Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Author:
Doulgeraki Triada
Dissertation committee:
Αικατερίνη Παυλάκη, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Χρίστος Παπαδημητρίου, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Αφροδίτη Νόννη, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Χαρίκλεια Γακιοπούλου, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Αλέξανδρος Ροδολάκης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Δημήτρης Χαιδόπουλος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Γιώργος Αγρογιάννης, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Original Title:
Η σημασία της μικροδορυφορικής αστάθειας (MSI) σε χαμηλής διαφοροποίησης αδενοκαρκινώματα του ενδομητρίου
Translated title:
Mismatch repair status in high-grade endometrial carcinomas of endometrioid and non-endometrioid type
Summary:
Purpose
Mismatch repair deficiency (MMRd) as a result of dysfunction of the genes responsible for DNA repair damage, namely MLH1, PMS2, MSH2 and MSH6, leads to the development of microsatellite instability (MSI). Carcinomas with microsatellite instability are one of the four molecular subtypes of endometrial cancer, according to the new classification by the Cancer Genome Atlas (TCGA) group, and they represent about 30% of endometrial cancer cases and are considered carcinomas of intermediate risk. Given that grade 3 carcinomas have more often an aggressive biological behaviour and a higher probability of metastatic disease, we considered it important to study microsatellite instability in this group of carcinomas. We also found important to include all histological types that consist this group, and to compare the expression of MMR proteins with the presence of wild type or abnormal p53 expression. The aim is to determine whether microsatellite instability alone or in relation to p53 expression could affect the biological behaviour of poorly differentiated endometrial carcinomas. In addition, it is very possible that these patients could benefit from a treatment targeting to inhibit the action of molecules associated with programmed cell death.
Methods
Candidates for inclusion in the present research protocol were women who had been diagnosed and treated with poorly differentiated (grade 3) endometrial cancer from 2001 to 2017 at the specialized Gynaecological Oncology Department of IASO Gynaecology Hospital. The collection and analysis of a variety of clinical and pathologic characteristics was carried out, following by the evaluation of the immunohistochemical expression of the four mismatch repair proteins, MLH1, PMS2, MSH2 and MSH6, as well as the expression of p53. Statistical analysis was performed with the statistical program SPSS version 23.0 (Armonk, NY).
Results
The final population of the study consists of 101 cases, of which 41 cases were endometrioid, while 60 were non-endometrioid carcinomas. The majority of MMRd tumors were of endometrioid type (73.3%), while MMR proficient (MMRp) cases were mainly of non-endometrioid histological type (73.8%) (p<0.001). Analysing histological types separately, endometrioid MMRd tumors were found to be statistically significantly associated with increased depth of myometrial invasion, lymph node metastases and advanced stage of disease (p=0.035, p=0.011 and p=0.028, respectively). Survival analysis revealed no statistically significant difference between MMR protein expression and outcome. Adjuvant therapy was not found to affect disease progression. When examining the MMR proteins separately, loss of MSH6 expression was found to be statistically significantly associated with lymph node metastases (p=0.04), while loss of expression of PMS2 and MLH1 with increased depth of myometrial invasion (p=0.019 and p =0.036, respectively). Finally, the presence of mutated p53 does not seem to negatively affect the biological behaviour of MMRd carcinomas.
Conclusions
In our group of high-grade endometrial car¬cinomas, MMR deficiency was statistically significantly more frequent in endometrioid than in non-endometrioid cancers. In addition, endometrioid MMRd carcinomas appear to be associated with features of aggressive disease but do not show worse survival when compared to MMRp carcinomas. Our findings support the two-protein testing algorithm compared to staining of all four proteins. The failure to identify a negative prognostic significance in p53 mutated MMRd carcinomas is compatible with what would be expected based on the “multiple classifier” theory.
Main subject category:
Health Sciences
Keywords:
Endometrial cancer, Microsatellite instability, Mismatch repair deficiency, Immunohistochemistry
Number of references:
184
