Integrated Immunophenotypic, Transcriptomic, and Epigenomic Characterization of Uterine Mesenchymal Neoplasms with Expert Pathologist Panel Review
Abstract
We propose to establish a multi-faceted resource to advance the understanding of rare uterine mesenchymal tumors. Uterine mesenchymal tumors primarily arise from the muscular wall of the uterus or from the stroma of the endometrium (superficial lining) of the uterus. Leiomyomas or fibroids as they are also referred to, are an example of very common benign mesenchymal tumors in the uterus. However, there are many other uterine mesenchymal tumors that are very rare, and most are malignant or potentially malignant. This proposal focuses on these rare mesenchymal tumors of the uterus. Such tumors are very challenging to diagnose even after a surgical resection, in part due to their rarity but also due to lack of specific diagnostic and prognostic biomarkers. Ambiguous and sometimes conflicting diagnostic opinions are challenging for patients to navigate, may result in both under- and over-treatment, and impede innovation on new personalized therapies tailored towards specific tumor types. Mesenchymal tumors often lack DNA mutational variants present in common tumors, and we must look at other elements of the tumor, such as RNA and epigenetic features, to gain further insight into the classification and prognostication of this group of tumors. It is of upmost importance to have integrated clinical information and histopathologic evaluation on these rare mesenchymal tumors to better understand their biology and clinical behavior. For patients, this is often the most important question-- what kind of therapy do I need? Is it going to recur? What is my prognosis? The first step in improving treatment is ensuring optimal pathologic diagnosis. The vast variability in pathologic diagnosis of uterine mesenchymal tumors is problematic for patients and physicians alike and represents an unmet need in the field. Our proposal has a few critical components, which brings together key stakeholders of the community. First, we will collect these tumors from collaborators worldwide and digitize all slides such that expert pathologists from all over the world can view all the cases. The advances in digital pathology capabilities have created an opportunity to widely share cases and opinions that was never before possible. Our platform allows pathologists to enter diagnoses, leave comments, and see other pathologists comments as well, enabling discussion of interesting cases and readily identifies cases with significant interobserver variability in diagnosis. This platform will also be compatible with artificial intelligence (AI) approaches to study the microscopic details of these tumors. Second, we will establish a secure database of de-identified tumors with associated clinical, pathologic, and molecular annotations that link to the digitized slides present on the platform. The slide-viewing platform for pathologists, along with the database and clinical annotations, is the foundation of this resource. We propose to make this repository of tumors available to the research community, with the proper documentation and regulatory approvals. We also plan to generate molecular data on subsets of collected tumors. We have selected to perform RNA gene expression studies, which can identify tumor-specific molecular alterations, and through computer programming and machine learning approaches, can also tell us abundances of other cell types present, such as immune cells, and make inferences about their activity in the tumor. The other molecular profiling we will undertake is whole genome methylation profiling, which is a way of looking at epigenetic changes in tumor DNA, which is one feature that can inform if a particular gene is turned on or off in the tumor. We will also record and annotate mutations identified from previously performed assays. The last critical component of this proposal is the establishment of a web-based resource, where patients and their families can learn about these tumors, both in writ
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310894
Entities
People
- Brooke Howitt
Organizations
- Stanford University
- United States Army