon 3 mutation is a well-established driver of nearly 30% of endometrioid endometrial cancers (EEC). Patients with EEC and CTNNB1 mutations have significantly worse recurrence free survival than EEC patients with wild-type CTNNB1, though the mechanism driving this survival disadvantage is not well understood. Exon 3 CTNNB1 mutations are thought to drive nuclear localization of the β-catenin protein, but previous studies from our group and others have demonstrated that mutant β-catenin does not robustly localize to the nucleus in these cancers. The purpose of this dissertation was to examine how differential localization of mutant β-catenin alters gene expression in EEC tumors, and how these transcriptional profiles may be tools for clinical actionability. We characterized β-catenin localization in a cohort of EEC tumors with exon 3 CTNNB1 mutations as non-nuclear, low nuclear, heterogenous, or nuclear (chapter 2). Spatial transcriptomics was then performed on tumors with intratumor nuclear and non-nuclear mutant β-catenin, using the protein localization to select for regions of interest (ROI) (chapter 3). Differential expression analysis of all nuclear and non-nuclear ROIs yielded distinct transcriptional profiles based on localization of β-catenin. Analysis revealed enrichment for Wnt-signaling and epithelial-to-mesenchymal transition pathways in nuclear ROIs and hormone signaling in non-nuclear ROIs. Hierarchical clustering yielded two clusters comprised of almost entirely nuclear or non-nuclear ROIs. A novel therapeutic target, TROP2, encoded by the TACSTD2 gene, was identified to be altered by Wnt/β-catenin signaling (chapter 4).These data provide evidence for highly heterogeneous intratumor transcriptional profiles dependent on β-catenin protein localization in EEC with CTNNB1 driver mutations. Additionally, this study reveals novel insights into β-catenin biology in endometrioid tumors and beyond. Future studies will investigate how these results can be used for translational applications in EEC tumors with CTNNB1 mutations.
- 일반주제명
- Pathology
- 일반주제명
- Oncology
- 일반주제명
- Cellular biology
- 일반주제명
- Biochemistry
- 키워드
- CTNNB1
- 키워드
- EEC tumors
- 기타저자
- The University of North Carolina at Chapel Hill Pathology
- 기본자료저록
- Dissertations Abstracts International. 87-02B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520260202104722
■006m o d
■007cr#unu||||||||
■020 ▼a9798291555125
■035 ▼a(MiAaPQ)AAI32121548
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a616.07
■1001 ▼aParrish, Molly Lynn.
■24510▼aInvestigating the Effects of Exon 3 CTNNB1 Mutations in Endometrioid Endometrial Cancers
■260 ▼a[Sl]▼bThe University of North Carolina at Chapel Hill▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a104 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-02, Section: B.
■500 ▼aAdvisor: Broaddus, Russell;Gladden, Andrew.
■5021 ▼aThesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2025.
■520 ▼aEndometrial cancer is the most common gynecological malignancy in the Western world, with steadily increasing annual incidence and mortality rates. CTNNB1 exon 3 mutation is a well-established driver of nearly 30% of endometrioid endometrial cancers (EEC). Patients with EEC and CTNNB1 mutations have significantly worse recurrence free survival than EEC patients with wild-type CTNNB1, though the mechanism driving this survival disadvantage is not well understood. Exon 3 CTNNB1 mutations are thought to drive nuclear localization of the β-catenin protein, but previous studies from our group and others have demonstrated that mutant β-catenin does not robustly localize to the nucleus in these cancers. The purpose of this dissertation was to examine how differential localization of mutant β-catenin alters gene expression in EEC tumors, and how these transcriptional profiles may be tools for clinical actionability. We characterized β-catenin localization in a cohort of EEC tumors with exon 3 CTNNB1 mutations as non-nuclear, low nuclear, heterogenous, or nuclear (chapter 2). Spatial transcriptomics was then performed on tumors with intratumor nuclear and non-nuclear mutant β-catenin, using the protein localization to select for regions of interest (ROI) (chapter 3). Differential expression analysis of all nuclear and non-nuclear ROIs yielded distinct transcriptional profiles based on localization of β-catenin. Analysis revealed enrichment for Wnt-signaling and epithelial-to-mesenchymal transition pathways in nuclear ROIs and hormone signaling in non-nuclear ROIs. Hierarchical clustering yielded two clusters comprised of almost entirely nuclear or non-nuclear ROIs. A novel therapeutic target, TROP2, encoded by the TACSTD2 gene, was identified to be altered by Wnt/β-catenin signaling (chapter 4).These data provide evidence for highly heterogeneous intratumor transcriptional profiles dependent on β-catenin protein localization in EEC with CTNNB1 driver mutations. Additionally, this study reveals novel insights into β-catenin biology in endometrioid tumors and beyond. Future studies will investigate how these results can be used for translational applications in EEC tumors with CTNNB1 mutations.
■590 ▼aSchool code: 0153.
■650 4▼aPathology
■650 4▼aOncology
■650 4▼aCellular biology
■650 4▼aBiochemistry
■653 ▼aCTNNB1
■653 ▼aEndometrioid endometrial cancers
■653 ▼aClinical actionability
■653 ▼aEEC tumors
■653 ▼aEndometrial cancer
■690 ▼a0571
■690 ▼a0992
■690 ▼a0379
■690 ▼a0487
■71020▼aThe University of North Carolina at Chapel Hill▼bPathology.
■7730 ▼tDissertations Abstracts International▼g87-02B.
■790 ▼a0153
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17358578▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
