Yoshiro Otsuki

Exploring the Genetic and Clinical Landscape of Dedifferentiated Endometrioid Carcinoma

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.

Promising Therapeutic Impact of a Selective Estrogen Receptor Downregulator, Fulvestrant, as Demonstrated In Vitro upon Low-Grade Serous Ovarian Carcinoma Cell Lines

Few studies have reported hormonal agent use in the treatment of low-grade serous ovarian carcinomas (LGSOCs), which are chemoresistant. Considering the need for novel effective therapies, we investigated the hormone receptor expression and hormonal inhibition efficacy in LGSOCs. Using immunohistochemistry, we assessed the estrogen receptor (ER) expression status in 33 cases of histologically confirmed serous ovarian tumors, including 10, 11, and 12 cases of LGSOCs, serous borderline tumors (SBTs), and serous cystadenomas (SCAs), respectively. The genetic background reported in our previous study was used in the current study. MPSC1 cells, which were established from LGSOCs, were used in cell proliferation assays. We observed a higher ER expression in LGSOCs and SBTs than in SCAs (70%, 81%, and 50%, respectively). Thus, LGSOCs and SBTs exhibit higher ER expression than SCAs. Moreover, the PIK3CA mutation positively correlated with ER expression in LGSOCs (p = 0.0113). MPSC1 cells showed low ER expression on Western blotting. MPSC1 cell proliferation was significantly inhibited by fulvestrant (a selective ER downregulator). The activation of ER and PI3K/AKT signaling pathways may play an important role in LGSOC carcinogenesis. ER downregulation with fulvestrant or combination therapy with PI3K inhibitors is a possible novel treatment for patients with LGSOCs.

Mutation Profiles of Ovarian Seromucinous Borderline Tumors in Japanese Patients

Ovarian seromucinous tumors (SMBTs) are relatively rare, and their carcinogenesis is largely unknown. In this study, the molecular features of SMBTs in Japan are assessed. DNA was extracted from microdissected paraffin-embedded sections from 23 SMBT cases. Genetic mutations (KRAS, BRAF, PIK3CA, and ERBB2) were evaluated using Sanger sequencing. Immunohistochemistry for p53, ARID1A, and PTEN was also performed as a surrogate for the loss of functional mutations in these tumor suppressor genes. The prevalence of KRAS, BRAF, PIK3CA, and ERBB2 mutations was 4.3% (1/23), 8.6% (2/23), 8.6% (2/23), and 17.3% (4/23), respectively. Overexpression or loss of p53 expression occurred in 26% (6/23), loss of ARID1A expression in 4.3% (1/23), and none of the cases showed expression of PTEN loss. These findings suggest that KRAS/BRAF/PIK3CA and PTEN mutations are rare carcinogenic events in SMBTs. The high frequency of positive p53 staining and a low frequency of loss of ARID1A staining suggests that SMBT carcinogenesis may be related to the alteration of p53 rather than that of ARID1A. ERBB2 oncogenic mutations may play an important role in the tumorigenesis of Japanese SMBTs.