Details of a Researcher - Masuda, Kenta

Papers - Masuda, Kenta

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Japanese society for cancer of the colon and rectum (JSCCR) guidelines 2024 for the clinical practice of hereditary colorectal cancer.

Tanakaya K, Yamaguchi T, Hirata K, Yamada M, Kumamoto K, Akiyama Y, Ishimaru K, Okamoto K, Kawasaki Y, Komine K, Sakamoto A, Shigeyasu K, Shibata Y, Shimamoto Y, Shimodaira H, Sekine S, Takao A, Takao M, Takamizawa Y, Takeuchi Y, Tanabe N, Taniguchi F, Chino A, Cho H, Doi S, Nakajima T, Nakamori S, Nakayama Y, Nagasaki T, Hasumi H, Banno K, Hinoi T, Fujiyoshi K, Horimatsu T, Masuda K, Miguchi M, Mizuuchi Y, Miyakura Y, Mutoh M, Yoshioka T, Tanaka S, Sakamoto K, Sakamaki K, Itabashi M, Ishida H, Tomita N, Sugihara K, Ajioka Y, Japanese Society for Cancer of the Colon, Rectum

International journal of clinical oncology 2025.11

ISSN 1341-9625

Approximately 5% of all colorectal cancers have a strong genetic component and are classified as hereditary colorectal cancer (HCRC). Some of the unique features commonly seen in HCRC cases include early age of onset, synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics require different management approaches, including diagnosis, treatment or surveillance, from those used in the management of sporadic colorectal cancer. Accurate diagnosis of HCRC is essential because it enables targeted surveillance and risk reduction strategies that improve patient outcomes. Recent genetic advances revealed several causative genes for polyposis and non-polyposis syndromes. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) first published guidelines for the management of HCRC in 2012, with subsequent revisions every 4 years. The 2024 update to the JSCCR guidelines for HCRC was developed by meticulously reviewing evidence from systematic reviews and the consensus of the JSCCR HCRC Guidelines Committee, which includes representatives from patient advocacy groups for FAP and Lynch syndrome. These guidelines provide an up-to-date summary of HCRC, along with clinical recommendations for managing FAP and Lynch syndrome.

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Current Situation and Future Directions of Risk-reducing Salpingo-oophorectomy.

Kenta Masuda, Yusuke Kobayashi, Tomoko Seki, Tomoko Yoshihama, Kohei Nakamura, Yumiko Goto, Mamiko Yamada, Aiko Nagayama, Sayaka Uchida, Ikumi Ono, Kumiko Misu, Megumi Yokota, Wataru Yamagami

The Keio journal of medicine 74 ( 3 ) 138 - 145 2025.09

Lead author, Corresponding author, Accepted, ISSN 0022-9717

High-grade serous carcinoma (HGSC), the most aggressive subtype of epithelial ovarian cancer, is strongly associated with hereditary breast and ovarian cancer (HBOC) syndrome and is primarily linked to germline BRCA1/2 pathogenic variants (PVs). The cumulative risks of ovarian cancer by the age of 70 years are 40% and 18% for carriers of BRCA1 and BRCA2 PVs, respectively. Risk-reducing salpingo-oophorectomy (RRSO) is a recommended preventive strategy that reduces the risk of ovarian cancer by more than 80% and may improve overall survival. However, surgical menopause after RRSO poses several challenges, including infertility and hormonal deficiency. Although the use of hormone replacement therapy may alleviate symptoms, it requires careful consideration of breast cancer risk. Emerging strategies, such as prophylactic salpingectomy with delayed oophorectomy, are being investigated to balance cancer prevention and patient quality of life. Further research is required to refine personalized prevention and management approaches for HBOC-associated ovarian cancer.

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The Keio HBOC Center: A Model of Hereditary Breast and Ovarian Cancer Management.

Yusuke Kobayashi, Kenta Masuda, Tomoko Seki, Takeo Kosaka, Minoru Kitago, Ikumi Ono, Kumiko Misu, Arisa Ueki, Tomoko Yoshihama, Aiko Nagayama, Yota Yasumizu, Yumiko Goto, Kohei Nakamura, Mamiko Yamada, Megumi Yokota, Sayaka Uchida, Mari Takeuchi, Takeru Funakoshi, Wataru Yamagami

The Keio journal of medicine 74 ( 3 ) 124 - 129 2025.09

ISSN 0022-9717

The management of hereditary breast and ovarian cancer (HBOC) in Japan has changed drastically with the expansion of indications for poly ADP-ribose polymerase inhibitors, the increase in diagnostic opportunities with the spread of companion diagnoses, and partial insurance coverage of HBOC management. These circumstances require a response that is coordinated across the entire hospital rather than from individual departments. In April 2021, we established the HBOC Center, which is operated by nine departments: Obstetrics and Gynecology, Reproduction, Surgery (breast group, hepato-pancreato-biliary group), Urology, Dermatology, Neuropsychiatry, the Center for Medical Genetics, and the Cancer Center. In addition to discussions of individual cases, our monthly conferences have enabled us to establish indication criteria and appropriate items for surveillance, visualize the examination flow in the hospital, construct a patient database, and provide open lectures to educate the public. The future HBOC management system should not only fulfill the existing requirements for risk-reducing surgery and facility standards but also offer comprehensive and diversified attention based on the needs of patients and their family members.

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Pancreatic Cancer in Hereditary Breast and Ovarian Cancer Syndrome: Is Early Detection Possible?

Kodai Abe, Minoru Kitago, Yusuke Kobayashi, Kenta Masuda, Tomoko Seki, Mamiko Yamada, Yumiko Goto, Ikumi Ono, Kumiko Misu, Kohei Nakamura, Yuko Kitagawa

The Keio journal of medicine 74 ( 3 ) 146 - 150 2025.09

ISSN 0022-9717

A program of recruiting families with hereditary pancreatic cancer and hereditary breast and ovarian cancer (HBOC) syndrome as high-risk individuals for pancreatic cancer surveillance using magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) has proven effective, resulting in the improvement of early detection rates and life expectancy. Given this, recent guidelines recommend pancreatic surveillance for patients with familial pancreatic cancer and pathological variants of ten genes, including BRCA1/2. In April 2021, our hospital established the HBOC Center, which is operated by nine departments, including obstetrics and gynecology, breast surgery, pancreatology, urology, medical genetics, dermatology, psychiatry and neurology, and oncology. Currently, MRCP or EUS is performed once or twice a year in 63 cases with pathogenic variants in 54 families. Although 4 cases (6.3%) revealed pancreatic microcysts or branched intraductal papillary mucinous neoplasms, no sign of pancreatic cancer was detected. Since January 2021, the germline BRCA1/2 test for companion diagnosis of pancreatic cancer has been covered by insurance, improving the accessibility of genetic testing among patients with pancreatic cancer. However, the BRCA1/2 positivity rate remains low at 1.3%, and its indication for use is very limited. The implementation of genetic testing, including BRCA1/2 analysis, is necessary for the prevention and early detection of pancreatic cancer in high-risk families.

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Exploring Breast Cancer Risk Management in HBOC Patients: Image Surveillance Versus Risk-reducing Surgery.

Tomoko Seki, Yusuke Kobayashi, Kenta Masuda, Kohei Nakamura, Mamiko Yamada, Yumiko Goto, Kumiko Misu, Ikumi Ono, Aiko Nagayama, Tetsu Hayashida, Yuko Kitagawa

The Keio journal of medicine 74 ( 3 ) 130 - 137 2025.09

ISSN 0022-9717

In Japan, the rising incidence of hereditary breast and ovarian cancer syndrome (HBOC) follows partial insurance coverage introduced in 2020. Compared with the general population (~11% lifetime risk), individuals with HBOC face a significantly higher lifetime risk of breast cancer (48%-76%), often presenting at younger ages. BRCA1 mutations are linked to triple-negative breast cancer, whereas BRCA2 mutations typically result in luminal-type disease. Key risk management strategies include surveillance and prophylactic surgery. Annual magnetic resonance imaging and mammography are recommended at younger ages than in the general population, despite concerns regarding contrast agents, radiation exposure, and examination-related burdens. Although risk-reducing mastectomy lowers breast cancer risk by over 90%, it remains underutilized because of cosmetic and psychological considerations. Nipple-sparing or skin-sparing mastectomy combined with immediate or delayed reconstruction offers a balance between risk reduction and postoperative outcomes, although safety and procedure details still warrant careful evaluation. Managing the high breast cancer risk associated with HBOC requires ongoing efforts to refine current strategies while minimizing patient burden.

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Clinical Sequence Revealed the Prevalence and Biological Significance of Somatic Pathogenic Variants in Thoracic Cancer: Implications for Germline Status.

Takahiro Fukushima, Kohei Nakamura, Hideki Terai, Keiko Ohgino, Ryutaro Kawano, Marin Ishikawa, Katsura Emoto, Hatsuyo Takaoka, Ayaka Saito, Fumimaro Ito, Shigenari Nukaga, Shinnosuke Ikemura, Ichiro Kawada, Kenta Masuda, Hiroyuki Yasuda, Hajime Okita, Keisuke Asakura, Kenzo Soejima, Kenjiro Kosaki, Hiroshi Nishihara, Koichi Fukunaga

Clinical lung cancer 26 ( 5 ) 407 - 419.e20 2025.07

ISSN 1525-7304

PURPOSE: Presumed germline pathogenic variants (PGPVs) are occasionally detected in thoracic cancer and their frequency and functional significance remain underexplored. We investigated the prevalence and biological significance of PGPVs identified in comprehensive genomic profiling (CGP) panels in patients with thoracic cancer. PATIENTS AND METHODS: Between January 2021 and August 2023, 204 patients with thoracic cancer were included in this study. A somatic cancer genomic profile system-FoundationOne CDx or an in-house system (Rapid-Neo)-was used for next-generation sequencing-based cancer gene panel tests. Potential PGPVs were identified by evaluating the variant allele frequency (VAF; cutoff > 10%) and pathogenicity based on ClinVar. RESULTS: PGPVs were detected at a frequency of 9.7% from cohort 1 and 8.1% from cohort 2 in thoracic cancer, based on real-world comprehensive genomic profiling panel testing. Copy number plot did not indicate any homologous recombination deficiency patterns in cases with BRCA1, BRCA2, and RAD51D pathogenic variants in thoracic cancer compared with those in hereditary breast and ovarian cancers. Only one hit of MSH6 pathogenic germline variant was observed for lung cancer tissue in the case of Lynch syndrome; therefore, high tumor mutational burden/microsatellite instability or mismatch repair deficiency was not observed, unlike that in endometrial cancer tissue in the same individual. CONCLUSION: This study underscores the importance of identifying PGPVs through CGP testing conducted in patients with thoracic cancer. Using frequency and functional analysis. Further investigation is warranted regarding the clinical significance of these PGPVs in managing patients with thoracic cancer and their families.

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LCN2-mediated ferroptosis resistance in tissue homeostasis and early-stage tumorigenesis of the fallopian tube epithelium.

Keiyo Imaeda, Tomohiro Tamura, Shimpei Nagai, Eiji Sugihara, Juntaro Yamasaki, Yuji Otsuki, Kohei Nakamura, Takashi Takeda, Kanako Nakamura, Yuya Nogami, Kosuke Tsuji, Tatsuyuki Chiyoda, Iori Kisu, Yusuke Kobayashi, Kouji Banno, Rui Yamaguchi, Kazuhiro Sakurada, Hideyuki Saya, Daisuke Aoki, Ahmed Ashour Ahmed, Osamu Nagano, Kenta Masuda, Wataru Yamagami

iScience 28 ( 6 ) 112654 - 112654 2025.06

Corresponding author, Accepted

While the fallopian tube epithelium (FTE) is known to be composed of various differentiated cells such as secretory and ciliated cells, the upstream regulatory mechanisms of cell differentiation that are essential for tissue homeostasis remain under investigation. In this study, we established human FTE organoids and identified quiescent cells within the early organoid formation by observing cellular proliferation heterogeneity. We also analyzed two single-cell transcriptomic data to trace the differentiation trajectory in human FTE, and found that the gene LCN2 serves as a marker gene of early stage of the trajectory. Genetically manipulated FTE organoids indicated that LCN2 inhibits ferroptosis and promotes cell survival under oxidative stress. In addition, the FTE organoids introduced p53 dysfunction, the common genetic characteristics of high-grade serous carcinoma, showed upregulated LCN2 expression and enhanced ferroptosis resistance. This study provides insights into the LCN2-mediated protective mechanism of human FTE quiescent cells and its potential role in tumorigenesis.

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mTOR-mediated p62/SQSTM1 stabilization confers a robust survival mechanism for ovarian cancer

Tomohiro Tamura, Shimpei Nagai, Kenta Masuda, Keiyo Imaeda, Eiji Sugihara, Juntaro Yamasaki, Miho Kawaida, Yuji Otsuki, Kentaro Suina, Hiroyuki Nobusue, Tomoko Akahane, Tatsuyuki Chiyoda, Iori Kisu, Yusuke Kobayashi, Kouji Banno, Kazuhiro Sakurada, Hajime Okita, Rui Yamaguchi, Ahmed Ashour Ahmed, Wataru Yamagami, Hideyuki Saya, Daisuke Aoki, Osamu Nagano

Cancer Letters (Elsevier BV) 616 217565 - 217565 2025.04

Corresponding author, Accepted, ISSN 0304-3835

Over 50 % of patients with high-grade serous carcinoma (HGSC) are homologous recombination proficient, making them refractory to platinum-based drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. These patients often develop progressive resistance within 6 months after primary treatment and tend to die early, thus new therapies are urgently needed. In this study, we comprehensively investigated this tumor type by leveraging a combination of machine learning analysis of a large published dataset and newly developed genetically engineered HGSC organoid models from murine fallopian tubes. Aberrant activation of RAS/PI3K signaling was a signature of poor prognosis in BRCA1/2 wild-type ovarian cancer, and mTOR-induced elevated p62 expression was a robust marker of chemotherapy-induced mTOR-p62-NRF2 signal activation. mTOR inhibition with everolimus decreased p62 and enhanced sensitivity to conventional chemotherapy, indicating that p62 serves as an important biomarker for therapeutic intervention. Combination therapy with conventional chemotherapy and mTOR inhibitors is a promising therapeutic strategy for refractory HGSC, with p62 as a biomarker.

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<i>BRCA1/2</i> reversion mutations in a pan‐cancer cohort

Kohei Nakamura, Hideyuki Hayashi, Ryutaro Kawano, Marin Ishikawa, Eriko Aimono, Takaaki Mizuno, Hajime Kuroda, Yasuyuki Kojima, Naoki Niikura, Aya Kawanishi, Kei Takeshita, Shinsuke Suzuki, Shinichi Ueno, Kosuke Okuwaki, Jiichiro Sasaki, Masatoshi Yamaguchi, Kenta Masuda, Tatsuyuki Chiyoda, Wataru Yamagami, Chihiro Okada, Sachio Nohara, Shigeki Tanishima, Hiroshi Nishihara

Cancer Science (Wiley) 115 ( 2 ) 635 - 647 2024.02

ISSN 1347-9032

Abstract

Tumor sensitivity to platinum (Pt)‐based chemotherapy and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors is increased by homologous recombination deficiency‐causing mutations; in particular, reversion mutations cause drug resistance by restoring protein function. Treatment response is predicted by breast cancer susceptibility gene 1/2 (BRCA1/2) mutations; however, BRCA1/2 reversion mutations have not been comprehensively studied in pan‐cancer cohorts. We aimed to characterize BRCA1/2 reversion mutations in a large pan‐cancer cohort of Japanese patients by retrospectively analyzing sequencing data for BRCA1/2 pathogenic/likely pathogenic mutations in 3738 patients with 32 cancer types. We identified somatic mutations in tumors or circulating cell‐free DNA that could restore the ORF of adverse alleles, including reversion mutations. We identified 12 (0.32%) patients with somatic BRCA1 (n = 3) and BRCA2 (n = 9) reversion mutations in breast (n = 4), ovarian/fallopian tube/peritoneal (n = 4), pancreatic (n = 2), prostate (n = 1), and gallbladder (n = 1) cancers. We identified 21 reversion events—BRCA1 (n = 3), BRCA2 (n = 18)—including eight pure deletions, one single‐nucleotide variant, six multinucleotide variants, and six deletion–insertions. Seven (33.3%) reversion deletions showed a microhomology length greater than 1 bp, suggesting microhomology‐mediated end‐join repair. Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP‐inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt‐based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and BRCA1 reversion mutations had no history of either treatment. Although reversion mutations commonly occur in BRCA‐associated cancers, our findings suggest that reversion mutations due to Pt‐chemotherapy might be correlated with BRCA1/2‐mediated tumorigenesis even in non‐BRCA‐associated histologies.

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Evaluation of the one-step nucleic acid amplification assay for detecting lymph node metastasis in patients with cervical and endometrial cancer: A multicenter prospective study.

Togami S, Tanimoto A, Yanazume S, Tokunaga H, Nagai T, Watanabe M, Yahata H, Asanoma K, Yamamoto H, Tanaka T, Ohmichi M, Yamada T, Todo Y, Yamada R, Kato H, Yamagami W, Masuda K, Kawaida M, Niikura H, Moriya T, Kobayashi H

Gynecologic oncology 170 70 - 76 2023.03

ISSN 0090-8258

Objective: This multicenter study aimed to evaluate the accuracy of the one-step nucleic acid amplification (OSNA) assay in diagnosing lymph node metastasis (LNM) in patients with cervical and endometrial cancers. Methods: Surgically removed LNs from patients with cervical and endometrial cancer were sectioned at 2-mm intervals along the short axis direction and alternately examined using the OSNA assay and conventional histopathological examination. Ultrastaging (200-μm LN sections) was performed for metastatic LNs using hematoxylin and eosin staining and immunostaining with an anti-CK19 antibody in cases where the OSNA assay and histopathological examination (performed using 2-mm LN sections) results showed discordance. Results: A total of 437 LNs from 133 patients were included; 61 patients (14%) showed metastasis by histopathological examination, with a concordance rate of 0.979 (95% confidence interval [CI]: 0.961–0.991) with the OSNA assay. The sensitivity and specificity of the OSNA assay were 0.918 (95% CI: 0.819–0.973) and 0.989 (95% CI: 0.973–0.997), respectively. Discordance between the two methods was observed in nine LNs (2.1%), and allocation bias of metastatic foci was identified as the major cause of discordance. Conclusions: The OSNA assay showed equally accurate detection of LN metastasis as the histopathological examination. We suggest that the OSNA assay may be a useful tool for the rapid intraoperative diagnosis of LN metastasis in patients with cervical and endometrial cancers.

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Current status of hereditary breast and ovarian cancer practice among gynecologic oncologists in Japan: a nationwide survey by the Japan Society of Gynecologic Oncology (JSGO).

Yusuke Kobayashi, Kenta Masuda, Akira Hiraswa, Kazuhiro Takehara, Hitoshi Tsuda, Yoh Watanabe, Katsutoshi Oda, Satoru Nagase, Masaki Mandai, Aikou Okamoto, Nobuo Yaegashi, Mikio Mikami, Takayuki Enomoto, Daisuke Aoki, Hidetaka Katabuchi

Journal of gynecologic oncology 33 ( 5 ) e61 2022.09

ISSN 2005-0380

OBJECTIVE: The practices pertaining to hereditary breast and ovarian cancer (HBOC) in Japan have been rapidly changing owing to the clinical development of poly(ADP-ribose) polymerase inhibitors, the increasing availability of companion diagnostics, and the broadened insurance coverage of HBOC management from April 2020. A questionnaire of gynecologic oncologists was conducted to understand the current status and to promote the widespread standardization of future HBOC management. METHODS: A Google Form questionnaire was administered to the members of the Japan Society of Gynecologic Oncology. The survey consisted of 25 questions in 4 categories: respondent demographics, HBOC management experience, insurance coverage of HBOC management, and educational opportunities related to HBOC. RESULTS: A total of 666 valid responses were received. Regarding the prevalence of HBOC practice, the majority of physicians responded in the negative and required human resources, information sharing and educational opportunities, and expanded insurance coverage to adopt and improve HBOC practice. Most physicians were not satisfied with the educational opportunities provided so far, and further expansion was desired. They remarked on the psychological burdens of many HBOC managements. Physicians reported these burdens could be alleviated by securing sufficient time to engage in HBOC management, creating easy-to-understand explanatory material for patients, collaboration with specialists in genetic medicine, and educational opportunities. CONCLUSION: Gynecologic oncologists in Japan are struggling to deal with psychological burdens in HBOC practice. To promote the clinical practice of HBOC management, there is an urgent need to strengthen human resources and improve educational opportunities, and expand insurance coverage for HBOC management.

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TP53 variants in p53 signatures and the clonality of STICs in RRSO samples.

Tomoko Akahane, Kenta Masuda, Akira Hirasawa, Yusuke Kobayashi, Arisa Ueki, Miho Kawaida, Kumiko Misu, Kohei Nakamura, Shimpei Nagai, Tatsuyuki Chiyoda, Wataru Yamagami, Shigenori Hayashi, Fumio Kataoka, Kouji Banno, Kokichi Sugano, Hajime Okita, Kenjiro Kosaki, Hiroshi Nishihara, Daisuke Aoki

Journal of gynecologic oncology 33 ( 4 ) e50 2022.07

Corresponding author, Accepted, ISSN 2005-0380

OBJECTIVE: Precursor lesions may be identified in fallopian tube tissue after risk-reducing salpingo-oophorectomy (RRSO) in patients with pathogenic variants of BRCA1/2. Serous tubal intraepithelial carcinoma (STIC) is considered a precursor of high-grade serous carcinoma, whereas the significance of the p53 signature remains unclear. In this study, we investigated the relationship between the p53 signature and the risk of ovarian cancer. METHODS: We analyzed the clinicopathological findings and conducted DNA sequencing for TP53 variants of p53 signatures and STIC lesions isolated using laser capture microdissection in 13 patients with pathogenic variants of BRCA1/2 who underwent RRSO and 17 control patients with the benign gynecologic disease. RESULTS: TP53 pathogenic variants were detected significantly higher in RRSO group than control (p<0.001). No difference in the frequency of p53 signatures were observed between groups (53.8% vs 29.4%; p=0.17). TP53 sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 TP53 mutations causing different p53 staining for STICs and another TP53 mutation shared between STIC and occult cancer. CONCLUSION: The sequence analysis for TP53 revealed 2 types of p53 signatures, one with a risk of progression to STIC and ovarian cancer with pathological variants in TP53 and the other with a low risk of progression without pathological variants in TP53 as seen in control.

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SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers.

Zhen Lu, Weiqun Mao, Hailing Yang, Janice M Santiago-O'Farrill, Philip J Rask, Jayanta Mondal, Hu Chen, Cristina Ivan, Xiuping Liu, Chang-Gong Liu, Yuanxin Xi, Kenta Masuda, Eli M Carrami, Meng Chen, Yitao Tang, Lan Pang, David S Lakomy, George A Calin, Han Liang, Ahmed A Ahmed, Hariprasad Vankayalapati, Robert C Bast Jr

The Journal of clinical investigation 132 ( 11 ) 2022.06

ISSN 00219738

Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have had an increasing role in the treatment of ovarian and breast cancers. PARP inhibitors are selectively active in cells with homologous recombination DNA repair deficiency caused by mutations in BRCA1/2 and other DNA repair pathway genes. Cancers with homologous recombination DNA repair proficiency respond poorly to PARP inhibitors. Cancers that initially respond to PARP inhibitors eventually develop drug resistance. We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and proficiency cancer cells. SIK2 is required for centrosome splitting and PI3K activation and regulates cancer cell proliferation, metastasis, and sensitivity to chemotherapy. Here, we showed that SIK2 inhibitors sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors. SIK2 inhibitors decreased PARP enzyme activity and phosphorylation of class-IIa histone deacetylases (HDAC4/5/7). Furthermore, SIK2 inhibitors abolished class-IIa HDAC4/5/7-associated transcriptional activity of myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding to regulatory regions with high chromatin accessibility in FANCD2, EXO1, and XRCC4 genes, resulting in repression of their functions in the DNA DSB repair pathway. The combination of PARP inhibitors and SIK2 inhibitors provides a therapeutic strategy to enhance PARP inhibitor sensitivity for ovarian cancer and TNBC.

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MEK inhibition suppresses metastatic progression of KRAS-mutated gastric cancer.

Juntaro Yamasaki, Yuki Hirata, Yuji Otsuki, Kentaro Suina, Yoshiyuki Saito, Kenta Masuda, Shogo Okazaki, Takatsugu Ishimoto, Hideyuki Saya, Osamu Nagano

Cancer science (Cancer Science) 113 ( 3 ) 916 - 925 2021.12

ISSN 1347-9032

Metastatic progression of tumors is driven by genetic alterations and tumor-stroma interaction. To elucidate the mechanism underlying the oncogene-induced gastric tumor progression, we have developed an organoid-based model of gastric cancer from GAstric Neoplasia (GAN) mice, which express Wnt1 and the enzymes COX2 and microsomal prostaglandin E synthase 1 in the stomach. Both p53 knockout (GAN-p53KO) organoids and KRASG12V -expressing GAN-p53KO (GAN-KP) organoids were generated by genetic manipulation of GAN mouse-derived tumor (GAN wild-type [WT]) organoids. In contrast with GAN-WT and GAN-p53KO organoids, which manifested Wnt addiction, GAN-KP organoids showed a Wnt-independent phenotype and the ability to proliferate without formation of a Wnt-regulated three-dimensional epithelial architecture. After transplantation in syngeneic mouse stomach, GAN-p53KO cells formed only small tumors, whereas GAN-KP cells gave rise to invasive tumors associated with the development of hypoxia as well as to liver metastasis. Spatial transcriptomics analysis suggested that hypoxia signaling contributes to the metastatic progression of GAN-KP tumors. In particular, such analysis identified a cluster of stromal cells located at the tumor invasive front that expressed genes related to hypoxia signaling, angiogenesis, and cell migration. These cells were also positive for phosphorylated extracellular signal-regulated kinase (ERK), suggesting that mitogen-activated protein kinase (MAPK) signaling promotes development of both tumor and microenvironment. The MEK (MAPK kinase) inhibitor trametinib suppressed the development of GAN-KP gastric tumors, formation of a hypoxic microenvironment, tumor angiogenesis, and liver metastasis. Our findings therefore establish a rationale for application of trametinib to suppress metastatic progression of KRAS-mutated gastric cancer.

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Meningitis caused by <i>Listeria monocytogenes</i> in a locally advanced cervical cancer patient with pyometra: A case report.

Matoba Y, Nishio H, Sekiguchi K, Uno S, Masuda K, Hiramatsu M, Takahashi M, Oishi M, Uwamino Y, Uchida S, Daté Y, Morisada T, Banno K, Nakahara J, Aoki D

Gynecologic oncology reports (Gynecologic Oncology Reports) 37 100799 2021.08

Locally advanced cervical cancer occasionally induces pyometra, but there have been no reports of meningitis where pyometra is the cause of infection. Here, we report a case of Listeria monocytogenes meningitis related to pyometra during concurrent chemoradiotherapy (CCRT) in a cervical cancer patient. The patient, a 77-year-old woman, was diagnosed with Stage IIB (FIGO 2018) cervical adenocarcinoma, and CCRT was initiated. Pyometra was exacerbated during CCRT, and after her first brachytherapy, she presented at our hospital with fever and decreased consciousness level. After admission to the Intensive Care Unit, the patient lost consciousness and experienced frequent seizures; tracheal intubation was required. Whole-body computed tomography revealed pyometra; therefore, transvaginal removal of the abscess was performed. Laboratory tests and vital signs indicated septic shock, and meropenem was administered. L. monocytogenes was detected in the abscess from the uterine cavity and the blood cultures on the third day of hospitalization. A lumbar puncture was performed on the same day to investigate whether the patient had meningitis. A FilmArray meningitis/encephalitis panel test of the spinal fluid revealed L. monocytogenes. After the diagnosis of meningitis with L. monocytogenes, ampicillin and gentamicin were started, and the blood test results gradually improved. Five months after the initial episode, her consciousness recovered, however she still received mechanical ventilatory support. L. monocytogenes infections can occur in patients undergoing chemotherapy, even without the use of steroids or immunosuppressive agents. In cases with pyometra, intrauterine manipulation can increase the risk of severe infection.

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Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumor-initiating cells.

Artibani M, Masuda K, Hu Z, Rauher PC, Mallett G, Wietek N, Morotti M, Chong K, KaramiNejadRanjbar M, Zois CE, Dhar S, El-Sahhar S, Campo L, Blagden SP, Damato S, Pathiraja PN, Nicum S, Gleeson F, Laios A, Alsaadi A, Santana Gonzalez L, Motohara T, Albukhari A, Lu Z, Bast RC Jr, Harris AL, Ejsing CS, Klemm RW, Yau C, Sauka-Spengler T, Ahmed AA

JCI insight (American Society for Clinical Investigation) 6 ( 11 ) 2021.06

Research paper (scientific journal), Joint Work, Accepted

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Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome

Kaneyasu T., Mori S., Yamauchi H., Ohsumi S., Ohno S., Aoki D., Baba S., Kawano J., Miki Y., Matsumoto N., Nagasaki M., Yoshida R., Akashi-Tanaka S., Iwase T., Kitagawa D., Masuda K., Hirasawa A., Arai M., Takei J., Ide Y., Gotoh O., Yaguchi N., Nishi M., Kaneko K., Matsuyama Y., Okawa M., Suzuki M., Nezu A., Yokoyama S., Amino S., Inuzuka M., Noda T., Nakamura S.

npj Breast Cancer (npj Breast Cancer) 6 ( 1 ) 25 - 25 2020.12

Research paper (scientific journal), Joint Work

© 2020, The Author(s). Panel sequencing of susceptibility genes for hereditary breast and ovarian cancer (HBOC) syndrome has uncovered numerous germline variants; however, their pathogenic relevance and ethnic diversity remain unclear. Here, we examined the prevalence of germline variants among 568 Japanese patients with BRCA1/2-wildtype HBOC syndrome and a strong family history. Pathogenic or likely pathogenic variants were identified on 12 causal genes for 37 cases (6.5%), with recurrence for 4 SNVs/indels and 1 CNV. Comparisons with non-cancer east-Asian populations and European familial breast cancer cohorts revealed significant enrichment of PALB2, BARD1, and BLM mutations. Younger onset was associated with but not predictive of these mutations. Significant somatic loss-of-function alterations were confirmed on the wildtype alleles of genes with germline mutations, including PALB2 additional somatic truncations. This study highlights Japanese-associated germline mutations among patients with BRCA1/2 wildtype HBOC syndrome and a strong family history, and provides evidence for the medical care of this high-risk population.

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Retrospective evaluation of risk-reducing salpingo-oophorectomy for BRCA1/2 pathogenic variant carriers among a cohort study in a single institution.

Kobayashi Y, Hirasawa A, Chiyoda T, Ueki A, Masuda K, Misu K, Kawaida M, Hayashi S, Kataoka F, Banno K, Kosaki K, Aoki D

Japanese journal of clinical oncology (Japanese journal of clinical oncology) 51 ( 2 ) 213 - 217 2020.10

Research paper (scientific journal), Joint Work, ISSN 0368-2811

© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com. BACKGROUND: Risk-reducing salpingo-oophorectomy is performed for the primary prevention of ovarian cancer in patients with hereditary breast-ovarian cancer syndrome. We performed risk-reducing salpingo-oophorectomy for the first time in Japan in 2008, and we experienced 20 cases of risk-reducing salpingo-oophorectomy through 2019. In the past, the use of risk-reducing salpingo-oophorectomy in Japan was restricted because it was not covered by a Japanese National Health Insurance. Since April 2020, risk-reducing salpingo-oophorectomy has been covered by insurance for patients with breast-ovarian cancer syndrome and pre-existing breast cancer, and this surgery is expected to become more widely implemented in Japan. METHODS: To contribute to the widespread use of risk-reducing salpingo-oophorectomy in the future, we retrospectively reviewed 20 cases of risk-reducing salpingo-oophorectomy at our hospital cohort study to clarify the issues in its implementation. RESULTS: The variant genes for which risk-reducing salpingo-oophorectomy was indicated were BRCA1 and BRCA2 in 13 (65%) and 7 patients (35%), respectively. The median age at which risk-reducing salpingo-oophorectomy was performed was 49 years (range, 38-58), 13 patients (65%) had gone through menopause, and 16 patients (80%) had a history of breast cancer. Of the five patients (25%) with vasomotor symptoms, four received Chinese medicine, and only one received hormone replacement therapy. Occult cancer was detected in the removed ovaries in two patients (10%), although no postoperative peritoneal carcinogenesis has been observed to date. CONCLUSIONS: Women who paid for risk-reducing salpingo-oophorectomy out of pocket were older than the recommended age at which the procedure should be performed, and this may explain the higher rate of occult cancers than previously reported. We need to perform risk-reducing salpingo-oophorectomy at the recommended age to ensure that the procedure is effective for primary prevention.

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Cowden syndrome complicated by schizophrenia: A first clinical report

Kobayashi Y., Takeda T., Kunitomi H., Ueki A., Misu K., Kowashi A., Takahashi T., Anko M., Watanabe K., Masuda K., Uchida T., Tominaga E., Banno K., Kosaki K., Aoki D.

European Journal of Medical Genetics (European Journal of Medical Genetics) 63 ( 8 ) 103959 2020.08

ISSN 17697212

© 2020 Elsevier Masson SAS Patients with Cowden syndrome exhibit mucocutaneous lesions, hamartomatous polyposis of the gastrointestinal tract, and macrocephaly, often complicated by malignant tumors, such as breast, thyroid, and uterine cancers. Autism spectrum and epilepsy have been known as neuropsychiatric symptoms associated with Cowden syndrome; however, to the best of our knowledge, there is no report on cases complicated by schizophrenia. Here, we report a first case of Cowden syndrome complicated by schizophrenia. A 49-year-old Japanese woman started experiencing auditory hallucinations in her teens. She had left breast cancer at the age of 34 years, and right breast cancer at the age of 37 years, all of which were surgically treated. She was also being treated by oral medications for Hashimoto's disease. On consulting her previous doctor for abnormal uterine bleeding that lasted for a year, she was diagnosed with endometrial cancer. However, immediately before surgery, her auditory hallucinations and paranoid delusions became severe, and she was referred to our hospital for detailed examination and treatment. No abnormalities were found on head MRI, and she was diagnosed with schizophrenia on the basis of neuropsychiatric examination findings. After her psychiatric symptoms were controlled by 2 mg of risperidone, she underwent surgery for endometrial cancer. Although there was no apparent family history, physical findings including macrocephaly and papillomatous skin lesions together with her past medical history of multiple malignant tumors suggested Cowden syndrome. Postoperatively, genetic testing revealed a pathogenic variant c.655C > T; p. Gln219* (NM_000314.4) in PTEN, leading to the confirmation of the diagnosis of Cowden syndrome.

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The Repertoire of Serous Ovarian Cancer Non-genetic Heterogeneity Revealed by Single-Cell Sequencing of Normal Fallopian Tube Epithelial Cells.

Hu Z, Artibani M, Alsaadi A, Wietek N, Morotti M, Shi T, Zhong Z, Santana Gonzalez L, El-Sahhar S, KaramiNejadRanjbar M, Mallett G, Feng Y, Masuda K, Zheng Y, Chong K, Damato S, Dhar S, Campo L, Garruto Campanile R, Soleymani Majd H, Rai V, Maldonado-Perez D, Jones S, Cerundolo V, Sauka-Spengler T, Yau C, Ahmed AA

Cancer cell (Cancer Cell) 37 ( 2 ) 226 - 242.e7 2020.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 1535-6108

The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH in serous ovarian cancer (SOC) can be accurately measured when informed by the molecular signatures of the normal fallopian tube epithelium (FTE) cells, the cells of origin of SOC. Surveying the transcriptomes of ∼6,000 FTE cells, predominantly from non-ovarian cancer patients, identified 6 FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH. Importantly, NGH-based stratification of ∼1,700 tumors robustly correlated with survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC. Using single-cell RNA sequencing, Hu et al. identify six subtypes of fallopian tube epithelium (FTE) cells in normal human fallopian tube tissues. The FTE cellular subtypes reveal intra-tumoral heterogeneity in serous ovarian cancer (SOC) and define SOC subtypes that correlate with patient prognosis.

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