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Dedifferentiated endometrial carcinoma (DDEC) is an aggressive endometrial cancer composed of two components: a well differentiated component and an undifferentiated component thought to arise clonally from the well differentiated component through dedifferentiation. In some cases, these tumours are presented as pure undifferentiated endometrial carcinomas (UECs) likely due to outgrowth of their undifferentiated components. A majority of DDECs and UECs are known to have defects in mismatch repair (MMR). They are also frequently deficient in components of SWItch/Sucrose Non-Fermentable (SWI/SNF) complexes, a family of chromatin remodelling complexes with roles in differentiation, and p53, both of which are known tumour suppressors. In this thesis, I assembled a cohort containing 88 DDEC/UEC cases, the largest cohort to date. The protein expression levels of SWI/SNF components, MMR, and p53 were evaluated by immunohistochemistry (IHC). Multiple SWI/SNF members were studied, including SMARCA4, ARID1A, ARID1B, SMARCB1, and SMARCA2 to determine the extent of the abnormality of SWI/SNF components and p53 in DDEC/UEC. The prognostic value of these mutations was also assessed. I found that SMARCA4/A2 dual loss, ARID1A/1B dual loss, and p53 abnormality occurred in 10/88 (11%), 25/88 (28%) and 53/87 (40%) cases, respectively. These three abnormality groups were not statistically associated in DDEC/UEC, representing distinct subgroups of DDEC/UECs. In addition, these defects occurred more frequently in the undifferentiated component, suggesting that they have roles in histologic dedifferentiation. However, neither SWI/SNF, MMR, nor p53 abnormality were found to be prognostic of survival. Lastly, the effect of ARID1B re-expression on the transcriptomes of ARID1A/1B dual deficient undifferentiated endometrial cancer cell lines was analyzed, to identify molecular pathways by which ARID1B loss may drive dedifferentiation. ARID1B re-expression did not consistently result in the upregulation of gene sets associated with differentiation across the two cell lines examined, indicating that the loss of ARID1B in an ARID1A-deficient context may not be sufficient to drive dedifferentiation in vitro. |
