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DeGrood, Maya Kevorkova

University of British Columbia

Endometrial cancer is the most common gynecologic malignancy in Canada with increasing rates of both incidence and mortality. Historically, histopathological subtyping of endometrial cancer was employed but was determined to be less than accurate at patient risk stratification. Recent advances in molecular subtyping have revealed mismatch repair deficient endometrial cancer as the second most deadly subtype. Mismatch repair deficient endometrial cancers may be acquired through somatic or germline aberrations to the four mismatch DNA repair genes: MLH1, PMS2, MSH2, and MSH6. Germline mutations to mismatch DNA repair genes results in Lynch Syndrome, an autosomal dominant hereditary cancer predisposition syndrome which increases the risk of endometrial cancer in affected individuals, however, the pathogenesis of Lynch Syndrome associated endometrial cancer has yet to be fully elucidated. To investigate the early pathogenic events following the introduction of MLH1 and PMS2 deficiencies, both in vivo and ex vivo models were utilized. A cohort (n = 6) of archival FFPE tissues, taken from prophylactic hysterectomies performed for Lynch Syndrome patients with germline MLH1 and PMS2 mutations, were immunohistochemically profiled for mismatch repair deficient endometrial glands. MLH1 deficient benign endometrial glands were identified in four cases with a novel report of zonal MLH1 deficient benign endometrial glands. In one case with zonal MLH1 deficient endometrial glands, multiplex immunohistochemical staining based panel was used to quantify endometrial epithelial cell differentiation by examination of secretory, ciliated, and proliferative cell types in both MLH1 proficient and deficient endometrial glands where no significant difference in cell type proportion was observed. MLH1 and PMS2 deficient endometrial organoid models were established using benign hysterectomy tissues and CRISPR-Cas9 mediated gene editing. Single cell RNA sequencing of MLH1 and PMS2 deficient endometrial organoids revealed no significant alterations in MLH1 deficient organoid cells and slight alterations to epithelial mesenchymal transition genes in PMS2 deficient organoids. Altogether, this data suggests that mismatch repair deficiency does not result in immediate changes to gene expression or cell differentiation in endometrial glands and that progression towards endometrial cancer is reliant on the accumulation of mutations.

Text

2023-01-03

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83545

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/