植野 さやか

BACKGROUND: Comprehensive genomic profiling (CGP) has been used to identify mutations in several hundred cancer-related genes. Patients may receive treatment that targets specific genetic mutations revealed by CGP. This study aimed to investigate the usefulness of CGP in gynecologic malignancies. METHODS: Hospital records including CGP and clinical information were reviewed from 20 institutions in the Kinki District of Japan for patients with gynecological malignancies who underwent CGP. RESULTS: A total of 724 patients were included, of whom 162 had cervical cancer, 157 had endometrial cancer, 327 had ovarian cancer, 29 had other cancers, and 49 had sarcomas. Actionable gene alterations were identified in 370 (51.1%). The most commonly altered genes were PIK3CA (14.4%), high loss of heterozygosity (12.4%), and high tumor mutation burden (10.9%). Matched therapy, based on actionable gene alterations, was administered to 73 patients (10.1%). Of these, 23 patients received matched therapy for a high tumor mutation burden, 10 for high microsatellite instability and BRCA1/2, six for ERBB2, and five for PIK3CA. Twenty-five patients died before receiving their CGP results. The objective response and disease control rates were 23.6% and 41.8%, respectively. Of the 122 patients to whom genetic counseling was recommended, 68 accepted. CONCLUSIONS: CGP testing for gynecological malignancies in Japan may improve therapeutic efficacy. However, several issues remain to be addressed, including the low matched therapy rate and death prior to availability of CGP test results.

BACKGROUND: Cancer gene panel testing (CGP) helps comprehensively analyze a large number of genes, extracting genetic information from the genome profile to aid treatment plans and drug therapy. Advances in drug therapy and surgical treatment for intrahepatic cholangiocarcinoma (ICC) have improved patient outcomes; however, it remains a typical intractable cancer with a poor prognosis. ICC is one of the key tumors for which effective treatment may be identified through CGP testing. This study aimed to identify ICC harboring actionable genetic variants using contrast-enhanced ultrasonography (CE-US). METHODS: We enrolled 26 ICC patients who underwent CE-US before chemotherapy or surgery. Three ultrasound specialists reviewed the images by consensus and assessed the imaging features, including vascularity. Pathological data were reviewed after diagnosis using CE-US. We retrospectively analyzed distinctive CE-US findings in patients with ICC with actionable genetic variants. RESULTS: Twelve ICC patients had actionable gene variants, including four FGFR2 fusions, one FGFR2 rearrangement, six IDH1 mutations, and one BRAF V600E mutation. Univariate analysis showed significant differences in bile duct invasion (p = 0.0217) and blood vessel penetration within the tumor (p = 0.0012). Multivariable logistic regression identified blood vessel penetration within the tumor (OR = 18.275; 95% CI: 1.331-250.925; p = 0.0297) as independently associated with actionable gene variants. CONCLUSION: Patients with ICC and blood vessel penetration on CE-US should be considered for CGP testing.

Background/Objective: Ovarian cancer (OC) is one of the most lethal gynecological cancers, having a worldwide mortality rate of 66% in 2020. The overall 5-year relative survival rate is only 21% for distant stages, due to the lack of early diagnosis. Epithelial OC, the most common high-grade serous carcinoma, carries p53 mutations in most cases. However, we found that the immediate early response 5 gene (IER5), a p53 target gene, is overexpressed in ovarian cancer cells. The molecular mechanism underlying the role of IER5 in OC has not been well studied. We previously reported that IER5 promotes the dephosphorylation and activation of heat shock factor-1 (HSF1), the master regulator of proteostasis, which induces heat shock protein (HSP) expression. Methods/Results: Here we show that Ier5 mRNA expression is higher in ovarian cancer cells (MOV, ID8G, and HM-1) compared to normal ovarian cells. We also show that OC cells floating in the ascites have higher Ier5 expression than the parental strain. Knockdown of Ier5 suppressed HSP upregulation and proliferation of OC, while overexpression of IER5 promoted HSP upregulation. Knockdown of Hsf1 showed results similar to Ier5 knockdown. Conclusions: These results indicate that the IER5-HSF1 pathway contributes to the proliferation and peritoneal dissemination of OC cells. We also found that higher expression of IER5 family genes is related to poorer prognosis of OC patients, suggesting the potential of the IER5 gene family as diagnostic markers for OC, as well as potential therapeutic targets.

BRCA1/2 genetic testing has become clinically important in breast cancer care, but increasing demand may put a burden on the shortage of healthcare professionals. We performed a single-center, pilot randomized controlled study to assess the effectiveness of employing a video educational tool that included standard pre-test genetic counseling elements related to BRCA1/2. Patients with operable breast cancer who met the criteria for genetic testing based on age, sex, subtype, and family history were recruited. Sixty consenting participants were randomized 1:1 and placed in groups that received either traditional face-to-face pre-test counseling or video-viewing and face-to-face decisional support. To assess decisional conflict in the participants, surveys based on the Decisional Conflict Scale (DCS) were administered two times, once immediately after intervention and again 2-4 weeks later. The time taken for counseling and confirmation of whether the participants had undergone testing were also recorded. The difference in the total DCS scores between the two groups was not significantly different for either of the survey periods, and there was no significant difference in the number of participants who underwent testing (23/30 [76.7%] vs. 26/30 [86.7%]; p = 0.51). However, the "effective decision" subscale score was significantly higher in the video group 2-4 weeks after counseling (31.01 ± 16.82 vs. 21.43 ± 16.09; p = 0.04 [mean ± SD]). The time taken for counseling was significantly shorter in the video group (8.00 ± 4.5 vs. 27.00 ± 7.61 min; p < 0.001 [median ± SD]). Our findings indicate the potential benefit of the video educational tool for providing BRCA1/2-related information. These tools may also enable healthcare professionals to spend more time supporting psychological issues. Notably, after some time, patients may question whether their decision was appropriate. Therefore, it is necessary to identify those in conflict and provide them with proper support.

BACKGROUND/AIM: Certain germline pathogenic variants (PVs), known as founder mutations, have been frequently observed in specific regions and ethnic groups. In Japan, several pathogenic variants of BRCA1/2 have been identified as founder mutations, with their distribution varying across different regions. This retrospective study aimed to further investigate the detailed distribution and correlation between genotype and clinical features among breast cancer patients. PATIENTS AND METHODS: This study was conducted at Kobe University Hospital and three collaborating institutions. It included breast cancer patients who underwent BRCA1/2 genetic testing between July 1, 2018, and March 31, 2021, and were found to have germline PVs. Clinical characteristics and breast cancer subtypes were compared between carriers of BRCA2 c.5576_5579del and those with other PVs. Additionally, the detection rate of BRCA2 c.5576_5579del was compared with that observed in a previous report. RESULTS: A total of 38 breast cancer patients were included; PVs in BRCA1 and BRCA2 were detected in 12 and 26 patients, respectively, 12 of whom were BRCA2 c.5576_5579del carriers. BRCA2 c.5576_5579del carriers were more likely to develop triple negative breast cancers among all BRCA2 PV carriers. BRCA2 c.5576_5579del accounted for 30.8% of the PVs detected, with a particularly high frequency of 72.7% at Kakogawa Central City Hospital. CONCLUSION: BRCA2 c.5576_5579del was detected with a particularly high frequency in Hyogo Prefecture, especially in Kakogawa city. In the future, a survey of the distribution of the BRCA2 c.5576_5579del carriers may provide more clarity regarding their localization.

Peritoneal dissemination of ovarian cancer (OC) correlates with poor prognosis, but the mechanisms underlying the escape of OC cells from the intraperitoneal immune system have remained unknown. We here identify pigment epithelium-derived factor (PEDF) as a promoting factor of OC dissemination, which functions through induction of CD206+ Interleukin-10 (IL-10)-producing macrophages. High PEDF gene expression in tumors is associated with poor prognosis in OC patients. Concentrations of PEDF in ascites and serum are significantly higher in OC patients than those with more benign tumors and correlated with early recurrence of OC patients, suggesting that PEDF might serve as a prognostic biomarker. Bromodomain and extraterminal (BET) inhibitors reduce PEDF expression and limit both OC cell survival and CD206+ macrophage induction in the peritoneal cavity. Our results thus implicate PEDF as a driver of OC dissemination and identify a BET protein-PEDF-IL-10 axis as a promising therapeutic target for OC.

Ataxia-telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline ATM pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the ATM gene, function of ATM kinase, clinical significance of ATM germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients.

Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed syngeneic lymphoma model to demonstrate that downregulation of Fas is required for both lymphoma development and lymphoma cell survival to evade immune cytotoxicity. CD40 signal activation significantly restored Fas expression and thereby induced apoptosis after Fas ligand treatment in both mouse and human lymphoma cells. Nevertheless, certain human lymphoma cell lines were found to be resistant to Fas-mediated apoptosis, with Livin (melanoma inhibitor of apoptosis protein; ML-IAP) identified as a driver of such resistance. High expression of Livin and low expression of Fas were associated with poor prognosis in patients with aggressive non-Hodgkin's lymphoma. Livin expression was tightly driven by bromodomain and extraterminal (BET) proteins BRD4 and BRD2, suggesting that Livin expression is epigenetically regulated in refractory lymphoma cells to protect them from Fas-mediated apoptosis. Accordingly, the combination of CD40-mediated Fas restoration with targeting of the BET proteins-Livin axis may serve as a promising immunotherapeutic strategy for refractory B-cell lymphoma. SIGNIFICANCE: These findings yield insights into identifying risk factors in refractory lymphoma and provide a promising therapy for tumors resistant to Fas-mediated antitumor immunity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4439/F1.large.jpg.