- Title
- Early serous ovarian carcinogenesis: understanding the genetic and lifestyle factors
- Creator
- Bangaraswamaiah Nagendra, Prathima
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2020
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- For the last century, carcinoma has been a consistent Emperor of all maladies. Carcinoma is not a single disease, but a family of diseases which have one common characteristic. Cancer is the loss of cellular regulation, norm and function in a particular cell, leading to uncontrolled growth and disruption of the normal physiology and biology of the organ where it occurs. In the last century, we have succeeded in recognising each of the carcinomas that humans encounter, and have characterised their anatomical, physiological, histological and in most cases molecular features. This has greatly enhanced our ability to treat carcinomas. 40% of all cancer incidences are today treatable with more than 60% of the patients surviving 5 years post incidence. We have not had this kind of success in cases of heterogenous tumours. These are carcinomas which depend on multiple signalling cascades for their growth advantage, thus circumventing traditional chemotherapy and targeted therapies. The other failure is lack of accurate and scalable detection mechanisms, especially in deep seated organs. The combination of these two factors leads to high mortality rates in such tumours. One such example is the serous ovarian carcinoma. It has two histological subtypes, High grade serous ovarian carcinoma (HGSOC) and Low grade serous ovarian carcinoma (LGSOC). HGSOC is a high heterogeneity carcinoma due to which relapse rates are 60% within 5 years. LGSOC although mostly detected in early stages is inherently chemoresistant leading to poor prognosis. The best way to circumvent such carcinomas is early detection. This needs evolutionary understanding of the disease. Our work focuses on understanding the earliest stages of SOC, drivers of these changes and deciphering the mechanisms of prevention. To achieve this, we probe dysplasia and preneoplasia in the Fallopian tubes, which are one of the sites of origin of SOC. The Fallopian tube secretory epithelial cells (FTSEC) are the closest molecular phenotype to SOC. Secretory cell outgrowths (SCOUTS), p53 signatures and papillary tubal hyperplasia are the dysplastic lesions acting as precursors of SOC in the Fallopian tube epithelium (FTE). FTE is primarily constituted of secretory and ciliated cells and the ratio between these cells is key to maintaining homeostasis. The disruption of this balance is the first step to SOC. The secretory cell type dominates and outgrows ciliated cells leading to dysplasia. All three aforementioned preneoplasia are made up of secretory cells. We undertook molecular characterisation of these three lesions. The morphological and immunohistochemical aspects of the lesions are well charted. Through histopathological analysis, use of microdissection, next generation animal models and next generation sequencing we sought to characterise molecular nature of these lesions. We found that Wnt signalling pathway is the driver of SCOUTS. We have established an accurate mouse model by constitutive activation of β-Catenin specifically in the FTSECs. We have further used this model to probe the role of ovarian hormonal milieu in progression of HGSOC. We found progesterone mitigates progression of SCOUT lesions and oestrogen enhances this progression. This is the first mouse model to accurately mimic early serous ovarian carcinogenesis. By molecular probing of morphologically normal Fallopian tubes in a case of p53 null-omental high grade serous carcinoma three years post risk reducing salpingo oophorectomy (RRSO), we found tumour associated aberrations, specifically identical TP53 mutations in FTE before RRSO and the omental tumour. This establishes the clonal identity and proves the precursor escape model in pelvic serous ovarian carcinomas. Papillary tubal hyperplasia are known to be putative precursors for LGSOC, atypical endosalpingiosis (AES) in the peritoneum and also intermediate Serous Borderline tumours (SBT). They are the only known precursors in the FT. LGSC is also the closest to the FTSECs. As no molecular attributes were known, through Whole exome sequencing (WES) and RNA sequencing (RNASeq) we have characterised molecular aberrations and also have established them as precursors for the accompanying AES. Study of these three lesions suggests, salpingectomy can be a good preventive measure in at least patients with high risk of ovarian cancer incidence. Progesterone can also be used as an effective preventive measure.
- Subject
- ovarian cancer; cancer; early stage carcinogenesis; Wnt signalling; progesterone; preventive strategies of cancer; cell fate; cell regulation; genetic testing BRCA1; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1411191
- Identifier
- uon:36310
- Rights
- Copyright 2020 Prathima Bangaraswamaiah Nagendra
- Language
- eng
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| Thumbnail | File | Description | Size | Format | |||
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| View Details Download | ATTACHMENT01 | Thesis | 15 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 2 MB | Adobe Acrobat PDF | View Details Download |