Exploring the Genetic and Clinical Landscape of Dedifferentiated Endometrioid Carcinoma

TL;DR

This study explores the genetic and clinical features of dedifferentiated endometrioid carcinoma in Japanese patients to improve treatment strategies.

Contribution

The study identifies distinct genetic mutations and potential targeted therapies for dedifferentiated endometrioid carcinoma.

Findings

DDEC had a 5-year progression-free survival of 40% and overall survival of 30%.

p53 mutations were more common and linked to poor prognosis in undifferentiated components.

Genetic differences between well-differentiated and undifferentiated components suggest varied therapeutic approaches.

Abstract

Dedifferentiated endometrioid carcinoma (DDEC) is rare, has a poor prognosis, and the genes responsible for dedifferentiation remain unclear. This study aimed to clarify the characteristics of DDEC in Japanese patients and develop treatment strategies. Eighteen DDEC cases were included; their clinicopathological features and prognoses were analyzed and compared to those of other histological subtypes. The samples were divided into well-differentiated and undifferentiated components; immunostaining and whole-exome sequencing (n = 3 cases) were conducted. The incidence of DDEC was 2.0% among endometrial cancers. The 5-year progression-free survival and the 5-year overall survival for DDEC was approximately 40% and 30%, respectively. Immunohistochemistry showed that 66.7% of patients were mismatch repair deficient. The rate of p53 mutations was higher than that reported in previous studies, and patients with p53 mutations in the undifferentiated components had a poor prognosis. Whole-exome sequencing revealed different gene mutations and mutation signatures between well-differentiated and undifferentiated components. New genetic mutations in undifferentiated regions were uncommon in all three cases. One case (case 1) exhibited homologous recombination deficiency, whereas the other two showed microsatellite instability-high and hypermutator phenotypes. Genetic analysis suggests that immune checkpoint and poly (ADP-ribose) polymerase inhibitors and drugs targeting the p53 pathway may be effective against DDEC.

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