Relation between MAD1 expression and chemosensitivity in High Grade Serous Ovarian Cancer.

Groot, I. de (Ietsen) (2017) Relation between MAD1 expression and chemosensitivity in High Grade Serous Ovarian Cancer. thesis, Medicine.

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Abstract

The relative low 5 year survival (30%) in high grade serous ovarian cancer (HGSOC) patients is partially due to resistance against chemotherapy. This makes chemosensitivity the main area of research in HGSOC. In this report we aimed to validate the result of an in silico study, in which high expression of the MAD1L1 gene was correlated with reduced progression free survival (PFS) (a marker for chemorespons) in HGSOC. MAD1L1 encodes for the MAD1 protein, which is known to play a role in the spindle assembly checkpoint. We performed immunohistochemistry for the MAD1 protein on tumor tissue of HGSOC pa-tients, treated with platinum based chemotherapy, using a tissue microarray. Tumor tissue was collected form patients undergoing first surgery followed by chemotherapy (primary surgery (PS)) or from patients undergoing first 3 cycles of chemotherapy followed by surgery (neoad-juvant chemotherapy (NACT)). We showed that tumors of the NACT cohort had a higher expression of MAD1, compared to tumors of the PS cohort. In the PS cohort, high expression of MAD1 was associated with reduced PFS for patients with residual tissue after surgery. We were not able to associate the expression of MAD1 with PFS in the NACT cohort. Further-more, in HGSOC cell lines we were not able to show an in vitro association of the protein levels of MAD1 or MAD2, or the MAD1:MAD2 ratio with chemosensitivity. Silencing of MAD1L1 gene reduced cell growth and caused more apoptotic cells in PEA2, a HGSOC cell line. However, we were not able to affect the chemosensitivity to paclitaxel or cisplatin in PEA2 after silencing MAD1L1 gene. In conclusion, we found that the MAD1 protein was associated with reduced PFS in vivo in patients with residual tissue after primary surgery, and that the MAD1L1 gene was essential for cell survival in vitro. Further research is necessary to functionally validate the MAD1L1 gene or MAD1 protein on chemosensitivity in vitro.

Item Type:	Thesis (Thesis)
Supervisor name:	Supervised by and Wisman, Bea and Tomar, Tushar and Jong, & Steven de and Department of Gynecologic Oncology [UMCG]
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:52
Last Modified:	25 Jun 2020 10:52
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/1347

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