Details of a Researcher - SASAKI Yasushi

Papers - SASAKI Yasushi

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Associations between serum insulin-like growth factor-related molecules and colorectal cancer risk by tumor location: a nested case-control study.

Yasushi Adachi, Masanori Nojima, Yingsong Lin, Yasushi Sasaki, Hiro-O Yamano, Hiroshi Nakase, Kenji Wakai, Mitsuru Mori, Akiko Tamakoshi

Digestion 1 - 19 2025.03 [Refereed] [International journal]

Introduction, The activity of the mitogen insulin-like growth factor (IGF) is controlled by IGF-binding protein (IGFBP). Colorectal cancers (CRCs) are heterogeneous, with left- and right-sided CRC showing different clinical and molecular characteristics. This case-control study, nested in the Japan Collaborative Cohort study, assessed associations between serum levels of IGF-related molecules and incidences of CRC by location. Methods, A baseline survey obtained serum samples from 39,242 participants. Subjects diagnosed with CRC during follow-up were regarded as cases. Conditional logistic regression modeling was used to calculate odds ratios (ORs) for cancer incidence associated with IGF-related molecules. Results, This analysis included 176 cases and 524 controls. No IGF-related molecules appeared associated with risks of overall or left-sided CRC. Both total IGFBP3 and free IGFBP3 (estimated as IGFBP3-(IGF1+IGF2)) were associated with incidence of right-sided CRC (P-for-trends=0.027 and 0.003, respectively), with the third tertile of total and free IGFBP3 showing the highest risk (OR=6.25 and 7.96, respectively). Free IGF, estimated as (IGF1+IGF2)/IGFBP3, was inversely associated with incidence of right-sided CRC (P-for-trends=0.014), with the third tertile showing the lowest risk (OR=0.18). Among subjects followed for over 3 years, association of IGF-related molecules with overall CRC was similar. Free IGFBP3 was associated with incidence of right-sided CRC (P-for-trends=0.004). Free IGF was inversely associated with incidence of right-sided CRC (P-for-trends=0.002). However, free IGFs were associated with risk of left-sided CRC (P-for-trends=0.041), with the third tertile showing the highest risk (OR=3.10). Conclusions, Serum IGF-related molecules are associated with risk of CRC. These associations might differ by tumor location.

DOI PubMed

Impact of Sensitive Circulating Tumor DNA Monitoring on CT Scan Intervals During Postoperative Colorectal Cancer Surveillance

Tomoko Sasaki, Takeshi Iwaya, Mizunori Yaegashi, Masashi Idogawa, Hayato Hiraki, Masakazu Abe, Yuka Koizumi, Noriyuki Sasaki, Akiko Yashima-Abo, Ryosuke Fujisawa, Fumitaka Endo, Shoichiro Tange, Koki Otsuka, Akira Sasaki, Mari Masuda, Masashi Fujita, Hidewaki Nakagawa, Fumiaki Takahashi, Yasushi Sasaki, Takashi Tokino, Satoshi S. Nishizuka

Annals of Surgery Open ( Ovid Technologies (Wolters Kluwer Health) ) 6 ( 1 ) e549 - e549 2025.02 [Refereed]

Objective: This study investigated whether digital polymerase chain reaction (dPCR)-based circulating tumor DNA (ctDNA) monitoring can allow longer intervals between computed tomography (CT) scans during postoperative surveillance of colorectal cancer (CRC). Background: Practical guidelines still recommend intensive postoperative surveillance of CRC using periodical CT scans and serum carcinoembryonic antigen testing. Methods: The longitudinal dynamics of ctDNA for 52 patients with CRC as measured by dPCR using probes targeting 87 individual tumor-specific mutations (1–5 per patient) were compared with results from conventional (ie, clinical) surveillance using serum tumor markers and CT. Results: A total of 382 CT procedures were carried out for the patient cohort (3.3/year per patient) and the median lead time from ctDNA relapse to clinical relapse was 182 days (range, 0–376 days). If the CT interval was annual, potential delays in the detection of clinical relapse would have occurred for 7 of the 10 patients who experienced clinical relapse (9 of 13 events), with a median delay of 164 days (range, 0–267 days). If annual CT surveillance was performed together with ctDNA monitoring, 218 (57.1%) CTs would not have been needed to detect the first clinical relapse. In addition, the ctDNA monitoring would have provided a lead time of 339 days for detection of clinical relapse (range, 42–533 days). Conclusions: Our findings suggest that the ctDNA monitoring as part of postoperative surveillance and clinical relapse detection for patients with CRC could allow the CT interval to be lengthened. Trial Registration: This trial was registered with University Hospital Medical Information Network Clinical Trial Registry (UMIN000045114).

DOI

Targeted dynamic phospho-proteogenomic analysis of gastric cancer cells suggests host immunity provides survival benefit.

Kohei Kume, Midori Iida, Takeshi Iwaya, Akiko Yashima-Abo, Yuka Koizumi, Akari Endo, Kaitlin Wade, Hayato Hiraki, Valerie Calvert, Julia Wulfkuhle, Virginia Espina, Doris R Siwak, Yiling Lu, Kazuhiro Takemoto, Yutaka Suzuki, Yasushi Sasaki, Takashi Tokino, Emanuel Petricoin 3rd, Lance A Liotta, Gordon B Mills, Satoshi S Nishizuka

Molecular & cellular proteomics : MCP 100870 - 100870 2024.10 [Refereed] [International journal]

Despite of massive emergence of molecular targeting drugs, the mainstay of advanced gastric cancer (GC) therapy is DNA-damaging drugs. Using a reverse-phase protein array-based proteogenomic analysis of a panel of eight GC cell lines, we identified genetic alterations and signaling pathways, potentially associated with resistance to DNA-damaging drugs, including 5-fluorouracil (5FU), cisplatin, and etoposide. Resistance to cisplatin and etoposide, but not 5FU, was negatively associated with global copy number loss, vimentin expression, and caspase activity, which are considered hallmarks of previously established EMT subtype. The segregation of 19,392 protein expression time courses by sensitive and resistant cell lines for the drugs tested revealed that 5FU-resistant cell lines had lower changes in global protein dynamics, suggesting their robust protein level regulation, compared to their sensitive counterparts, whereas the cell lines that are resistant to other drugs showed increased protein dynamics in response to each drug. Despite faint global protein dynamics, 5FU-resistant cell lines showed increased STAT1 phosphorylation and PD-L1 expression in response to 5FU. In publicly available cohort data, expression of STAT1 and NFκB target genes induced by proinflammatory cytokines was associated with prolonged survival in GC. In our validation cohort, total lymphocyte count (TLC), rather than PD-L1 positivity, predicted a better relapse-free survival rate in GC patients with 5FU-based adjuvant chemotherapy than those with surgery alone. Moreover, TLC+ patients who had no survival benefit from adjuvant chemotherapy were discriminated by expression of IκBα, a potent negative regulator of NFκB. Collectively, our results suggest that 5FU resistance observed in cell lines may be overcome by host immunity or by combination therapy with immune checkpoint blockade.

DOI PubMed

Synchronous cancers of the stomach and esophagus in a patient with autoimmune gastritis and pernicious anemia: a case report and review of the literature.

Toshiyuki Kubo, Yasushi Adachi, Yasushi Sasaki, Yasuyo Adachi, Yukinari Yoshida, Takao Endo, Yoshifumi Ishii, Hiroaki Takahashi, Akira Goto

International cancer conference journal 13 ( 4 ) 367 - 373 2024.10 [Refereed] [International journal]

Type-A gastritis/autoimmune gastritis (AIG) has gained renewed attention due to declining Helicobacter pylori infection rates and increasing eradication. AIG is associated with pernicious anemia (PA) and is prone to complicate various tumors, such as gastric cancer and neuroendocrine tumors. This report describes a case of AIG with PA in which gastric and esophageal cancers arose simultaneously. An 86-year-old woman had been diagnosed with PA and AIG 9 years earlier. As routine blood tests revealed high levels of carcinoembryonic antigen, she underwent esophagogastroduodenoscopy, which revealed a type 0-IIa lesion in the middle part of the stomach and a type 0-IIa + IIb lesion in the lower esophagus. Endoscopic submucosal dissection was performed on both lesions, since neither distant nor lymph node metastases were identified. Histological examination showed gastric tubular adenocarcinoma and esophageal squamous cell carcinoma. Immunohistology revealed that cells from neither cancer expressed gastrin, gastrin receptor, or p53. Whole-exome sequencing showed 8 gene mutations in the esophageal cancer and 6 mutations in 5 genes in the gastric cancer. The reason for the lack of p53 immunostaining was that TP53 was mutated in these cancers, although TP53 mutations differed. Thus, TP53 mutations may not be detected by immunostaining alone. When treating patients with AIG/PA, clinicians must be aware of the possibility of esophageal cancer coexisting with gastric cancer.

DOI PubMed

口腔がんにおける悪性化関連遺伝子群転写抑制機構の解明(Nuclear protein X represses the transcription of malignancy-related genes in oral cancer cell lines)

丹下正一朗, 後藤生子, 川島秀器, 井戸川雅史, 佐々木泰史, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 83回 P - 2241 2024.09

Association of serum superoxide dismutase activity and the incidence of colorectal cancer in a nested case-control study.

Yasushi Adachi, Masanori Nojima, Mitsuru Mori, Hiro-O Yamano, Yasushi Sasaki, Hiroshi Nakase, Yingsong Lin, Kenji Wakai, Akiko Tamakoshi

Cancer epidemiology 87 102455 - 102455 2023.09 [Refereed] [International journal]

BACKGROUND: Superoxide dismutase (SOD) is an antioxidant enzyme that degrades superoxide, a major causative factor in carcinogenesis. We assessed associations between serum SOD activities and incidence of colorectal carcinoma (CRC) in a case-control study nested in the Japan Collaborative Cohort (JACC) study. METHODS: At baseline, 39,242 subjects donated serum samples. Participants diagnosed with CRC during follow-up were regarded as cases. Odds ratios (ORs) for CRC incidence associated with SOD were evaluated with conditional logistic regression models. In the current study, 176 cases and 524 controls were analyzed. RESULTS: For the overall cohort, a decreasing trend in risk of CRC with increasing SOD was observed (P for trend=0.054) and the fourth quartile of SOD level showed the lowest risk compared to the first (OR=0.52, 95% confidence interval [CI]=0.29-0.93). This was significant in men (P for trend=0.001), with the fourth quartile of SOD level showing the lowest risk compared to the first (OR, 0.23; 95%CI, 0.09-0.60). It was also exclusively observed for rectal cancer and left-sided CRC (P for trend, 0.037 and 0.020, respectively), with the fourth quartile again showing the lowest risk compared to the first (OR, 0.28 and 0.38; 95%CI, 0.09-0.84 and 0.16-0.91, respectively). Limiting subjects to those followed-up over 2 years, all trends remained unchanged. CONCLUSIONS: Our findings suggest that serum SOD activity correlates inversely with risk of CRC, particularly in men and individuals with rectal cancer/left-sided CRC.

DOI PubMed J-GLOBAL

Esophageal intraepithelial squamous cell neoplasia with epidermalization-A case with molecular analysis.

Takao Endo, Toshiyuki Kubo, Yasushi Sasaki, Hiroaki Takahoshi, Yoshifumi Ishii, Yasushi Adachi

Pathology international 2023.06 [Refereed] [International journal]

DOI PubMed

Serum soluble Fas levels and incidence of liver cancer in nested case-control study.

Yasushi Adachi, Masanori Nojima, Mitsuru Mori, Toshiyuki Kubo, Noriyuki Akutsu, Yasushi Sasaki, Hiroshi Nakase, Yingsong Lin, Youichi Kurozawa, Kenji Wakai, Akiko Tamakoshi

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 82nd 2022.12 [Refereed] [International journal]

BACKGROUND: Soluble Fas (sFas) plays various roles in carcinogenesis and tumor dissemination by preventing apoptosis via binding to Fas ligand. We analyzed associations of serum sFas levels with the incidence of liver cancer in a prospective case-control study nested in the JACC Study. METHODS: A baseline survey was conducted from 1988, with blood samples obtained from 39,242 subjects. Patients diagnosed with liver cancer were regarded as cases. Two or three controls were selected and matched for sex, age, and geographical area. Conditional logistic regression was used to estimate odds ratios (ORs) for cancer incidence associated with sFas. RESULTS: This study contained 86 cases and 249 controls. After controlling for alcohol intake, body mass index, smoking, and hepatitis viral infection, participants with high sFas showed elevated risk of cancer (P-trend = 0.003) and the third tertile of sFas showed a higher risk compared to the first tertile (OR = 3.53, 95% confidence interval (CI) = 1.28-9.69). In hepatocellular carcinoma, high sFas was associated with elevated risk (P-trend < 0.001). In men and the elderly, subjects in the highest tertiles showed higher cancer risk. Limiting subjects to those followed for 3 years, high sFas was related to liver cancer risk (P-trend = 0.033) and the third tertile showed a higher risk compared to the first (OR = 2.94, 95%CI = 0.94-9.14). CONCLUSIONS: High serum sFas may be related to future risk of liver cancer. IMPACT: Our findings highlight this biomarker for further analysis in pooled investigations with different/larger prospective cohorts.

DOI PubMed J-GLOBAL

Genomic analysis of an aggressive case with metastatic intrahepatic mucinous cholangiocarcinoma.

Yoshiharu Masaki, Noriyuki Akutsu, Yasushi Adachi, Keisuike Ishigami, Norikazu Iwata, Takao Endo, Yoshifumi Ishii, Yasushi Sasaki, Minoru Nagayama, Yasutoshi Kimura, Hiroshi Nakase

Clinical journal of gastroenterology 15 ( 4 ) 809 - 817 2022.08 [Refereed] [Domestic journal]

Intrahepatic mucinous cholangiocarcinoma (IHMC) is rare and behaves notoriously; however, the details of the clinicopathological characteristics of IHMC remain unknown. A 70-year-old man was admitted for examination of the hepatic mass in the S1 segment. He underwent extended left hepatic lobectomy. Histopathological evaluation demonstrated mixed papillary carcinoma that comprised well to moderately differentiated tubular adenocarcinoma and signet-ring cell carcinoma with large amounts of mucus lakes. Tumor was relapsed 9 months after surgery. Although he received chemotherapy with the combination of gemcitabine and cisplatin, he had renal failure and discontinued the chemotherapy. He received palliative radiotherapy for metastasis in the cervical spine. Then, the patient treated with S-1, however, he died 16 months after the initial diagnosis. The autopsy findings showed multiple nodules in the lungs, pleura, kidneys, adrenal glands, stomach, pancreas, and lymph nodes. Histological examination revealed that all nodules were IHMC. Next-generation sequencing revealed that somatic mutations in ADGRB3, TAF1L and EPHA3 may affect carcinogenesis, and those in TAF1, EPHA3, PIK3C2B, FN1, ERBB3, BRIP1, SYNE1 and TGFBR2 may affect metastasis. Molecular carcinogenesis of IHMC may be distinct from that of ordinary cholangiocarcinoma. Further studies are needed to elucidate the genetic mutations and their functions in IHMC.

DOI PubMed

Individualized circulating tumor DNA monitoring in head and neck squamous cell carcinoma.

Ryunosuke Kogo, Tomomi Manako, Takeshi Iwaya, Satoshi Nishizuka, Hayato Hiraki, Yasushi Sasaki, Masashi Idogawa, Takashi Tokino, Ayaka Koide, Noritaka Komune, Ryuji Yasumatsu, Takashi Nakagawa

Cancer medicine 2022.03 [Refereed] [International journal]

There is no useful biomarker to evaluate treatment response and early relapse in head and neck squamous cell carcinoma (HNSCC). Circulating tumor DNA (ctDNA) is a promising biomarker for detecting minimal residual diseases and monitoring treatment effect. We investigated whether individualized ctDNA analysis could help monitor treatment response and relapse in HNSCC. Mutation analysis of tumor and peripheral blood mononuclear cell (PBMC) DNAs of 26 patients with HNSCC was performed using a custom squamous cell carcinoma (SCC) panel. The identified individualized mutated genes were defined as ctDNA candidates. We investigated whether frequent ctDNA monitoring via digital PCR (dPCR) is clinically valid for HNSCC patients. TP53 was the most frequently mutated gene and was detected in 14 of 24 cases (58.2%), wherein two cases were excluded owing to the absence of tumor-specific mutations in the SCC panel. Six cases were excluded because of undesignable and unusable primer-probes for dPCR. Longitudinal ctDNA was monitored in a total of 18 cases. In seven cases, ctDNA tested positive again or did not test negative, and all seven cases relapsed after initial curative treatment. In 11 cases, after initial curative treatment, ctDNA remained negative and patients were alive without recurrence. Patients who remained negative for ctDNA during follow-up after initial curative treatment (n = 11) had a significantly better prognosis than those who reverted to ctDNA positivity (n = 7; p < 0.0001; log-rank test). Individualized ctDNA monitoring using SCC panel and dPCR might be a novel and promising biomarker for HNSCC.

DOI PubMed

Mutation Analysis of Radioresistant Early-Stage Cervical Cancer.

Tae Oike, Yoshihito Sekiguchi, Yuya Yoshimoto, Takahiro Oike, Ken Ando, Wenchao Gu, Yasushi Sasaki, Takashi Tokino, Akira Iwase, Tatsuya Ohno

International journal of molecular sciences 23 ( 1 ) 51 2021.12 [Refereed] [International journal]

Radiotherapy is a definitive treatment for early-stage cervical cancer; however, a subset of this disease recurs locally, necessitating establishment of predictive biomarkers and treatment strategies. To address this issue, we performed gene panel-based sequencing of 18 stage IB cervical cancers treated with definitive radiotherapy, including two cases of local recurrence, followed by in vitro and in silico analyses. Simultaneous mutations in KRAS and SMAD4 (KRASmt/SMAD4mt) were detected only in a local recurrence case, indicating potential association of this mutation signature with radioresistance. In isogenic cell-based experiments, a combination of activating KRAS mutation and SMAD4 deficiency led to X-ray resistance, whereas either of these factors alone did not. Analysis of genomic data from 55,308 cancers showed a significant trend toward co-occurrence of mutations in KRAS and SMAD4. Gene Set Enrichment Analysis of the Cancer Cell Line Encyclopedia dataset suggested upregulation of the pathways involved in epithelial mesenchymal transition and inflammatory responses in KRASmt/SMAD4mt cancer cells. Notably, irradiation with therapeutic carbon ions led to robust killing of X-ray-resistant KRASmt/SMAD4mt cancer cells. These data indicate that the KRASmt/SMAD4mt signature is a potential predictor of radioresistance, and that carbon ion radiotherapy is a potential option to treat early-stage cervical cancers with the KRASmt/SMAD4mt signature.

DOI PubMed

DLEU1 promotes oral squamous cell carcinoma progression by activating interferon-stimulated genes.

Yui Hatanaka, Takeshi Niinuma, Hiroshi Kitajima, Koyo Nishiyama, Reo Maruyama, Kazuya Ishiguro, Mutsumi Toyota, Eiichiro Yamamoto, Masahiro Kai, Akira Yorozu, Shohei Sekiguchi, Kazuhiro Ogi, Hironari Dehari, Masashi Idogawa, Yasushi Sasaki, Takashi Tokino, Akihiro Miyazaki, Hiromu Suzuki

Scientific reports 11 ( 1 ) 20438 - 20438 2021.10 [Refereed] [International journal]

Long noncoding RNAs (lncRNAs) are deeply involved in cancer development. We previously reported that DLEU1 (deleted in lymphocytic leukemia 1) is one of the lncRNAs overexpressed in oral squamous cell carcinoma (OSCC) cells, where it exhibits oncogenic activity. In the present study, we further clarified the molecular function of DLEU1 in the pathogenesis of OSCC. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis revealed that DLEU1 knockdown induced significant changes in the levels of histone H3 lysine 4 trimethylation (H3K4me3) and H3K27 acetylation (H3K27ac) in OSCC cells. Notably, DLEU1 knockdown suppressed levels of H3K4me3/ H3K27ac and expression of a number of interferon-stimulated genes (ISGs), including IFIT1, IFI6 and OAS1, while ectopic DLEU1 expression activated these genes. Western blot analysis and reporter assays suggested that DLEU1 upregulates ISGs through activation of JAK-STAT signaling in OSCC cells. Moreover, IFITM1, one of the ISGs induced by DLUE1, was frequently overexpressed in primary OSCC tumors, and its knockdown inhibited OSCC cell proliferation, migration and invasion. These findings suggest that DLEU1 exerts its oncogenic effects, at least in part, through activation of a series ISGs in OSCC cells.

DOI PubMed

Early dynamics of circulating tumor DNA predict chemotherapy responses for patients with esophageal cancer.

Ryosuke Fujisawa, Takeshi Iwaya, Fumitaka Endo, Masashi Idogawa, Noriyuki Sasaki, Hayato Hiraki, Shoichiro Tange, Tomomi Hirano, Yuka Koizumi, Masakazu Abe, Tomoko Takahashi, Mizunori Yaegashi, Yuji Akiyama, Mari Masuda, Akira Sasaki, Fumiaki Takahashi, Yasushi Sasaki, Takashi Tokino, Satoshi S Nishizuka

Carcinogenesis 42 ( 10 ) 1239 - 1249 2021.09 [Refereed] [International journal]

We investigated whether early circulating tumor DNA (ctDNA) changes, measured using digital PCR (dPCR), can predict later chemotherapy responses in esophageal squamous cell cancer (ESCC). We compared the dynamics of ctDNA and tumor volumes during chemotherapy in 42 ESCC. The accuracy of predictions of later chemotherapy responses were evaluated by the ratio of the variant allele frequency (VAF) of ctDNA (post-/pre-ctDNA) and the total tumor volume (post-/pre-volume) before and after an initial chemotherapy cycle using a receiver-operating characteristic curve analysis. Total positive and negative objective responses (ORs) were defined as either >50% or ≤50% reductions, respectively, in the total tumor volume at the end of first-line chemotherapy. Mutation screening of 43 tumors from 42 patients revealed 96 mutations. The pretreatment dPCR-ctDNA data were informative in 38 patients, using 70 selected mutations (1-3 per patient). The areas under the curve (AUCs) for the post-/pre-volume and post-/pre-ctDNA levels used in predicting the total OR were 0.85 and 0.88, respectively. The optimal cutoff value of post-/pre-ctDNA was 0.13. In 20 patients with post-/pre-volume ≥50%, the total OR could be predicted by the post-/pre-ctDNA with high accuracy; the AUC by post-/pre-ctDNA was higher than that by post-/pre-volume (0.85 vs 0.76, respectively). Patients with low post-/pre-ctDNA (n = 18) had a significantly better overall survival rate than those with high post-/pre-ctDNA (n = 20; P = 0.03). Early ctDNA changes after an initial cycle of chemotherapy predict later responses to treatment with high accuracy in ESCC patients.

DOI PubMed

Generation of functional liver organoids on combining hepatocytes and cholangiocytes with hepatobiliary connections ex vivo.

Naoki Tanimizu, Norihisa Ichinohe, Yasushi Sasaki, Tohru Itoh, Ryo Sudo, Tomoko Yamaguchi, Takeshi Katsuda, Takafumi Ninomiya, Takashi Tokino, Takahiro Ochiya, Atsushi Miyajima, Toshihiro Mitaka

Nature communications 12 ( 1 ) 3390 - 3390 2021.06 [Refereed] [International journal]

In the liver, the bile canaliculi of hepatocytes are connected to intrahepatic bile ducts lined with cholangiocytes, which remove cytotoxic bile from the liver tissue. Although liver organoids have been reported, it is not clear whether the functional connection between hepatocytes and cholangiocytes is recapitulated in those organoids. Here, we report the generation of a hepatobiliary tubular organoid (HBTO) using mouse hepatocyte progenitors and cholangiocytes. Hepatocytes form the bile canalicular network and secrete metabolites into the canaliculi, which are then transported into the biliary tubular structure. Hepatocytes in HBTO acquire and maintain metabolic functions including albumin secretion and cytochrome P450 activities, over the long term. In this study, we establish functional liver tissue incorporating a bile drainage system ex vivo. HBTO enable us to reproduce the transport of hepatocyte metabolites in liver tissue, and to investigate the way in which the two types of epithelial cells establish functional connections.

DOI PubMed

Generation of functional liver tissue by establishing hepatobiliary connections ex vivo

Tanimizu N, Ichinohe N, Sasaki Y, Itoh T, Sudo R, Yamaguchi T, Katsuda T, Tokino T, Ochiya T, Miyajima A, Mitaka T

2020.11

DOI

Frequent tumor burden monitoring of esophageal squamous cell carcinoma with circulating tumor DNA using individually designed digital PCR.

Takeshi Iwaya, Fumitaka Endo, Fumiaki Takahashi, Takashi Tokino, Yasushi Sasaki, Satoshi S Nishizuka

Gastroenterology 160 ( 1 ) 463 - 465 2020.10 [Refereed] [International journal]

DOI PubMed

Mutation profiling of uterine cervical cancer patients treated with definitive radiotherapy.

Yuya Yoshimoto, Yasushi Sasaki, Kazutoshi Murata, Shin-Ei Noda, Yuhei Miyasaka, Junko Hamamoto, Mio Furuya, Junko Hirato, Yoshiyuki Suzuki, Tatsuya Ohno, Takashi Tokino, Takahiro Oike, Takashi Nakano

Gynecologic oncology 159 ( 2 ) 546 - 553 2020.09 [Refereed] [International journal]

OBJECTIVE: To elucidate tumor mutation profiles associated with outcomes of uterine cervical cancer (UCC) patients treated with definitive radiotherapy. METHODS: Ninety-eight patients with newly diagnosed and pathologically confirmed UCC (82 squamous cell carcinomas, 12 adenocarcinomas, and four adenosquamous carcinomas) who were treated with definitive radiotherapy were analyzed. DNA was extracted from pre-treatment tumor biopsy specimens. The exons of 409 cancer-related genes were sequenced using a next-generation sequencer. Genetic mutations were identified and analyzed for correlations with clinical outcome. RESULTS: Recurrent mutations were observed in PIK3CA (35.7%), ARID1A (25.5%), NOTCH1 (19.4%), FGFR3 (16.3%), FBXW7 (19.4%), TP53 (13.3%), EP300 (12.2%), and FGFR4 (10.2%). The prevalence of mutations in FGFR family genes (i.e., FGFR1-4) was almost as high (24.5%) as that in PIK3CA and ARID1A, both of which are well-studied drivers of UCC. Fifty-five percent (21 of 38) of the identified FGFR mutations were located in the FGFR protein tyrosine kinase domain. Five-year progression-free survival (PFS) rates for FGFR mutation-positive patients (n = 24) were significantly worse than those for FGFR mutation-negative patients (n = 74) (43.9% vs. 68.5%, respectively; P = 0.010). Multivariate analysis identified FGFR mutations as significant predictors of worse 5 year PFS (P = 0.005), independent of clinicopathological variables. CONCLUSIONS: FGFR mutations are associated with worse PFS in UCC patients treated with definitive radiotherapy. These results warrant further validation in prospective studies.

DOI PubMed

Aggressive variant of splenic marginal zone lymphoma characterized using a cancer panel test and treated with rituximab-containing chemotherapy: A case report.

Kazuya Ishiguro, Yasushi Sasaki, Yoshitake Takagi, Takeshi Niinuma, Hiromu Suzuki, Takashi Tokino, Toshiaki Hayashi, Tohru Takahashi, Tetsuyuki Igarashi, Yoshihiro Matsuno

Medicine 99 ( 35 ) e21938 2020.08 [Refereed] [International journal]

RATIONALE: Aggressive variant of splenic marginal zone lymphoma (AV-SMZL) is a very rare disease that is often associated with TP53 mutations and has a poor prognosis. On the other hand, recent advances in genome sequencing techniques enable us to understand the molecular characteristics of rare cancers such as AV-SMZL. Here we present a case of AV-SMZL analyzed using a genetic test. PATIENT CONCERNS: A 66-year-old woman was admitted with splenomegaly and lymphocytosis. Computed tomography revealed marked splenomegaly without lymphadenopathy in any other areas. The serum soluble interleukin-2 receptor (sIL-2R) level was significantly elevated. Peripheral and bone marrow blood tests showed an increase in abnormal lymphocytes. DIAGNOSIS: A splenectomy revealed an SMZL pattern with increased numbers of large cells and mitotic cells and a high Ki-67 positivity rate, which led to a diagnosis of AV-SMZL. Although TP53 mutation was not detected, mutations in NOTCH2, NCOA4, PTEN, EPHA3, and KMT2D were identified. Among these, the mutations in NCOA4, PTEN, and EPHA3 were novel pathogenic mutations in SMZL, which suggests they may be related to the aggressiveness and persistence of the disease. INTERVENTIONS: The patient was administered a rituximab-containing regimen and rituximab-maintenance therapy. OUTCOMES: The patient continues to exhibit a complete response. LESSONS: This is a case of AV-SMZL in which a cancer panel test successfully detected genetic alterations that are potentially associated with its pathogenesis. These findings suggest that genetic analysis is useful for making diagnoses as well as for determining treatment strategies in AV-SMZL.

DOI PubMed

Circulating-tumor DNA from Two Types of Blood Collection Tubes for Monitoring Tumor Burden Validated with Esophageal Squamous Cell Carcinoma Patients

Fumitaka Endo, Takeshi Iwaya, Yasushi Sasaki, Takehiro Chiba, Mizunori Yaegashi, Kohei Kume, Kei Sato, Atsuhiro Arisue, Ryoko Kawagishi, Teppei Matuo, Yuji Akiyama, Akira Sasaki, Yuji Suzuki, Takashi Tokino, Mari Masuda, Tesshi Yamada, Hidewaki Nakagawa, Satoshi S Nishizuka

( Cold Spring Harbor Laboratory ) 2020.08 [Refereed]

Objective: To evaluate long-term whole blood (WB) storage at room temperature (RT), plasma and peripheral blood mononuclear cell (PBMC) DNA was collected simultaneously using BD Vacutainer® CPT™ Mononuclear Cell Preparation Tubes (CPT) and Streck Cell-Free DNA Blood Collection Tubes (BCT®). Methods: Plasma DNA was isolated from both types of tubes at various time points at RT. DNA from PBMCs was extracted using CPT from WB stored in BCT. The extracted DNA was used to monitor esophageal cancer treatment. Results: BCT maintained steady levels of plasma DNA for up to nine days. After transfer of BCT-stored WB to CPT, PBMC-DNA were yielded with suitable quality for up to seven days. ctDNA from esophageal cancer patients carrying TP53 mutations reflected treatment efficacy. Conclusion: BCT/CPT combinatory procedure allows storage of blood samples for up to seven days at RT for valid clinical assays using ctDNA.

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Integrated genetic and epigenetic analysis of cancer-related genes in non-ampullary duodenal adenomas and intramucosal adenocarcinomas.

Ryosuke Ota, Takeshi Sawada, Sho Tsuyama, Yasushi Sasaki, Hiromu Suzuki, Yasuharu Kaizaki, Kenkei Hasatani, Eiichiro Yamamoto, Hiroyoshi Nakanishi, Satoko Inagaki, Shigetsugu Tsuji, Naohiro Yoshida, Hisashi Doyama, Hiroshi Minato, Keishi Nakamura, Satomi Kasashima, Eiji Kubota, Hiromi Kataoka, Takashi Tokino, Takashi Yao, Toshinari Minamoto

The Journal of pathology 2020.08 [Refereed] [International journal]

The molecular and clinical characteristics of non-ampullary duodenal adenomas and intramucosal adenocarcinomas are not fully understood because they are rare. To clarify these characteristics, we performed genetic and epigenetic analysis of cancer-related genes in these lesions. One-hundred seven non-ampullary duodenal adenomas and intramucosal adenocarcinomas, including 100 small intestinal type tumors (90 adenomas and 10 intramucosal adenocarcinomas) and 7 gastric type tumors (2 pyloric gland adenomas and 5 intramucosal adenocarcinomas), were investigated. Using bisulfite pyrosequencing, we assessed the methylation status of CpG island methylator phenotype (CIMP) markers and MLH1. Then using next-generation sequencing, we performed targeted exome sequence analysis within 75 cancer-related genes in 102 lesions. There were significant differences in the clinicopathological and molecular variables between small intestinal and gastric type tumors, which suggests the presence of at least two separate carcinogenic pathways in non-ampullary duodenal adenocarcinomas. The prevalence of CIMP-positive lesions was higher in intramucosal adenocarcinomas than adenomas. Thus, concurrent hypermethylation of multiple CpG islands is likely associated with development of non-ampullary duodenal intramucosal adenocarcinomas. Mutation analysis showed that APC was the most frequently mutated gene in these lesions (56/102; 55%), followed by KRAS (13/102; 13%), LRP1B (10/102; 10%), GNAS (8/102; 8%), ERBB3 (7/102; 7%), and RNF43 (6/102; 6%). Additionally, the high prevalence of diffuse or focal nuclear β-catenin accumulation (87/102; 85%) as well as mutations of WNT pathway components (60/102; 59%) indicate the importance of WNT signaling to the initiation of duodenal adenomas. The higher than previously reported frequency of APC gene mutations in small bowel adenocarcinomas as well as the difference in the APC mutation distributions between small intestinal type adenomas and intramucosal adenocarcinomas may indicate the adenoma-carcinoma sequence has only limited involvement in duodenal carcinogenesis. This article is protected by copyright. All rights reserved.

DOI PubMed

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Papers - SASAKI Yasushi