Publications by authors named "Masatoshi Kusuhara"

98 Publications

Sharing genetic test results of germline pathogenic variants of hereditary cancer with relatives: A single-center cross-sectional study.

Jpn J Clin Oncol 2021 Jul 8. Epub 2021 Jul 8.

Graduate School of Health Management, Keio University, Tokyo, Japan.

Objective: This study aimed to determine whether Japanese cancer patients share test results of germline pathogenic variants of hereditary cancer with their relatives.

Methods: This single-center cross-sectional study enrolled 21 Japanese patients who received results of germline pathogenic variants of hereditary cancer at least 6 months prior.

Results: All patients shared their test results with at least one relative, with the following sharing rates: 85.7% for first-degree relatives, 10% for second-degree relatives and 8.3% for third-degree relatives. Patients most commonly shared the information with their children aged >18 years (86.7%), followed by their siblings (73.6%), spouses (64.7%) and parents (54.5%). Three categories were extracted from qualitative analysis: 'characteristics of my cancer', 'knowledge and caution about inheritability' and 'utilization of medical care.'

Conclusions: The rate of test result sharing with first-degree relatives was comparable with those in Europe and the USA. Patients with germline pathogenic variants also tended to share their test results more with their children and siblings than with their parents. Informing their relatives of the results was suggestive of the motivation to influence their relatives' health outcome and contribute to the well-being of their children and siblings.
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http://dx.doi.org/10.1093/jjco/hyab110DOI Listing
July 2021

BMP4 and PHLDA1 are plausible drug-targetable candidate genes for KRAS G12A-, G12D-, and G12V-driven colorectal cancer.

Mol Cell Biochem 2021 May 12. Epub 2021 May 12.

Shizuoka Cancer Center, Shizuoka, Japan.

Despite the frequent detection of KRAS driver mutations in patients with colorectal cancer (CRC), no effective treatments that target mutant KRAS proteins have been introduced into clinical practice. In this study, we identified potential effector molecules, based on differences in gene expression between CRC patients carrying wild-type KRAS (n = 390) and those carrying KRAS mutations in codon 12 (n = 240). CRC patients with wild-type KRAS harboring mutations in HRAS, NRAS, PIK3CA, PIK3CD, PIK3CG, RALGDS, BRAF, or ARAF were excluded from the analysis. At least 11 promising candidate molecules showed greater than two-fold change between the KRAS G12 mutant and wild-type and had a Benjamini-Hochberg-adjusted P value of less than 1E-08, evidence of significantly differential expression between these two groups. Among these 11 genes examined in cell lines transfected with KRAS G12 mutants, BMP4, PHLDA1, and GJB5 showed significantly higher expression level in KRAS G12A, G12D, and G12V transfected cells than in the wild-type transfected cells. We expect that this study will lead to the development of novel treatments that target signaling molecules functioning with KRAS G12-driven CRC.
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http://dx.doi.org/10.1007/s11010-021-04172-8DOI Listing
May 2021

Comprehensive genomic analysis contrasting primary colorectal cancer and matched liver metastases.

Oncol Lett 2021 Jun 12;21(6):466. Epub 2021 Apr 12.

Shizuoka Cancer Center, Shizuoka 411-8777, Japan.

Recent studies have revealed that colorectal cancer (CRC) displays intratumor genetic heterogeneity, and that the cancer microenvironment plays an important role in the proliferation, invasion and metastasis of CRC. The present study performed genomic analysis on paired primary CRC and synchronous colorectal liver metastasis (CRLM) tissues collected from 22 patients using whole-exome sequencing, cancer gene panels and microarray gene expression profiling. In addition, immunohistochemical analysis was used to confirm the protein expression levels of genes identified as highly expressed in CRLM by DNA microarray analysis. The present study identified 10 genes that were highly expressed in CRLM compared with in CRC, from 36,022 probes obtained from primary CRC, CRLM and normal liver tissues by gene expression analysis with DNA microarrays. Of the 10 genes identified, five were classified as encoding 'matricellular proteins' [(osteopontin, periostin, thrombospondin-2, matrix Gla protein (MGP) and glycoprotein nonmetastatic melanoma protein B (GPNMB)] and were selected for immunohistochemical analysis. Osteopontin was strongly expressed in CRLM (6 of 22 cases: 27.3%), but not in CRC (0 of 22: 0%; P=0.02). Periostin also exhibited strong immunoreactivity in CRLM (17 of 22: 68.2%) compared with in CRC (7 of 22: 31.8%; P=0.006). Thrombospondin-2 exhibited strong immunoreactivity in both CRC and CRLM (54.5% in CRC, 45.5% in CRLM; P=0.55). GPNMB and MGP were rarely positive for both CRC and CRLM. A comparison of immunoreactive positive factors for these five genes revealed the complexities of gene expression in CRLM. Of the cases examined, 16 (72.7%) cases of CRC showed zero or only one positive immunoreactive factor. By contrast, CRLM showed more frequent and multiple immunoreactive factors; for example, 16 cases (72.7%) shared two or more factors, which was statistically more frequent than in CRC (P=0.007). The present study revealed the genomic heterogeneity between paired primary CRC and CRLM, in terms of cancer cell microenvironment. This finding may lead to novel diagnostic and therapeutic targets in the era of genome-guided personalized cancer treatment.
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http://dx.doi.org/10.3892/ol.2021.12727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063276PMC
June 2021

Genomic profiling of multiple tissues in two patients with multiple endocrine neoplasia type 1.

Biomed Res 2021 ;42(2):89-94

Shizuoka Cancer Center.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor syndrome. This hereditary cancer is caused by germline variants in MEN1. Two patients with MEN1 were identified via whole exome sequencing and gene expression profile analysis, conducted for 5,063 patients with various types of cancers. We obtained multiple tumors from each patient; tumors derived from these two MEN1 patients had a loss of the normal MEN1 allele and frequently chromosomal copy number changes. Thus, we investigated whether structural variants were present in the MEN1 patient genomes. Whole-genome sequencing revealed no catastrophic rearrangements, and the tumor samples had very low somatic variants. The two patients had germline variants in MEN1 and some chromosomal copy number changes including on chromosome 11. The only pathogenic variant detected was the MEN1 germline variant, and chromosomal rearrangements led to tumorigenesis in somatic cells. Furthermore, the MEN1 tumor samples displayed a specific signature characterized by T:A>C:G transition. Studies of multiple tumors obtained from single patients are rare in hereditary cancer syndromes, and our results provide insights that the second hit of the tumor suppressor gene MEN1 may be caused by a gross genome rearrangement, not a small insertion and deletion, nor a change in epigenetic regulation.
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http://dx.doi.org/10.2220/biomedres.42.89DOI Listing
January 2021

Metabolic Profiling of Human Gastric Cancer Cells Treated With Salazosulfapyridine.

Technol Cancer Res Treat 2020 Jan-Dec;19:1533033820928621

Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.

Purpose: The adhesion molecule cluster of differentiation 44v9 interacts with and stabilizes the cystine/glutamate exchanger protein, which functions as a transporter of cystine. Stabilized cystine/glutamate exchanger increases extracellular cystine uptake and enhances glutathione production. Augmented levels of reduced glutathione mitigate reactive oxygen species and protect cancer cells from apoptosis. Salazosulfapyridine blocks cystine/glutamate exchanger activity and mitigates the supply of cystine to increase intracellular ROS production, thereby increasing cell susceptibility to apoptosis. This enhances the effect of anticancer drugs such as cisplatin. Currently, salazosulfapyridine is being developed as a promising anticancer agent. In the present study, we elucidated the molecular mechanism associated with salazosulfapyridine by investigating the salazosulfapyridine-induced changes in glutathione metabolism in cultured gastric cancer cell lines.

Methods: The effect of salazosulfapyridine treatment on glutathione metabolism was investigated in 4 gastric cancer (AGS, MKN1, MKN45, and MKN74) and 2 colorectal cancer (HCT15 and HCT116) cell lines using metabolomic analyses. In addition, the effect of inhibition of the reduced form of nicotinamide adenine dinucleotide phosphate by 2-deoxyglucose on glutathione metabolism was evaluated.

Results: Under hypoxia, enhanced glycolysis resulted in lactate accumulation with an associated reduction in nicotinamide adenine dinucleotide phosphate. Salazosulfapyridine treatment decreased the cysteine content and inhibited the formation of glutathione. Combined treatment with salazosulfapyridine and 2-deoxyglucose significantly inhibited cell proliferation. 2-Deoxyglucose, an inhibitor of glycolysis, depleted nicotinamide adenine dinucleotide phosphate required for the formation of glutathione.

Conclusions: Our results indicate that in cancer cells having a predominant glycolytic pathway, metabolomic analyses under hypoxic conditions enable the profiling of global metabolism. In addition, inhibiting the supply of nicotinamide adenine dinucleotide phosphate by blocking glycolysis is a potential treatment strategy for cancer, in addition to cystine blockade by salazosulfapyridine.
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http://dx.doi.org/10.1177/1533033820928621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385828PMC
July 2020

Disclosure of secondary findings in exome sequencing of 2480 Japanese cancer patients.

Hum Genet 2021 Feb 24;140(2):321-331. Epub 2020 Jul 24.

Research Institute of Shizuoka Cancer Center, Shizuoka, Japan.

High-throughput sequencing has greatly contributed to precision medicine. However, challenges remain in reporting secondary findings (SFs) of germline pathogenic variants and managing the affected patients. The aim of this study was to examine the incidence of SFs in Japanese cancer patients using whole exome sequencing (WES) and to understand patient preferences regarding SF disclosure. WES was conducted for 2480 cancer patients. Genomic data were screened and classified for variants of 59 genes listed by the American College of Medical Genetics and Genomics SF v2.0 and for an additional 13 hereditary cancer-related genes. Majority of the participants (68.9%; 1709/2480) opted for disclosure of their SFs. Thirty-two pathogenic or likely pathogenic variants, including BRCA1 (7 patients), BRCA2 (4), CHEK2 (4), PTEN (3), MLH1 (3), SDHB (2), MSH6 (1), NF1 (1), EXT2 (1), NF1 (1), NTRK1 (1), MYH7 (3), MYL2 (1), TNNT2 (1), LDLR (2), FBN1 (1), and KCNH2 (1) were recognized in 36 patients (1.5%). Twenty-eight (77.8%) patients underwent genetic counseling and received their SF results. Eighteen (64.3%) patients underwent clinical management for SFs. Genetic validation tests were administered significantly more frequently to patients with than without a SF-related personal history (P = 0.025). This was a first attempt at a large-scale systematic exome analysis in Japan; nevertheless, many cancer patients opted for disclosure of SFs and accepted or considered clinical management.
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http://dx.doi.org/10.1007/s00439-020-02207-6DOI Listing
February 2021

Molecular profile of a pleomorphic adenoma of the hard palate: A case report.

Medicine (Baltimore) 2020 Jul;99(29):e21207

Division of Head and Neck Surgery, Shizuoka Cancer Center Hospital.

Rationale: Pleomorphic adenoma (PA) is the most common benign tumor of salivary glands. PAs have the potential for regional and distant metastases that preserve their benign phenotype; they also have the potential for malignant transformation. The molecular pathogenesis of malignant neoplasms has been studied extensively in recent years, unlike that of benign tumors, such as PA.

Patient Concerns: In this case report, we identified the molecular signatures of a 57-year-old Japanese woman. Our patient presented with a swelling of the hard palate with an erosive appearance.

Diagnoses: The patient was diagnosed with a right hard palate tumor suspected to be a malignant neoplasm.

Interventions: Partial maxillary resection and reconstruction were performed.

Outcomes: There was no obstacle to swallowing or dysarthria after surgery. There was no sign of recurrent palatal tumor 4 years after the operation. Using next generation sequencing, 5 nonsynonymous mutations and CHCHD7-PLAG1 fusion genes were detected. Moreover, gene expression profiling indicated the possibility of the activation of several cancer-related signaling pathways. Although the PLAG1 gene is predicted to play a crucial role in PA tumorigenesis, its over-expression is reported to mediate multiple downstream factors. In this case, various up- and downregulated RNA signaling pathways, including MAP kinase signaling, PI3K/AKT1/MTOR signaling, JAK/STAT signaling, and PD-L1 signaling, were revealed.

Lessons: These molecular profiles of PA may elucidate the mechanism of metastasis, preserving its benign phenotype and carcinoma ex PA.
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http://dx.doi.org/10.1097/MD.0000000000021207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373603PMC
July 2020

Effect of preoperative chemoradiotherapy on the immunological status of rectal cancer patients.

J Radiat Res 2020 Sep;61(5):766-775

Immunotherapy Division, Shizuoka Cancer Center Research Institute, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.

The aim of the study was to investigate the effect of chemo-radiation on the genetic and immunological status of rectal cancer patients who were treated with preoperative chemoradiotherapy (CRT). The expression of immune response-associated genes was compared between rectal cancer patients treated (n = 9) and not-treated (n = 10) with preoperative CRT using volcano plot analysis. Apoptosis and epithelial-to-mesenchymal transition (EMT) marker genes were analysed by quantitative PCR (qPCR). Other markers associated with the tumor microenvironment (TME), such as tumor-infiltrating lymphocytes (TIL) and immune checkpoint molecules, were investigated using immunohistochemistry (IHC). The clinical responses of preoperative CRT for 9 rectal cancer patients were all rated as stable disease, while the pathological tumor regression score (TRG) revealed 6 cases of grade2 and 3 cases of grade1. According to the genetic signature of colon cancers, treated tumors belonged to consensus molecular subtype (CMS)4, while not-treated tumors had signatures of CMS2 or 3. CRT-treated tumors showed significant upregulation of EMT-associated genes, such as CDH2, TGF-beta and FGF, and cancer stem cell-associated genes. Additionally, qPCR and IHC demonstrated a suppressive immunological status derived from the upregulation of inflammatory cytokines (IL-6, IL-10 and TGF-beta) and immune checkpoint genes (B7-H3 and B7-H5) and from M2-type macrophage accumulation in the tumor. The induction of EMT and immune-suppressive status in the tumor after strong CRT treatment urges the development of a novel combined therapy that restores immune-suppression and inhibits EMT, ultimately leading to distant metastasis control.
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http://dx.doi.org/10.1093/jrr/rraa041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482156PMC
September 2020

Assessment of associations between clinical and immune microenvironmental factors and tumor mutation burden in resected nonsmall cell lung cancer by applying machine learning to whole-slide images.

Cancer Med 2020 07 12;9(13):4864-4875. Epub 2020 May 12.

Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.

Background: It is unclear whether clinical factors and immune microenvironment (IME) factors are associated with tumor mutation burden (TMB) in patients with nonsmall cell lung cancer (NSCLC).

Materials And Methods: We assessed TMB in surgical tumor specimens by performing whole exome sequencing. IME profiles, including PD-L1 tumor proportion score (TPS), stromal CD8 tumor-infiltrating lymphocyte (TIL) density, and stromal Foxp3 TIL density, were quantified by digital pathology using a machine learning algorithm. To detect factors associated with TMB, clinical data, and IME factors were assessed by means of a multiple regression model.

Results: We analyzed tumors from 200 of the 246 surgically resected NSCLC patients between September 2014 and September 2015. Patient background: median age (range) 70 years (39-87); male 37.5%; smoker 27.5%; pathological stage (p-stage) I/II/III, 63.5/22.5/14.0%; histological type Ad/Sq, 77.0/23.0%; primary tumor location upper/lower, 58.5/41.5%; median PET SUV 7.5 (0.86-29.8); median serum CEA (sCEA) level 3.4 ng/mL (0.5-144.3); median serum CYFRA 21-1 (sCYFRA) level 1.2 ng/mL (1.0-38.0); median TMB 2.19/ Mb (0.12-64.38); median PD-L1 TPS 15.1% (0.09-77.4); median stromal CD8 TIL density 582.1/mm (120.0-4967.6);, and median stromal Foxp3 TIL density 183.7/mm (6.3-544.0). The multiple regression analysis identified three factors associated with higher TMB: smoking status: smoker, increase PET SUV, and sCEA level: >5 ng/mL (P < .001, P < .001, and P = .006, respectively).

Conclusions: The IME factors assessed were not associated with TMB, but our findings showed that, in addition to smoking, PET SUV and sCEA levels may be independent predictors of TMB. TMB and IME factors are independent factors in resected NSCLC.
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http://dx.doi.org/10.1002/cam4.3107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333844PMC
July 2020

Metabolomic profiling of gastric cancer tissues identified potential biomarkers for predicting peritoneal recurrence.

Gastric Cancer 2020 09 26;23(5):874-883. Epub 2020 Mar 26.

Division of Gastric Surgery, Shizuoka Cancer Center, 1007, Shimonagakubo Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.

Background: Metabolomics is useful for analyzing the nutrients necessary for cancer progression, as the proliferation is regulated by available nutrients. We studied the metabolomic profile of gastric cancer (GC) tissue to elucidate the associations between metabolism and recurrence.

Methods: Cancer and adjacent non-cancerous tissues were obtained in a pair-wise manner from 140 patients with GC who underwent gastrectomy. Frozen tissues were homogenized and analyzed by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Metabolites were further assessed based on the presence or absence of recurrence.

Results: Ninety-three metabolites were quantified. In cancer tissues, the lactate level was significantly higher and the adenylate energy charge was lower than in non-cancerous tissues. The Asp, β-Ala, GDP, and Gly levels were significantly lower in patients with recurrence than in those without. Based on ROC analyses to determine the cut-off values of the four metabolites, patients were categorized into groups at high risk and low risk of peritoneal recurrence. Logistic regression and Cox proportional hazard analyses identified β-Ala as an independent predictor of peritoneal recurrence (hazard ratio [HR] 5.21 [95% confidence interval 1.07-35.89], p = 0.029) and an independent prognostic factor for the overall survival (HR 3.44 [95% CI 1.65-7.14], p < 0.001).

Conclusions: The metabolomic profiles of cancer tissues differed from those of non-cancerous tissues. In addition, four metabolites were significantly associated with recurrence in GC. β-Ala was both a significant predictor of peritoneal recurrence and a prognostic factor.
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http://dx.doi.org/10.1007/s10120-020-01065-5DOI Listing
September 2020

Japanese version of The Cancer Genome Atlas, JCGA, established using fresh frozen tumors obtained from 5143 cancer patients.

Cancer Sci 2020 Feb 22;111(2):687-699. Epub 2020 Jan 22.

Division of Ophthalmology, Shizuoka Cancer Center Hospital, Shizuoka, Japan.

This study aimed to establish the Japanese Cancer Genome Atlas (JCGA) using data from fresh frozen tumor tissues obtained from 5143 Japanese cancer patients, including those with colorectal cancer (31.6%), lung cancer (16.5%), gastric cancer (10.8%) and other cancers (41.1%). The results are part of a single-center study called "High-tech Omics-based Patient Evaluation" or "Project HOPE" conducted at the Shizuoka Cancer Center, Japan. All DNA samples and most RNA samples were analyzed using whole-exome sequencing, cancer gene panel sequencing, fusion gene panel sequencing and microarray gene expression profiling, and the results were annotated using an analysis pipeline termed "Shizuoka Multi-omics Analysis Protocol" developed in-house. Somatic driver alterations were identified in 72.2% of samples in 362 genes (average, 2.3 driver events per sample). Actionable information on drugs that is applicable in the current clinical setting was associated with 11.3% of samples. When including those drugs that are used for investigative purposes, actionable information was assigned to 55.0% of samples. Germline analysis revealed pathogenic mutations in hereditary cancer genes in 9.2% of samples, among which 12.2% were confirmed as pathogenic mutations by confirmatory test. Pathogenic mutations associated with non-cancerous hereditary diseases were detected in 0.4% of samples. Tumor mutation burden (TMB) analysis revealed 5.4% of samples as having the hypermutator phenotype (TMB ≥ 20). Clonal hematopoiesis was observed in 8.4% of samples. Thus, the JCGA dataset and the analytical procedures constitute a fundamental resource for genomic medicine for Japanese cancer patients.
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http://dx.doi.org/10.1111/cas.14290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004528PMC
February 2020

Characterization of tumour mutation burden in patients with non-small cell lung cancer and interstitial lung disease.

Respirology 2020 08 6;25(8):850-854. Epub 2019 Nov 6.

Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.

Background And Objective: The efficacy expectation of immune checkpoint inhibitors against NSCLC in patients with ILD seems to be high because these populations are supposed to have high TMB. However, information about the characterization of TMB in patients with NSCLC and ILD is limited. Therefore, this study aimed to evaluate TMB in samples of NSCLC with ILD and clarify factors that influence TMB values.

Methods: The medical records of patients with NSCLC who underwent thoracic surgery at our institution between January 2014 and January 2017 were retrospectively reviewed. Whole-exome sequencing with an Ion Proton system and gene expression profiling of fresh surgical specimens were performed.

Results: Among 367 patients with NSCLC, 62 (16.9%) were diagnosed with ILD. All samples were collected from primary tumours with a median TMB of approximately 2.1 (range: 0.1-64.4) mutation/Mb. Among 81 squamous cell carcinomas, we compared 27 tumours with concomitant ILD and 54 tumours without ILD. Univariate analyses revealed that tumours with concomitant ILD showed lower TMB values than those without ILD. Multivariate analysis revealed that concomitant ILD was significantly associated with low TMB values. Conversely, no difference was noted in the TMB value of adenocarcinoma between patients with and without ILD.

Conclusion: Squamous cell carcinoma and adenocarcinoma with ILD do not have high TMB values. Therefore, considering the risk of severe pneumonitis, immune checkpoint inhibitors should not be used routinely against patients with NSCLC and ILD based on the expectation of high TMB values.
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http://dx.doi.org/10.1111/resp.13726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496253PMC
August 2020

Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors.

Cancer Sci 2019 Dec 14;110(12):3821-3833. Epub 2019 Oct 14.

Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, Japan.

Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression. Herein, we aimed to identify driver genes and signaling pathways relevant to GIST progression. We investigated genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, and gene expression for 65 clinical specimens of surgically dissected GIST, consisting of six metastatic tumors and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations included oncogenic mutations and amplification-dependent expression enhancement for oncogenes (OG), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSG). We assigned activated OG and inactivated TSG to 27 signaling pathways, the activation of which was compared between malignant GIST (metastasis and high-risk GIST) and less malignant GIST (low- and very low-risk GIST). Integrative molecular profiling indicated that a greater incidence of genetic alterations of driver genes was detected in malignant GIST (96%, 22 of 23) than in less malignant GIST (73%, 24 of 33). Malignant GIST samples groups showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and the cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K-related genes, the expression of which was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GIST. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GIST.
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http://dx.doi.org/10.1111/cas.14202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890443PMC
December 2019

Germline mismatch repair gene variants analyzed by universal sequencing in Japanese cancer patients.

Cancer Med 2019 Sep 6;8(12):5534-5543. Epub 2019 Aug 6.

Shizuoka Cancer Center Research Institute, Shizuoka, Japan.

Background: Lynch syndrome (LS) is the commonest inherited cancer syndrome caused by pathogenic variants of germline DNA mismatch repair (g.MMR) genes. Genome-wide sequencing is now increasingly applied for tumor characterization, but not for g.MMR. The aim of this study was to evaluate the incidence and pathogenicity of g.MMR variants in Japanese cancer patients.

Methods: Four g.MMR genes (MLH1, MSH2, MSH6, and PMS2) were analyzed by next generation sequencing in 1058 cancer patients (614 male, 444 female; mean age 65.6 years) without past diagnosis of LS. The g.MMR variant pathogenicity was classified based on the ClinVar 2015 database. Tumor MMR immunohistochemistry, microsatellite instability (MSI), and BRAF sequencing were also investigated in specific cases.

Results: Overall, 46 g.MMR variants were detected in 167 (15.8%) patients, 17 likely benign variants in 119 patients, 24 variants of uncertain significance (VUSs) in 68 patients, two likely pathogenic variants in two patients, and three pathogenic variants in three (0.3%) patients. The three pathogenic variants included two colorectal cancers with MLH1 loss and high MSI and one endometrial cancer with MSH6 loss and microsatellite stability. Two likely pathogenic variants were shifted to VUSs by ClinVar (2018). One colon cancer with a likely benign variant demonstrated MLH1 loss and BRAF mutation, but other nonpathogenic variants showed sustained MMR and microsatellite stability.

Conclusions: Universal sequencing of g.MMR genes demonstrated sundry benign variants, but only a small proportion of cancer patients had pathogenic variants. Pathogenicity evaluation using the ClinVar database agreed with MSI, MMR immunohistochemistry, and BRAF sequencing.
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http://dx.doi.org/10.1002/cam4.2432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745857PMC
September 2019

Associations Between Loss of ARID1A Expression and Clinicopathologic and Genetic Variables in T1 Early Colorectal Cancer.

Am J Clin Pathol 2019 09;152(4):463-470

Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan.

Objectives: To evaluate the relationships between adenine-thymine-rich interactive domain 1A (ARID1A) expression and the clinicopathologic features in T1 colorectal cancer (CRC) and to investigate whether the presence of ARID1A protein is related to genetic changes.

Methods: We retrospectively studied 219 surgically resected T1 CRCs. ARID1A expression was assessed by immunohistochemical methods, and the correlation between ARID1A expression and clinicopathologic features was evaluated. The relationship between ARID1A expression and 409 cancer-related gene mutations was also evaluated using next-generation sequencing (NGS).

Results: Immunohistochemical staining indicated negative ARID1A expression in 4.6%. Loss of ARID1A expression was significantly associated with younger age, lymphatic invasion, and lymph node metastasis (LNM). NGS showed that PKHD1, RNF213, and MSH6 mutations were more frequent in ARID1A-negative tumors, whereas KRAS mutations were more common in ARID1A-positive tumors.

Conclusions: In T1 CRC, negative ARID1A expression was correlated with early onset, lymphatic invasion, and LNM. Mutations in some cancer-related genes were possibly related with ARID1A expression.
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http://dx.doi.org/10.1093/ajcp/aqz062DOI Listing
September 2019

Clinicopathological and mutational analyses of colorectal cancer with mutations in the POLE gene.

Cancer Med 2019 08 25;8(10):4587-4597. Epub 2019 Jun 25.

Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, Japan.

Here, we investigated the clinicopathological and mutation profiles of colorectal cancer (CRC) with POLE mutations. Whole-exome sequencing was performed in 910 surgically resected primary CRCs. Tumors exceeding 500 counts of nonsynonymous single nucleotide variants (SNVs) were classified as hypermutators, whereas the remaining were classified as nonhypermutators. The hypermutators were subdivided into 2 groups. CRCs harboring more than 20% C-to-A and less than 3% C-to-G transversions were classified as POLE category tumors, whereas the remaining were classified as common-hypermutators. Gene expression profiling (GEP) analysis was performed in 892 (98.0%) tumors. Fifty-seven (6.3%) and 10 (1.1%) tumors were classified common-hypermutators and POLE category tumors, respectively. POLE category tumors harbored a significantly higher SNV count than common-hypermutators, and all POLE category tumors were associated with exonuclease domain mutations, such as P286R, F367C, V411L, and S297Y, in the POLE gene. Patients with POLE category tumors were significantly younger than those with nonhypermutators and common-hypermutators. All POLE mutations in the early-onset (age of onset ≤50 years old) POLE category (7 tumors) were P286R mutations. GEP analysis revealed that PD-L1 and PD-1 gene expression levels were significantly increased in both common-hypermutators and POLE category tumors compared with those in nonhypermutators. CD8A expression was significantly upregulated in POLE category tumors compared with that in nonhypermutators. Thus, we concluded that CRCs with POLE proofreading deficiency had characteristics distinct from those of other CRCs. Analysis of POLE proofreading deficiency may be clinically significant for personalized management of CRCs.
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http://dx.doi.org/10.1002/cam4.2344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712448PMC
August 2019

Cancer-associated cerebral infarction during direct oral anticoagulant treatment in cancer patients: a case series.

Int Cancer Conf J 2019 Jul 19;8(3):130-135. Epub 2019 Mar 19.

3Research Institute, Shizuoka Cancer Center, Shizuoka, Japan.

The effect of direct oral anticoagulants (DOACs) on cancer-associated cerebral infarction (CI) is unclear. We present the clinical course of 20 consecutive patients with cancer-associated CI that developed during treatment with DOACs. The incidence rate of cancer-associated CI during the treatment with DOACs was 3.4%. The median modified Rankin scale (mRS) and Karnofsky performance status (KPS) after CI were 5 and 30, respectively. The median survival time after CI was 1 month. In the group in which the thrombus due to venous thromboembolism (VTE) was reduced before CI, the median mRS, KPS, and prognosis after CI were significantly better than in those of the group with unchanged thrombus. Cancer-associated CI also developed in patients taking DOACs and those who did not show VTE recurrence. When the VTE thrombus decreased or disappeared with DOAC treatment, the clinical course after cancer-associated CI was improved.
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http://dx.doi.org/10.1007/s13691-019-00370-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545186PMC
July 2019

Mutational burden and signatures in 4000 Japanese cancers provide insights into tumorigenesis and response to therapy.

Cancer Sci 2019 Aug 24;110(8):2620-2628. Epub 2019 Jun 24.

Shizuoka Cancer Center, Nagaizumi, Japan.

Tumor mutational burden (TMB) and mutational signatures reflect the process of mutation accumulation in cancer. However, the significance of these emerging characteristics remains unclear. In the present study, we used whole-exome sequencing to analyze the TMB and mutational signature in solid tumors of 4046 Japanese patients. Eight predominant signatures-microsatellite instability, smoking, POLE, APOBEC, UV, mismatch repair, double-strand break repair, and Signature 16-were observed in tumors with TMB higher than 1.0 mutation/Mb, whereas POLE and UV signatures only showed moderate correlation with TMB, suggesting the extensive accumulation of mutations due to defective POLE and UV exposure. The contribution ratio of Signature 16, which is associated with hepatocellular carcinoma in drinkers, was increased in hypopharynx cancer. Tumors with predominant microsatellite instability signature were potential candidates for treatment with immune checkpoint inhibitors such as pembrolizumab and were found in 2.8% of cases. Furthermore, based on microarray analysis, tumors with predominant signatures were classified into 2 subgroups depending on the expression of immune-related genes reflecting differences in the immune context of the tumor microenvironment. Tumor subpopulations differing in the content of infiltrating immune cells might respond differently to immunotherapeutics. An understanding of cancer characteristics based on TMB and mutational signatures could provide new insights into mutation-driven tumorigenesis.
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http://dx.doi.org/10.1111/cas.14087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676127PMC
August 2019

A Fragrant Environment Containing α-Pinene Suppresses Tumor Growth in Mice by Modulating the Hypothalamus/Sympathetic Nerve/Leptin Axis and Immune System.

Integr Cancer Ther 2019 Jan-Dec;18:1534735419845139

1 Shizuoka Cancer Center Research Institute, Shizuoka, Japan.

The environment is thought to affect outcomes in patients with cancer; however, this relationship has not been proven directly. Recently, an enriched environment, as a model of a positive environment, has been shown to suppress tumor growth by lowering leptin production through a pathway involving the hypothalamus/sympathetic nerve/leptin axis. We previously reported that a fragrant environment (FE) containing α-pinene suppressed tumor growth in mice; however, the underlying mechanism has not been elucidated. Accordingly, in this study, we investigated changes in the neuroendocrine and immune systems following exposure to an FE. Mice were exposed to α-pinene (5 h/day) for 4 weeks prior to tumor implantation with murine melanoma cells and 3 weeks after transplantation. In addition to the evaluation of tumor growth, the blood, spleen, and hypothalamus were collected 3 weeks after transplantation, and neuroendocrinological and immunological parameters were measured. Tumor size was ~40% smaller in mice exposed to FE. Moreover, plasma noradrenaline concentrations, which reflected sympathetic nervous activity, tended to increase, and leptin levels were significantly decreased in FE-exposed mice. Levels of stress hormones, such as plasma corticosterone and adrenaline, did not change in the 2 groups. In the hypothalamus, brain-derived neurotrophic factor protein levels and glucose-1-phosphate concentrations were decreased in the FE group. Additionally, numbers of B cells, CD4 T cells, CD8 T cells, and natural killer cells increased in the FE-exposed mice. These neurohormonal and immunological changes in the FE-exposed mice suggested that the FE may activate the hypothalamus/sympathetic nerve/leptin axis and immune system, thereby retarding tumor growth.
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http://dx.doi.org/10.1177/1534735419845139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484235PMC
December 2019

Identification of a neoantigen epitope in a melanoma patient with good response to anti-PD-1 antibody therapy.

Immunol Lett 2019 04 14;208:52-59. Epub 2019 Mar 14.

Immunotherapy Division, Shizuoka Cancer Center Research Institute, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan. Electronic address:

Recent advances in next-generation sequencing have enabled rapid and efficient evaluation of the mutational landscape of cancers. As a result, many cancer-specific neoantigens, which can generate antitumor cytotoxic T-cells inside tumors, have been identified. Previously, we reported a metastatic melanoma case with high tumor mutation burden, who obtained complete remission after anti-PD-1 therapy and surgical resection. The rib metastatic lesion, which was used for whole-exome sequencing and gene expression profiling in the HOPE project, showed upregulated expression of PD-L1 mRNA and a high single-nucleotide variants number of 2712. In the current study, we focused on a metastatic melanoma case and candidate epitopes among nonsynonymous mutant neoantigens of 1348 variants were investigated using a peptide-HLA binding algorithm, in vitro cytotoxic T-cell induction assay and HLA tetramer staining. Specifically, from mutant neoantigen data, a total of 21,066 9-mer mutant epitope candidates including a mutated amino acid anywhere in the sequence were applied to the NetMHC binding prediction algorithm. From in silico data, we identified the top 26 mutant epitopes with strong-binding capacity. A cytotoxic T-cell induction assay using 5 cancer patient-derived PBMCs revealed that the mutant ARMT1 peptide sequence (FYGKTILWF) with HLA-A*2402 restriction was an efficient neoantigen, which was detected at a frequency of approximately 0.04% in the HLA-A24 tetramer stain. The present success in identifying a novel mutant antigen epitope might be applied to clinical neoantigen screening in the context of an NGS-equipped medical facility for the development of the next-generation neoantigen cancer vaccines.
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http://dx.doi.org/10.1016/j.imlet.2019.02.004DOI Listing
April 2019

Use of direct oral anti-coagulants for the treatment of venous thromboembolism in patients with advanced cancer: a prospective observational study.

Int J Clin Oncol 2019 Jul 12;24(7):876-881. Epub 2019 Feb 12.

Clinical Research Promotion Unit, Clinical Research Support Center, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.

Background: The efficacy of direct oral anti-coagulants (DOACs) for the treatment of venous thromboembolism (VTE) in Japanese patients with advanced cancer is largely unknown.

Methods: This prospective single-center observational study enrolled Japanese patients with unresectable advanced cancer who started DOAC treatment for new-onset VTE between December 2015 and May 2018. Patients were followed for 3 months to evaluate bleeding and VTE recurrences. The primary study endpoint was major and non-major bleeding.

Results: One hundred and forty-five of 147 enrolled patients were analyzed. Of these, 8 [5.5%, 95% confidence interval (CI) 2.8-10.5] and 29 patients (20%, 95% CI 14.3-27.2) experienced major and non-major bleeding, respectively. Patients with bleeding were more likely to have a poor performance status (PS) [hazard rate (HR) 2.04, 95% CI 1.15-3.63] and more frequent use of non-steroidal anti-inflammatory drugs (NSAIDs) (HR 2.75, 95% CI 1.62-4.67) relative to those without bleeding. In a multivariate analysis, combined DOAC and NSAID use correlated significantly with bleeding (odds ratio 4.63, 95% CI 1.70-12.9, p = 0.003). Among 105 of 145 patients included in the VTE recurrence assessment, 9 experienced a VTE recurrence (8.6%, 95% CI 4.6-15.5).

Conclusions: Our findings confirm the risk of bleeding during DOAC treatment for VTE in Japanese patients with advanced cancer, particularly those with poor PS and those using NSAIDs. The risk of bleeding in these patients may be reduced by avoiding the combined use of DOACs and NSAIDs.
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http://dx.doi.org/10.1007/s10147-019-01415-zDOI Listing
July 2019

Effect of Switching from the Initial Direct Oral Anticoagulant to Another One on Exacerbation of Venous Thromboembolism in Patients with Cancer: A Retrospective Study.

Ann Vasc Dis 2018 Dec;11(4):531-534

Research Institute, Shizuoka Cancer Center, Shizuoka, Japan.

: To determine the effect of switching from the initial direct oral anticoagulant (DOAC) to another DOAC on exacerbation of deep vein thrombosis (DVT). : We retrospectively reviewed the data of patients with advanced cancer who experienced exacerbated DVT during initial treatment with DOAC due to new venous thromboembolism (VTE). After switching to another DOAC for VTE recurrence, changes in the thrombus and bleeding were evaluated for 3 months. Eighteen patients met these criteria. We compared the effect of anticoagulant switching on the switched-drug group in those 18 patients with the effect of no anticoagulant switching on the single-drug group of patients (n=78) with a similar background. : The recurrence rate of VTE in the switched-drug group was 6%. Non-major bleeding occurred in 11% of patients. Recurrent VTE occurred in 6% of patients in both the switched-drug and single-drug groups, respectively [risk ratio (RR): 0.9, 95% confidence interval (CI): 0.11-7.6]. Non-major bleeding occurred in 11% and 14% of patients in the switched-drug and single-drug groups, respectively (RR: 0.79, 95%CI: 0.19-3.2). : Switching DOAC may be a treatment option for exacerbation of DVT in patients with advanced cancer.
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http://dx.doi.org/10.3400/avd.oa.18-00072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326063PMC
December 2018

Genetic alterations of driver genes as independent prognostic factors for disease-free survival in patients with resected non-small cell lung cancer.

Lung Cancer 2019 02 5;128:152-157. Epub 2018 Dec 5.

Division of Thoracic Surgery, Shizuoka Cancer Center, Japan.

Objectives: This study assessed the associations between the molecular signatures and clinical information in non-small cell lung cancer (NSCLC) patients with postoperative disease-free survival (p-dfs) to identify novel prognostic factors, focusing on associations with driver gene alterations.

Materials And Methods: Between February 2014 and September 2015, 242 patients with NSCLC, including 192 patients with adenocarcinoma (Ad) and 50 patients with squamous cell carcinoma (Sq), underwent surgery and were enrolled in this study. Surgically resected tissues were subjected to whole exome sequencing. Mt detected in 138 cancer-related genes were evaluated as driver mutations. A multivariate analysis using the multi-state model was used to establish the associations between co-variables and p-dfs.

Results: Postoperative recurrence (p-rec) was observed in 49 (20.2%) and 19 (7.9%) patients with Ad and Sq, respectively. The median (range) follow-up period for all the censored cases was 2.5 (2.0-3.5) years. The characteristics of the patients with postoperative recurrence were as follows: median age (range), 71 (50-87) years; male, 38 (56%); smoker, 51 (75%); p-stage (I/II/III), 30 (44%)/19 (28%)/19 (28%); histological type (Ad/Sq), 49 (72%)/19 (28%); adjuvant chemotherapy (yes/no), 30 (44%)/38 (56%); and driver gene alteration (presence/absence), 65 (96%)/3 (4%). In univariate analyses, age (<70/≧70 years), smoking history (yes/no), p-stage (I, II/III), histological type (Ad/Sq), and driver mutation (presence/absence) were favorable prognostic factors (P = .017, P = .048, P = .0002, P = .006, P = .029, respectively). A multivariate analysis also revealed a significant association between the driver mutation status and p-dfs (P = .046; odds ratio [OR], 2.86; 95% confidence interval [CI], 1.02-8.08), when adjusted according to histological type (P = .10), smoking status (P = .09), gender (P = .51), age (P = .008) and p-stage (P = .00003).

Conclusion: The driver mutation status may be an independent prognostic factor of p-dfs in NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2018.12.005DOI Listing
February 2019

Classification of tumor microenvironment immune types based on immune response-associated gene expression.

Int J Oncol 2019 Jan 2;54(1):219-228. Epub 2018 Nov 2.

Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka 411-8777, Japan.

In 2014, the Shizuoka Cancer Center launched project High‑tech Omics‑based Patient Evaluation (HOPE), which features whole exome sequencing (WES) and gene expression profiling (GEP) of fresh surgical specimens from cancer patients. With the development of clinical trials of programmed death‑1 (PD‑1)/PD‑ligand 1 (PD‑L1) blockade, PD‑L1 expression and a high tumor mutation burden become possible biomarkers that could be used to predict immune responses. In this study, based on WES and GEP data from 1,734 tumors from the HOPE project, we established a tumor microenvironment (TME) immune‑type classification consisting of 4 types to evaluate the immunological status of cancer patients and analyze immunological pathways specific for immune types. Project HOPE was conducted in accordance with the Ethical Guidelines for Human Genome and Genetic Analysis Research with the approval of the Institutional Review Board. Based on the expression level of the PD‑L1 and CD8B genes, the immunological status was divided into 4 types as follows: A, PD‑L1+CD8B+; B, PD‑L1+CD8B‑; C, PD‑L1‑CD8B‑; and D, PD‑L1‑CD8B+. Type A, with PD‑L1+ and CD8B+, exhibited an upregulation of cytotoxic T lymphocyte (CTL) killing‑associated genes, T‑cell activation genes, antigen‑presentation and dendritic cell (DC) maturation genes, and T‑cell‑attracting chemokine genes, which promoted Th1 antitumor responses. By contrast, type C, with PD‑L1‑ and CD8B‑, exhibited a low expression of T‑cell‑activating genes and an upregulation of cancer driver gene signaling, which suggested an immune‑suppressive status. With regard to hypermutator tumors, PD‑L1+ hypermutator cases exhibited a specific upregulation of the IL6 gene compared with the PD‑L1‑ cases. On the whole, our data indicate that the classification of the TME immune types may prove to be a useful tool for evaluating the immunological status and predicting antitumor responses and prognosis.
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http://dx.doi.org/10.3892/ijo.2018.4617DOI Listing
January 2019

Transcriptional activation of a chimeric retrogene PIPSL in a hominoid ancestor.

Gene 2018 Dec 8;678:318-323. Epub 2018 Aug 8.

Graduate School of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga, Japan. Electronic address:

Retrogenes are a class of functional genes derived from the mRNA of various intron-containing genes. PIPSL was created through a unique mechanism, whereby distinct genes were assembled at the RNA level, and the resulting chimera was then reverse transcribed and integrated into the genome by the L1 retrotransposon. Expression of PIPSL RNA via its transcription start sites (TSSs) has been confirmed in the testes of humans and chimpanzee. Here, we demonstrated that PIPSL RNA is expressed in the testis of the white-handed gibbon. The 5'-end positions of gibbon RNAs were confined to a narrow range upstream of the PIPSL start codon and overlapped with those of orangutan and human, suggesting that PIPSL TSSs are similar among hominoid species. Reporter assays using a luciferase gene and the flanking sequences of human PIPSL showed that an upstream sequence exhibits weak promoter activity in human cells. Our findings suggest that PIPSL might have acquired a promoter at an early stage of hominoid evolution before the divergence of gibbons and ultimately retained similar TSSs in all of the lineages. Moreover, the upstream sequence derived from the phosphatidylinositol-4-phosphate 5-kinase, type I, alpha 5' untranslated region and/or neighboring repetitive sequences in the genome possibly exhibits promoter activity. Furthermore, we observed that a TATA-box-like sequence has emerged by nucleotide substitution in a lineage leading to humans, with this possibly responsible for a broader distribution of the human PIPSL TSSs.
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http://dx.doi.org/10.1016/j.gene.2018.08.033DOI Listing
December 2018

Tumor mutational burden analysis of 2,000 Japanese cancer genomes using whole exome and targeted gene panel sequencing.

Biomed Res 2018 ;39(3):159-167

Shizuoka Cancer Center.

Tumor mutational burden (TMB) is an emerging characteristic in cancer and has been associated with microsatellite instability, defective DNA replication/repair, and response to PD-1 and PD-L1 blockade immunotherapy. When estimating TMB, targeted panel sequencing is performed using a few hundred genes; however, a comparison of TMB results obtained with this platform and with whole exome sequencing (WES) has not been performed for various cancer types. In the present study, we compared TMB results using the above two platforms in 2,908 solid tumors that were obtained from Japanese patients. For next-generation sequencing, we used fresh-frozen tissue specimens. The Ion Proton System was employed to detect somatic mutations in the coding genome and to sequence an available cancer panel that targeted 409 genes. We then selected 2,040 samples with sufficient tumor cellularity for TMB analysis. In tumors with TMB-high (TMB ≥ 20 mutations/Mb), TMB derived from WES correlated well with the estimated TMB (eTMB) based on panel sequencing, whereas TMB in the remaining tumors showed a weak correlation. In particular, eTMB was overestimated in tumors with low-frequency mutations, resulting in the accumulation of EGFR mutations not being discriminated as a feature of lung cancer with low-frequency mutations. The eTMB in tumors harboring POLE mutations and microsatellite instability was not overestimated, suggesting that panel sequencing could accurately estimate TMB in tumors with high-frequency mutations such as hypermutator tumors. These results may provide helpful information for interpreting TMB results based on clinical sequencing using a targeted gene panel.
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http://dx.doi.org/10.2220/biomedres.39.159DOI Listing
October 2018

Molecular profiling and sequential somatic mutation shift in hypermutator tumours harbouring POLE mutations.

Sci Rep 2018 06 7;8(1):8700. Epub 2018 Jun 7.

Shizuoka Cancer Center, Sunto-gun, Shizuoka, 411-8777, Japan.

Defective DNA polymerase ε (POLE) proofreading leads to extensive somatic mutations that exhibit biased mutational properties; however, the characteristics of POLE-mutated tumours remain unclear. In the present study, we describe a molecular profile using whole exome sequencing based on the transition of somatic mutations in 10 POLE-mutated solid tumours that were obtained from 2,042 Japanese patients. The bias of accumulated variations in these mutants was quantified to follow a pattern of somatic mutations, thereby classifying the sequential mutation shift into three periods. During the period prior to occurrence of the aberrant POLE, bare accumulation of mutations in cancer-related genes was observed, whereas PTEN was highly mutated in conjunction with or subsequent to the event, suggesting that POLE and PTEN mutations were responsible for the development of POLE-mutated tumours. Furthermore, homologous recombination was restored following the occurrence of PTEN mutations. Our strategy for estimation of the footprint of somatic mutations may provide new insight towards the understanding of mutation-driven tumourigenesis.
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http://dx.doi.org/10.1038/s41598-018-26967-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992218PMC
June 2018

The down-regulation of the CYP2C19 gene is associated with aggressive tumor potential and the poorer recurrence-free survival of hepatocellular carcinoma.

Oncotarget 2018 Apr 24;9(31):22058-22068. Epub 2018 Apr 24.

Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, Japan.

Project HOPE (High-tech Omics-based Patient Evaluation) began in 2014 using integrated gene expression profiling (GEP) of cancer tissues as well as diathesis of each patient who underwent an operation at our institution. The aim of this study was to clarify the association between the expression of cytochrome P450s (CYP) genes and recurrence of hepatocellular carcinoma (HCC). The present study included 92 patients. Genes with aberrant expression were selected based on a ≥10-fold difference in the expression between tumor and non-tumor tissues. The GEP analysis showed that the down-regulated genes in tumor tissue were CYP3A4 in 56 patients (61%), CYP2C8 in 44 patients (48%), CYP2C19 in 30 patients (33%), CYP2D6 in 11 patients (12%), CYP3A5 in 7 patients (8%) and CYP1B1 in 2 patients (2%). There was no patients with down-regulation of the CYP17A1 gene. A multivariate analysis revealed that the presence of microscopic portal invasion (hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.30-5.05 = 0.006), the presence of intrahepatic-metastasis (HR 3.09 95% CI 1.52-6.29 = 0.002) and down-regulation of the CYP2C19 gene (HR 3.69 95% CI 1.83-7.46 < 0.001) were independent predictors for the recurrence-free survival (RFS). The down-regulation of the CYP2C19 gene were correlated with the RFS in HCC.
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http://dx.doi.org/10.18632/oncotarget.25178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955155PMC
April 2018

A novel intronic variant in a young Japanese patient with Lynch syndrome.

Hum Genome Var 2018 23;5. Epub 2018 Apr 23.

8Shizuoka Cancer Center Research Institute, Shizuoka, Japan.

Lynch syndrome, an autosomal dominantly inherited disease, is characterized by an increased risk of developing colorectal cancer. We found a novel germline variant of (IVS6+2T>C) that caused Lynch syndrome in a young Japanese patient who had multiple colorectal cancers. Accurate diagnosis will be highly beneficial in clinical practice for surveillance and genetic counseling of patients and their relatives.
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http://dx.doi.org/10.1038/s41439-018-0002-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938003PMC
April 2018
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