Publications by authors named "Masashi Fujita"

171 Publications

Serial Changes in Cardiac Strain and Contractility After Hematopoietic Stem Cell Transplantation in Patients with Hematologic Malignancies.

Int Heart J 2021 May 15;62(3):575-583. Epub 2021 May 15.

Department of Onco-Cardiology, Osaka International Cancer Institute.

Hematopoietic stem cell transplantation (HSCT) is occasionally associated with cardiac dysfunction during long-term follow-up. Global longitudinal strain (GLS) has emerged as an early predictor of cardiotoxicity associated with cancer therapy; however, the serial changes in GLS before and after HSCT have not been elucidated. To clarify the association between HSCT and GLS, we investigated serial changes in GLS before and after HSCT. We evaluated cardiac function before and 1, 3, and 6 months after HSCT in 38 consecutive HSCT patients enrolled in this study. Overall, GLS and left ventricular (LV) ejection fraction (EF) temporally decreased 1 month post-HSCT. LVEF completely recovered to baseline at 3 months after HSCT, whereas GLS partially recovered 6 months after HSCT. Except for five patients who died within 6 months, GLS values in the low EF group (LVEF ≤ 55% at 6 months post-HSCT, n = 6) were significantly and consistently lower than those in the normal EF group (LVEF > 55% at 6 months post-HSCT, n = 27) at any time during follow-up. These findings suggest that GLS before HSCT might be associated with a decrease in LVEF after HSCT in patients with hematologic malignancies. Further prospective and long-term data will be important for understanding the management of HSCT-associated cardiac dysfunction.
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http://dx.doi.org/10.1536/ihj.20-434DOI Listing
May 2021

Prognostic Impact of Cancer Activity on Clinically Relevant Bleeding Events After Percutaneous Coronary Intervention.

J Med Invest 2021 ;68(1.2):29-37

Department of Onco-Cardiology, Osaka International Cancer Institute, Osaka, Japan.

Purpose : Limited data exist about clinically relevant bleeding events related to antiplatelet therapy after percutaneous coronary intervention (PCI) in cancer patients. We investigated the risk factors for clinically relevant bleeding events in patients with cancer after PCI with stent implantation. Patients and Methods : Patients with solid cancer subjected to first PCI were divided into active (n = 45) and non-active cancer groups (n = 44). The active group included non-operable patients on treatment or with metastasis ; the non-active included those already subjected to or for whom radical surgery was planned within 3 months after the index PCI. Results : During a median follow-up of 2.2 years, 11 bleeding events occurred, with only one occurring in the non-active cancer group. Half of them occurred during the dual-antiplatelet therapy (DAPT) period, and the rest occurred during single-antiplatelet therapy (SAPT) period. Kaplan-Meier analysis showed significantly more bleeding events in the active cancer group (p = 0.010). Multivariate Cox regression hazard analysis revealed cancer activity as a significant independent risk factor for bleeding (p = 0.023) ; but not for three-point major adverse cardiovascular events. Conclusion : Clinically relevant bleeding risk after PCI was significantly lower in non-active cancer. Active cancer group had clinically relevant bleeding during both DAPT and SAPT periods. J. Med. Invest. 68 : 29-37, February, 2021.
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http://dx.doi.org/10.2152/jmi.68.29DOI Listing
January 2021

Multicentre cohort study of the impact of percutaneous coronary intervention on patients with concurrent cancer and ischaemic heart disease.

BMC Cardiovasc Disord 2021 Apr 13;21(1):177. Epub 2021 Apr 13.

Cancer Control Centre, Osaka International Cancer Institute, Osaka, Japan.

Background: The incidence of concurrent cancer and ischaemic heart disease (IHD) is increasing; however, the long-term patient prognoses remain unclear.

Methods: Five-year all-cause mortality data pertaining to patients in the Osaka Cancer Registry, who were diagnosed with colorectal, lung, prostate, and gastric cancers between 2010 and 2015, were retrieved and analysed together with linked patient administrative data. Patient characteristics (cancer type, stage, and treatment; coronary risk factors; medications; and time from cancer diagnosis to index admission for percutaneous coronary intervention [PCI] or IHD diagnosis) were adjusted for propensity score matching. Three groups were identified: patients who underwent PCI within 3 years of cancer diagnosis (n = 564, PCI + group), patients diagnosed with IHD within 3 years of cancer diagnosis who did not undergo PCI (n = 3058, PCI-/IHD + group), and patients without IHD (n = 27,392, PCI-/IHD- group). Kaplan-Meier analysis was used for comparisons.

Results: After propensity score matching, the PCI + group had better prognosis (n = 489 in both groups, hazard ratio 0.64, 95% confidence interval 0.51-0.81, P < 0.001) than the PCI-/IHD + group. PCI + patients (n = 282) had significantly higher mortality than those without IHD (n = 280 in each group, hazard ratio 2.88, 95% confidence interval 1.90-4.38, P < 0.001).

Conclusions: PCI might improve the long-term prognosis in cancer patients with IHD. However, these patients could have significantly worse long-term prognosis than cancer patients without IHD. Since the present study has some limitations, further research will be needed on this important topic in cardio-oncology.
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http://dx.doi.org/10.1186/s12872-021-01968-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045293PMC
April 2021

Symptomatic Sinus Bradycardia in a Patient with Solitary Fibrous Tumor/Hemangiopericytoma Treated with Pazopanib.

Intern Med 2021 Apr 5. Epub 2021 Apr 5.

Department of Onco-Cardiology, Osaka International Cancer Institute, Japan.

Pazopanib, a multi-targeted tyrosine kinase inhibitor, is associated with cardiovascular adverse events, such as hypertension, cardiac dysfunction, and thromboembolism. However, symptomatic pazopanib-related bradycardia is uncommon. We herein report a case of symptomatic bradycardia of 35 beats per minute in a patient with solitary fibrous tumor/hemangiopericytoma (SFT/HPC) treated with pazopanib for 1 month. His heart rate recovered to a normal range soon after pazopanib cessation. He restarted pazopanib at a reduced dose, which was continued without SFT/HPC progression or bradycardia recurrence. This case highlights the possibility of bradycardia induced by pazopanib and the importance of monitoring the patient's heart rate.
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http://dx.doi.org/10.2169/internalmedicine.5347-20DOI Listing
April 2021

Association of equol with obesity in postmenopausal women.

Menopause 2021 03 15;28(7):807-810. Epub 2021 Mar 15.

Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan.

Objective: Equol, which is an active metabolite of isoflavone, has a beneficial impact on metabolic diseases such as dyslipidemia and hyperglycemia. However, the effect of equol on obesity remains uncertain. This study was performed to determine the association between equol and obesity in postmenopausal women.

Methods: We evaluated 386 women in their 50s-60s who underwent health check-ups from February 2018 to January 2019 at Watari Hospital Health Center in Fukushima, Japan. Overweight and visceral obesity were defined as a body mass index ≥25 kg/m2 and waist circumference ≥ 90 cm, respectively. Participants were asked to complete a questionnaire about their ordinary lifestyle. Participants were defined as equol producers when urinary equol level was 1.0 μM or more. The proportion of individuals with obesity (overweight and visceral obesity) and lifestyle factors were compared between equol producers and nonproducers. In addition, the association between equol and obesity was examined using logistic regression analysis with adjustment for lifestyle factors.

Results: Of the 386 participants, 106 (27.5%) women were equol producers. The proportions of women who were overweight (13.2% vs 25.7%) and had visceral obesity (6.6% vs 20.7%) were significantly lower in the equol-producing group than in the nonproducing group. Multivariable logistic regression analysis showed that equol production was significantly associated with overweight (odds ratio =0.47, 95% confidence interval: 0.25-0.88) and visceral obesity (odds ratio =0.30, 95% confidence interval: 0.13-0.68).

Conclusions: Equol is significantly associated with obesity in postmenopausal women.
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http://dx.doi.org/10.1097/GME.0000000000001761DOI Listing
March 2021

Frequent post-operative monitoring of colorectal cancer using individualised ctDNA validated by multiregional molecular profiling.

Br J Cancer 2021 Apr 3;124(9):1556-1565. Epub 2021 Mar 3.

Division of Biomedical Research and Development, Iwate Medical University Institute for Biomedical Sciences, Iwate, Japan.

Background: Circulating tumour DNA (ctDNA) is known as a tumour-specific personalised biomarker, but the mutation-selection criteria from heterogeneous tumours remain a challenge.

Methods: We conducted multiregional sequencing of 42 specimens from 14 colorectal tumours of 12 patients, including two double-cancer cases, to identify mutational heterogeneity to develop personalised ctDNA assays using 175 plasma samples.

Results: "Founder" mutations, defined as a mutation that is present in all regions of the tumour in a binary manner (i.e., present or absent), were identified in 12/14 tumours. In contrast, "truncal" mutations, which are the first mutation that occurs prior to the divergence of branches in the phylogenetic tree using variant allele frequency (VAF) as continuous variables, were identified in 12/14 tumours. Two tumours without founder and truncal mutations were hypermutators. Most founder and truncal mutations exhibited higher VAFs than "non-founder" and "branch" mutations, resulting in a high chance to be detected in ctDNA. In post-operative long-term observation for 10/12 patients, early relapse prediction, treatment efficacy and non-relapse corroboration were achievable from frequent ctDNA monitoring.

Conclusions: A single biopsy is sufficient to develop custom dPCR probes for monitoring tumour burden in most CRC patients. However, it may not be effective for those with hypermutated tumours.
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http://dx.doi.org/10.1038/s41416-021-01266-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076308PMC
April 2021

Prognostic Effect of Incidental Pulmonary Embolism on Long-Term Mortality in Cancer Patients.

Circ J 2021 Feb 17. Epub 2021 Feb 17.

Department of Onco-Cardiology, Osaka International Cancer Institute.

Background: The effect of incidental pulmonary embolism (PE) on long-term prognosis in cancer patients is unclear. This study assessed the characteristics of cancer and venous thromboembolism (VTE) and the effect of incidental PE identified by oncologists on long-term survival of patients with cancer.Methods and Results:This single-center, retrospective, cohort study used hospital-based cancer registry data from the Osaka International Cancer Institute linked with electronic medical records and administrative data from Japan's Diagnosis Procedure Combination Per-diem Payment System. Overall, 15,689 cancer patients underwent contrast-enhanced thoracic computed tomography during 2010-2018. After excluding patients with missing data, symptomatic patients, or patients with suspected PE, 174 with incidental PE (PE+ group) and 13,197 with no PE (PE- group) were identified. The total incidence of incidental PE was 1.3%. No deaths from thrombotic events were identified in the PE+ group. Both groups were adjusted for cancer- and VTE-related characteristics using inverse probability weighting. After adjusting for immortal time bias in the PE+ group, Kaplan-Meier analysis revealed that all-cause mortality was higher in the PE+ group (hazard ratio, 2.26; 95% confidence interval, 1.53-3.33). A Cox proportional hazard model revealed that metastatic cancer and a history of curative treatment were significant prognostic factors, whereas central PE and residual proximal deep vein thrombosis were not.

Conclusions: Incidental PE in cancer patients indicates poorer prognosis. Cancer-related but not thrombosis-related factors determine prognosis.
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http://dx.doi.org/10.1253/circj.CJ-20-1160DOI Listing
February 2021

Molecular Classification and Tumor Microenvironment Characterization of Gallbladder Cancer by Comprehensive Genomic and Transcriptomic Analysis.

Cancers (Basel) 2021 Feb 10;13(4). Epub 2021 Feb 10.

Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.

Gallbladder cancer (GBC), a rare but lethal disease, is often diagnosed at advanced stages. So far, molecular characterization of GBC is insufficient, and a comprehensive molecular portrait is warranted to uncover new targets and classify GBC. We performed a transcriptome analysis of both coding and non-coding RNAs from 36 GBC fresh-frozen samples. The results were integrated with those of comprehensive mutation profiling based on whole-genome or exome sequencing. The clustering analysis of RNA-seq data facilitated the classification of GBCs into two subclasses, characterized by high or low expression levels of TME (tumor microenvironment) genes. A correlation was observed between gene expression and pathological immunostaining. TME-rich tumors showed significantly poor prognosis and higher recurrence rate than TME-poor tumors. TME-rich tumors showed overexpression of genes involved in epithelial-to-mesenchymal transition (EMT) and inflammation or immune suppression, which was validated by immunostaining. One non-coding RNA, , exhibited elevated expression in stroma-rich tumors, and knockout in GBC cell lines decreased its invasion ability and altered the EMT pathway. Mutation profiles revealed (47%) as the most commonly mutated gene, followed by (13%) and (11%). Mutations of , , and the genes related to the TGF-β signaling pathway were enriched in TME-rich tumors. This comprehensive analysis demonstrated that TME, EMT, and TGF-β pathway alterations are the main drivers of GBC and provides a new classification of GBCs that may be useful for therapeutic decision-making.
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http://dx.doi.org/10.3390/cancers13040733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916565PMC
February 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

Population-based Screening for Hereditary Colorectal Cancer Variants in Japan.

Clin Gastroenterol Hepatol 2020 Dec 11. Epub 2020 Dec 11.

RIKEN Center for Integrative Medical Sciences, Yokohama.

Background & Aims: Colorectal cancer (CRC) is one of the most common cancers in the world. A small proportion of CRCs can be attributed to recognizable hereditary germline variants of known CRC susceptibility genes. To better understand cancer risk, it is necessary to explore the prevalence of hereditary CRC and pathogenic variants of multiple cancer-predisposing genes in non-European populations.

Methods: We analyzed the coding regions of 27 cancer-predisposing genes in 12,503 unselected Japanese CRC patients and 23,705 controls by target sequencing and genome-wide SNP chip. Their clinical significance was assessed using ClinVar and the guidelines by ACMG/AMP.

Results: We identified 4,804 variants in the 27 genes and annotated them as pathogenic in 397 and benign variants in 941, of which 43.6% were novel. In total, 3.3% of the unselected CRC patients and 1.5% of the controls had a pathogenic variant. The pathogenic variants of MSH2 (odds ratio (OR) = 18.1), MLH1 (OR = 8.6), MSH6 (OR = 4.9), APC (OR = 49.4), BRIP1 (OR=3.6), BRCA1 (OR = 2.6), BRCA2 (OR = 1.9), and TP53 (OR = 1.7) were significantly associated with CRC development in the Japanese population (P-values<0.01, FDR<0.05). These pathogenic variants were significantly associated with diagnosis age and personal/family history of cancer. In total, at least 3.5% of the Japanese CRC population had a pathogenic variant or CNV of the 27 cancer-predisposing genes, indicating hereditary cancers.

Conclusions: This largest study of CRC heredity in Asia can contribute to the development of guidelines for genetic testing and variant interpretation for heritable CRCs.
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http://dx.doi.org/10.1016/j.cgh.2020.12.007DOI Listing
December 2020

Factors associated with hepatocellular carcinoma occurrence after HCV eradication in patients without cirrhosis or with compensated cirrhosis.

PLoS One 2020 7;15(12):e0243473. Epub 2020 Dec 7.

Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan.

The present study aimed to investigate the incidence of hepatocellular carcinoma (HCC) and factors related to HCC occurrence after direct-acting antiviral (DAA) treatment in the Fukushima Liver Academic Group (FLAG). We conducted a multicenter retrospective cohort study of 1068 patients without cirrhosis (NC) or with compensated liver cirrhosis (LC) who achieved a sustained virologic response (SVR). First, we compared the cumulative HCC incidence and survival rates in NC (n = 880) and LC (n = 188) patients without a history of HCC treatment. Second, we performed multivariate analysis of factors related to HCC occurrence after DAA treatment. Overall, the average age was 65 years, and the male/female ratio was 511/557. Thirty-nine (4%) patients developed HCC. The cumulative 4-year HCC incidence and survival rates were 3.0% and 99.8% in NC patients and 11.5% and 98.5% in LC patients, respectively. The independent factors affecting HCC occurrence identified by multivariate analysis were the serum albumin (ALB) level before SVR for NC patients and the ALBI score, platelet count, and diabetes before SVR for LC patients. The factors related to HCC occurrence differed between NC and LC patients. Careful surveillance of post-SVR patients with these risk factors is needed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243473PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721183PMC
January 2021

Osimertinib is associated with reversible and dose-independent cancer therapy-related cardiac dysfunction.

Lung Cancer 2021 03 16;153:186-192. Epub 2020 Nov 16.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Introduction: The use of osimertinib is associated with the risk of cancer therapy-related cardiac dysfunction (CTRCD) for EGFR-mutated non-small cell lung cancer (NSCLC) patients. In this study, we aimed to clarify the clinical features of patients with CTRCD associated with osimertinib.

Methods: A total of 183 cases of advanced EGFR-mutated NSCLC who received osimertinib monotherapy from January 2014 to December 2019 were evaluated. Longitudinal changes in LVEF were evaluated in 58 patients by serial echocardiography before and after osimertinib administration.

Results: Of 58 patients, 16 patients (8.7%) had decreased LVEF of 10 units or more and 8 patients (4.4%) met the CTRCD criteria. Overall, LVEF significantly decreased after osimertinib treatment from a mean value of 69% (range, 52-82%) at baseline to 66% (26-75%) (p < 0.001). During osimertinib treatment, LVEF remained low but did not decline any further. Discontinuation, dose reduction, or switching to another EGFR tyrosine kinase inhibitors resulted in recovery in 6 out of 8 CTRCD patients. Multivariate analysis showed that history of heart disease was a significant predictor of CTRCD (ORR, 4.97; 95% confidence interval [CI], 1.26-19.6; P = 0.022).

Conclusions: Osimertinib was associated with the risk of CTRCD, which is dose-independent and reversible with drug withdrawal.
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http://dx.doi.org/10.1016/j.lungcan.2020.10.021DOI Listing
March 2021

An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping.

Cell 2020 11 6;183(5):1420-1435.e21. Epub 2020 Nov 6.

Department of Pulmonary Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.

Gastroenteropancreatic (GEP) neuroendocrine neoplasm (NEN) that consists of neuroendocrine tumor and neuroendocrine carcinoma (NEC) is a lethal but under-investigated disease owing to its rarity. To fill the scarcity of clinically relevant models of GEP-NEN, we here established 25 lines of NEN organoids and performed their comprehensive molecular characterization. GEP-NEN organoids recapitulated pathohistological and functional phenotypes of the original tumors. Whole-genome sequencing revealed frequent genetic alterations in TP53 and RB1 in GEP-NECs, and characteristic chromosome-wide loss of heterozygosity in GEP-NENs. Transcriptome analysis identified molecular subtypes that are distinguished by the expression of distinct transcription factors. GEP-NEN organoids gained independence from the stem cell niche irrespective of genetic mutations. Compound knockout of TP53 and RB1, together with overexpression of key transcription factors, conferred on the normal colonic epithelium phenotypes that are compatible with GEP-NEN biology. Altogether, our study not only provides genetic understanding of GEP-NEN, but also connects its genetics and biological phenotypes.
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http://dx.doi.org/10.1016/j.cell.2020.10.023DOI Listing
November 2020

Association of serum 25-hydroxyvitamin D levels with severe necroinflammatory activity and inflammatory cytokine production in type I autoimmune hepatitis.

PLoS One 2020 5;15(11):e0239481. Epub 2020 Nov 5.

Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan.

25-Hydroxyvitamin D [25(OH)D] has been reported to be associated with several chronic liver diseases. The relationship between 25(OH)D and autoimmune hepatitis (AIH) pathogenesis is incompletely understood. We investigated the association of serum total and free 25(OH)D levels with necroinflammatory activity and cytokine levels in 66 patients with AIH diagnosed in our hospital. The median age at AIH diagnosis was 57 years, and the male:female ratio was 7:59. The median serum total 25(OH)D level in therapy-naïve patients with AIH was 14.2 ng/mL (interquartile range [IQR], 11.4-17.9 ng/mL). Of the 66 patients with AIH, 36 had serum total 25(OH)D levels of < 15 ng/mL and were considered to have vitamin D deficiency, and 30 had serum total 25(OH)D levels of ≥ 15 ng/mL. Patients with acute-onset AIH had significantly lower serum total 25(OH)D levels than those with chronic-onset AIH. In particular, serum total 25(OH)D levels were significantly lower in patients with severe forms of AIH. Furthermore, the serum total 25(OH)D level was positively correlated with the serum albumin level and prothrombin time and negatively correlated with the serum total bilirubin level and necroinflammatory activity in AIH. Multivariate logistic regression analysis showed that the serum total 25(OH)D level was an independent factor for severe necroinflammatory activity. Interestingly, AIH patients with serum total 25(OH)D levels of < 15 ng/mL had higher levels of inflammatory cytokines such as interferon-γ and interleukin-33. Free 25(OH)D levels were correlated with total 25(OH)D levels, and the percentage of free 25(OH)D was significantly associated with necroinflammatory activity. In conclusion, 25(OH)D deficiency may play an important role in predicting AIH severity via inflammatory cytokine production.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239481PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643962PMC
December 2020

Effects of sleep quality on non-alcoholic fatty liver disease: a cross-sectional survey.

BMJ Open 2020 10 29;10(10):e039947. Epub 2020 Oct 29.

Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan.

Background: The effects of sleep quality on the risk of developing non-alcoholic fatty liver disease (NAFLD) remain uncertain. The purpose of this study was to clarify the association between sleep quality and NAFLD.

Methods: The data of 4828 participants who underwent health check-ups at four hospitals were analysed. Sleep quality was evaluated by the Pittsburgh Sleep Quality Index (PSQI), which comprised seven elements scored from 0 to 3. The global PSQI score and the score for each element were compared between NAFLD and non-NAFLD groups separately by sex. Logistic regression analysis was performed to determine the association between NAFLD and each PSQI score.

Results: In both men and women, the mean PSQI score for sleep medication use was significantly higher in non-NAFLD than in NAFLD. With regard to sleep medication use in men, the OR (95% CI) for NAFLD was lower with a score of 3 (OR 0.60, 95% CI 0.38-0.95) than with a score of 0 on multivariate logistic regression analysis adjusted for age, smoking habits and physical activity. The OR for NAFLD based on daytime dysfunction was also higher with a score of 3 than with a score of 0 in both men (OR 2.82, 95% CI 1.39-5.75) and women (OR 2.08, 95% CI 1.10-3.92). After adjustment for body mass index, the sleep latency scores in men and daytime dysfunction in women were associated with NAFLD.

Conclusion: Sleep quality was associated with NAFLD, and there were sex differences.
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http://dx.doi.org/10.1136/bmjopen-2020-039947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597499PMC
October 2020

Integrative immunogenomic analysis of gastric cancer dictates novel immunological classification and the functional status of tumor-infiltrating cells.

Clin Transl Immunology 2020 17;9(10):e1194. Epub 2020 Oct 17.

Department of Immunotherapeutics The University of Tokyo Hospital Tokyo Japan.

Objectives: A better understanding of antitumor immunity will help predict the prognosis of gastric cancer patients and tailor the appropriate therapies in each patient. Therefore, we propose a novel immunological classification of gastric cancer.

Methods: We performed whole-exome sequencing (WES), RNA-Seq and flow cytometry in 29 gastric cancer patients who received surgery. The TCGA data set of 323 gastric cancer patients and RNA-Seq data of 45 patients who received pembrolizumab (Kim . 2018; : 1449-1458) were also analysed.

Results: Immunogram analysis of cancer-immunity interaction of gastric cancer revealed immune signatures of four main types, designated Hot1, Hot2, Intermediate and Cold. Immunologically hot tumors displayed a dysfunctional T-cell signature, while cold tumors had an exclusion signature. tumor-infiltrating lymphocyte analysis documented T-cell dysfunction with the expression of checkpoint molecules and impaired cytokine production. The T-cell function was more profoundly damaged in Hot1 than Hot2 tumors. Patients in Hot2 subtypes had better survival in our cohort and TCGA cohort. Although these immunological subtypes overlapped to some degree with the molecular subtypes in the TCGA, intratumoral immune responses cannot be predicted solely based on histological or molecular subtyping of gastric cancer. Molecular and immunological classifications complement each other to predict the responses to anti-PD-1 therapy and have the potential to be a biomarker for the treatment of gastric cancer.

Conclusion: The immunological classification of gastric cancer resulted in four subtypes. Hot tumors were further divided into two subtypes, between which the functional status of T cells was different.
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http://dx.doi.org/10.1002/cti2.1194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568758PMC
October 2020

Deep immunophenotyping at the single-cell level identifies a combination of anti-IL-17 and checkpoint blockade as an effective treatment in a preclinical model of data-guided personalized immunotherapy.

J Immunother Cancer 2020 10;8(2)

Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan

Background: Although immune checkpoint blockade is effective for several malignancies, a substantial number of patients remain refractory to treatment. The future of immunotherapy will be a personalized approach adapted to each patient's cancer-immune interactions in the tumor microenvironment (TME) to prevent suppression of antitumor immune responses. To demonstrate the feasibility of this kind of approach, we developed combination therapy for a preclinical model guided by deep immunophenotyping of the TME.

Methods: Gastric cancer cell lines YTN2 and YTN16 were subcutaneously inoculated into C57BL/6 mice. YTN2 spontaneously regresses, while YTN16 grows progressively. Bulk RNA-Seq, single-cell RNA-Seq (scRNA-Seq) and flow cytometry were performed to investigate the immunological differences in the TME of these tumors.

Results: Bulk RNA-Seq demonstrated that YTN16 tumor cells produced CCL20 and that CD8 T cell responses were impaired in these tumors relative to YTN2. We have developed a vertical flow array chip (VFAC) for targeted scRNA-Seq to identify unique subtypes of T cells by employing a panel of genes reflecting T cell phenotypes and functions. CD8 T cell dysfunction (cytotoxicity, proliferation and the recruitment of interleukin-17 (IL-17)-producing cells into YTN16 tumors) was identified by targeted scRNA-Seq. The presence of IL-17-producing T cells in YTN16 tumors was confirmed by flow cytometry, which also revealed neutrophil infiltration. IL-17 blockade suppressed YTN16 tumor growth, while tumors were rejected by the combination of anti-IL-17 and anti-PD-1 (Programmed cell death protein 1) mAb treatment. Reduced neutrophil activation and enhanced expansion of neoantigen-specific CD8 T cells were observed in tumors of the mice receiving the combination therapy.

Conclusions: Deep phenotyping of YTN16 tumors identified a sequence of events on the axis CCL20->IL-17-producing cells->IL-17-neutrophil-angiogenesis->suppression of neoantigen-specific CD8 T cells which was responsible for the lack of tumor rejection. IL-17 blockade together with anti-PD-1 mAb therapy eradicated these YTN16 tumors. Thus, the deep immunological phenotyping can guide immunotherapy for the tailored treatment of each individual patient's tumor.
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http://dx.doi.org/10.1136/jitc-2020-001358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583806PMC
October 2020

Analysis of mutational and proteomic heterogeneity of gastric cancer suggests an effective pipeline to monitor post-treatment tumor burden using circulating tumor DNA.

PLoS One 2020 7;15(10):e0239966. Epub 2020 Oct 7.

Division of Biomedical Research and Development, Iwate Medical University Institute of Biomedical Sciences, Yahaba, Japan.

Circulating tumor DNA (ctDNA) is released from tumor cells into blood in advanced cancer patients. Although gene mutations in individual tumors can be diverse and heterogenous, ctDNA has the potential to provide comprehensive biomarker information. Here, we performed multi-region sampling (three sites) per resected specimen from 10 gastric cancer patients followed by targeted sequencing and proteomic profiling using reverse-phase protein arrays. A total of 126 non-synonymous mutations were identified from 30 samples from 10 tumors. Of these, 16 (12.7%) were present in all three regions and were designated as founder mutations. Variant allele frequencies (VAFs) of founder mutations were significantly higher than those of non-founder mutations. Phylogenetic analysis also demonstrated a good concordance between founder and truncal mutations, defined as mutations shared by all simulated clones at the trunk of the tumor phylogenetic tree. These findings led us to prioritize founder mutations for quantitative ctDNA monitoring by digital PCR with individually-designed primer/probe sets. In preoperative plasma, the average ctDNA VAF of founder mutations was significantly higher than that of non-founder mutations (p = 0.039). Proteomic heterogeneity was present across the tumor regions both within and between patients independent of mutational status. Our results suggest that, in practice, mutations having high VAF identified without multi-regional sequencing may be immediately useful for quantitative ctDNA monitoring but do not provide sufficient information to predict the proteomic composition of tumors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239966PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540850PMC
November 2020

Pazopanib-induced mixed liver injury in a patient with soft-tissue sarcoma, but without the UGT1A1*28 mutation: a case report.

Clin J Gastroenterol 2021 Feb 29;14(1):224-228. Epub 2020 Sep 29.

Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan.

A 72-year-old man who underwent pazopanib therapy for soft-tissue sarcoma in the left leg was referred to our department because of elevated levels of liver enzymes. Laboratory tests showed high alanine aminotransferase, alkaline phosphatase, and total bilirubin levels. He was treated with intravenous methylprednisolone (mPSL) therapy (125 mg/day) followed by oral prednisolone and ursodeoxycholic acid therapy, but his liver enzyme abnormality deteriorated and he presented with jaundice. The intravenous mPSL (250 mg/day) treatment was effective and the abnormal levels of liver enzymes and jaundice were improved. He does not carry the UGT1A1*28 mutant allele. Based on our findings, patients presenting with markedly increased liver enzyme levels and jaundice after pazopanib may require steroid therapy.
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http://dx.doi.org/10.1007/s12328-020-01253-xDOI Listing
February 2021

Acute myocardial infarction caused by tumor embolus originating from upper tract urothelial carcinoma: a case report.

Cardiooncology 2020 7;6:18. Epub 2020 Sep 7.

Department of Onco-Cardiology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567 Japan.

Coronary emboli from malignant tumors rarely cause acute myocardial infarction. We report the case of a patient with tumor embolism from an upper tract urothelial carcinoma that caused acute myocardial infarction via a patent foramen ovale. Coronary blood flow was restored by embolus aspiration without stenting. Clinicians must consider malignant tumor embolism as a possible cause of acute myocardial infarction.
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http://dx.doi.org/10.1186/s40959-020-00073-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487790PMC
September 2020

Association between serum ficolin-1 level and disease progression in primary biliary cholangitis.

PLoS One 2020 11;15(9):e0238300. Epub 2020 Sep 11.

Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan.

Pattern recognition molecules (PRMs) in the complement system contribute to homeostasis as mediators of complement activation. The contribution of PRMs to primary biliary cholangitis (PBC) is unknown. In the current study, we aimed to assess the association between PRMs and the clinical findings of PBC. A total of 122 PBC patients and 20 healthy controls were enrolled. We measured four different PRMs (mannose-binding lectin [MBL], ficolin-1, ficolin-2 and ficolin-3) using stored sera, and retrospectively analyzed the associations between PRMs and laboratory findings, histological findings, and the development of cirrhosis-related conditions. Ficolin-1 levels were significantly higher in the PBC patients than in the healthy controls (152 ng/mL vs 102 ng/mL, P = 0.034), but no significant differences were observed regarding MBL, ficolin-2, and ficolin-3 levels. Ficolin-1 was significantly correlated with alkaline phosphatase (ALP). Low ficolin-1 levels were significantly associated with the development of cirrhosis-related conditions independent for histological stage and ALP levels (hazard ratio: 0.933; 95% confidence interval: 0.875-0.994; P = 0.032). Patients with low levels of ficolin-1 (< 77 ng/mL) had a significantly increased rate of developing cirrhosis-related conditions. Low ficolin-1 levels were associated with disease progression independent of histological stage and ALP levels in patients with PBC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238300PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485786PMC
October 2020

Intratumor Abscess in a Posttraumatic Hepatic Inflammatory Pseudotumor Spreading Out of the Liver.

Intern Med 2021 Jan 5;60(2):235-240. Epub 2020 Sep 5.

Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan.

A 45-year-old woman with abdominal pain after minor trauma was referred to our hospital. Computed tomography (CT) showed a hypovascular tumor in the left liver lobe. A tumor biopsy revealed granuloma, although no findings indicated malignancy or infection. A follow-up imaging study showed spread of the hepatic tumor. Her abdominal pain worsened after a second minor trauma. CT revealed an intratumor abscess, and pus overflowed from the patient's umbilicus. The abscess was improved by antibiotics and drainage therapy. In this case, unusual imaging findings and an atypical disease course of a hepatic inflammatory pseudotumor were observed.
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http://dx.doi.org/10.2169/internalmedicine.5166-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872811PMC
January 2021

Serum Gas6 and Axl as non-invasive biomarkers of advanced histological stage in primary biliary cholangitis.

Hepatol Res 2020 Dec 30;50(12):1337-1346. Epub 2020 Sep 30.

Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan.

Aim: Advanced histological stage is an important factor in individual risk stratification in patients with primary biliary cholangitis (PBC). Non-invasive biomarkers for advanced histological stage are needed. We assessed the utility of Gas6 and Axl as biomarkers for advanced histological stage in patients with PBC.

Methods: A total of 113 biopsy-proven PBC patients and 20 healthy controls were included in this study. Serum Axl and Gas6 were measured using enzyme-linked immunosorbent assay. The Gas6 / albumin ratio and Axl / albumin ratio were also evaluated as biomarkers of histological stage.

Results: Serum Axl (42.6 ng/mL vs. 30.6 ng/mL, P < 0.001) and Gas6 (21.1 ng/mL vs. 18.8 ng/mL, P = 0.007) levels in PBC patients were significantly higher than those in healthy controls. The Axl / albumin ratio was 10.4, and the Gas6 / albumin ratio was 7.6 in patients with PBC. Gas6 and Axl were significantly correlated with aspartate aminotransferase, bilirubin, albumin, and platelets. Gas6 and Axl levels in patients with an advanced Scheuer stage and an advanced Nakanuma stage were significantly higher than those in other patients. The area under the receiver operating characteristic curve (AUROC) of Axl, Gas6, Axl / albumin, and Gas6 / albumin for diagnosing Scheuer stage 4 was 0.733, 0.837, 0.845, and 0.893, respectively. The AUROC of Axl, Gas6, Axl / albumin, and Gas6 / albumin for diagnosing Nakanuma stage 4 was 0.794, 0.834, 0.869, and 0.898, respectively.

Conclusion: High levels of Gas6 and Axl were associated with advanced histological stage in PBC patients. Furthermore, the Gas6 / albumin ratio and the Axl / albumin ratio showed a high AUROC for diagnosing advanced histological stage.
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http://dx.doi.org/10.1111/hepr.13568DOI Listing
December 2020

Endogenization and excision of human herpesvirus 6 in human genomes.

PLoS Genet 2020 08 10;16(8):e1008915. Epub 2020 Aug 10.

Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Sequences homologous to human herpesvirus 6 (HHV-6) are integrated within the nuclear genome of about 1% of humans, but it is not clear how this came about. It is also uncertain whether integrated HHV-6 can reactivate into an infectious virus. HHV-6 integrates into telomeres, and this has recently been associated with polymorphisms affecting MOV10L1. MOV10L1 is located on the subtelomere of chromosome 22q (chr22q) and is required to make PIWI-interacting RNAs (piRNAs). As piRNAs block germline integration of transposons, piRNA-mediated repression of HHV-6 integration has been proposed to explain this association. In vitro, recombination of the HHV-6 genome along its terminal direct repeats (DRs) leads to excision from the telomere and viral reactivation, but the expected "solo-DR scar" has not been described in vivo. Here we screened for integrated HHV-6 in 7,485 Japanese subjects using whole-genome sequencing (WGS). Integrated HHV-6 was associated with polymorphisms on chr22q. However, in contrast to prior work, we find that the reported MOV10L1 polymorphism is physically linked to an ancient endogenous HHV-6A variant integrated into the telomere of chr22q in East Asians. Unexpectedly, an HHV-6B variant has also endogenized in chr22q; two endogenous HHV-6 variants at this locus thus account for 72% of all integrated HHV-6 in Japan. We also report human genomes carrying only one portion of the HHV-6B genome, a solo-DR, supporting in vivo excision and possible viral reactivation. Together these results explain the recently-reported association between integrated HHV-6 and MOV10L1/piRNAs, suggest potential exaptation of HHV-6 in its coevolution with human chr22q, and clarify the evolution and risk of reactivation of the only intact (non-retro)viral genome known to be present in human germlines.
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http://dx.doi.org/10.1371/journal.pgen.1008915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444522PMC
August 2020

Tumor Fibroblast Growth Factor Receptor 4 Level Predicts the Efficacy of Lenvatinib in Patients With Advanced Hepatocellular Carcinoma.

Clin Transl Gastroenterol 2020 05;11(5):e00179

Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Objectives: Biomarkers for optimizing the outcome of treatment with lenvatinib in patients with advanced hepatocellular carcinoma remain to be established despite intensive and comprehensive genomic research. Lenvatinib is characterized by its prominent inhibitory potency for fibroblast growth factor receptor (FGFR) 4 compared with earlier tyrosine kinase inhibitors. Thus, in this study, we focused on simplified quantification of FGFR4 in tumors as a potential predictive indicator.

Methods: According to The Cancer Genome Atlas data set curation, FGFR4 messenger RNA is broadly overexpressed in hepatocellular carcinoma in the absence of gene alteration. Gene set enrichment analysis revealed that the aggressiveness of the tumor was closely related to the FGFR4 level. To confirm the relationship between the benefits of lenvatinib and tumor addiction to the FGFR4 pathway, we analyzed protein levels in tumors and peripheral blood obtained from 57 prospectively registered patients treated with lenvatinib.

Results: Positive immunohistochemistry (>10% of tumor cells) for FGFR4 in biopsy samples before treatment was associated with a longer progression-free survival (2.5 vs 5.5 months, P = 0.01) and a favorable objective response rate (31% vs 81%, P = 0.006). By contrast, the concentration of soluble FGFR4 in peripheral blood as measured by an enzyme-linked immunosorbent assay was not associated with survival outcomes, because its fluctuations reflect hepatic fibrosis. Additional RNA sequencing analysis using archival surgical specimens (n = 90) suggested that alternative RNA splicing of FGFR4 in cancer may also explain this discrepancy.

Discussion: The tumor FGFR4 level was an independent predictor of response to lenvatinib.
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http://dx.doi.org/10.14309/ctg.0000000000000179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263646PMC
May 2020

Sigmoid Colon Varices due to Massive Thrombosis of a Noncirrhotic Extrahepatic Portosystemic Shunt.

Intern Med 2020 Nov 14;59(21):2705-2710. Epub 2020 Jul 14.

Department of Gastroenterology, Fukushima Medical University, Japan.

A 33-year-old man presented with hepatic encephalopathy and was diagnosed to have a noncirrhotic extrahepatic portosystemic shunt (NCPSS). He presented with abdominal pain 16 months after the NCPSS diagnosis. Computed tomography revealed thrombosis between the intrahepatic portal vein and the left internal iliac vein, including the NCPSS, and varices of the sigmoid colon. Thrombosis was treated with danaparoid sodium and antithrombin III followed by edoxaban. After treatment, the thrombosis disappeared from the intrahepatic portal vein, but it remained in the NCPSS. The sigmoid colon varices were followed up without any treatment. Follow-up is needed in NCPSS patients in order to make an early detection of complications.
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http://dx.doi.org/10.2169/internalmedicine.4925-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691034PMC
November 2020

Skeletal muscle volume loss among liver cirrhosis patients receiving levocarnitine predicts poor prognosis.

Medicine (Baltimore) 2020 Jul;99(28):e21061

Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Japan.

Sarcopenia has a negative impact on the prognosis of patients with liver cirrhosis (LC). We investigated the significance of skeletal muscle volume and its changes in LC patients taking levocarnitine (L-carnitine).We retrospectively analyzed 51 LC patients taking L-carnitine from December 2012 to March 2019. Skeletal mass index was calculated as the left-right sum of the major × minor axis of psoas muscle at the third lumbar vertebra, divided by height squared (psoas muscle index [PMI]). Patients were classified into 2 groups (low and normal PMI) depending on PMI < 6.0 and < 3.4 cm/m for men and women, respectively. Changes in PMI per month during L-carnitine administration (ΔPMI/m) were calculated, and we classified the patients into 2 groups (severe and mild muscle atrophy) depending on ΔPMI/m below the lower quartile. We assessed overall survival (OS).At the start of L-carnitine administration, there were no significant differences in OS between groups with low and normal PMI. Multivariate analysis showed that ΔPMI/m (hazard ratio [HR], 0.007; P = .005) and L-carnitine administration period (HR, 0.956; P = .021) were significantly associated with OS. Patients with severe muscle atrophy had a significantly lower OS than those with mild muscle atrophy. There was the positive correlation relationship between ΔPMI/m and L-carnitine administration period.Among LC patients taking L-carnitine, progressive muscle volume loss was a predictor of poor prognosis. L-carnitine administration for longer may be able to prevent muscle volume loss and lead to a better prognosis in LC patients.
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http://dx.doi.org/10.1097/MD.0000000000021061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360248PMC
July 2020

Pembrolizumab-induced sclerosing cholangitis in a lung adenocarcinoma patient with a remarkable response to chemotherapy: a case report.

Clin J Gastroenterol 2020 Dec 8;13(6):1310-1314. Epub 2020 Jul 8.

Department of Gastroenterology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan.

A 68-year-old man with advanced lung adenocarcinoma was admitted to our department because of high levels of alkaline phosphatase (ALP) after 4 courses of chemotherapy, including pembrolizumab. An imaging study showed findings of sclerosing cholangitis in the intrahepatic bile duct. Liver histology revealed infiltration of CD8-positive T cells into the portal tract. Corticosteroid and ursodeoxycholic acid were administered, and the ALP levels and findings of sclerosing cholangitis gradually improved. Furthermore, his lung carcinoma was remarkably decreased by chemotherapy, and he did not show progression of cancer without treatment. Our case suggests that early treatment before developing jaundice may be effective for sclerosing cholangitis in the intrahepatic bile duct due to immune checkpoint inhibitors.
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http://dx.doi.org/10.1007/s12328-020-01178-5DOI Listing
December 2020

Whole genome sequencing analysis identifies recurrent structural alterations in esophageal squamous cell carcinoma.

PeerJ 2020 26;8:e9294. Epub 2020 Jun 26.

Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in the Asian region, including Japan. A previous study reported mutational landscape of Japanese ESCCs by using exome sequencing. However, somatic structural alterations were yet to be explored. To provide a comprehensive mutational landscape, we performed whole genome sequencing (WGS) analysis of biopsy specimens from 20 ESCC patients in a Japanese population. WGS analysis identified non-silent coding mutations of and in ESCC. We detected six mutational signatures in ESCC, one of which showed significant association with smoking status. Recurrent structural variations, many of which were chromosomal deletions, affected genes such as and in 25%-30% of tumors. Somatic copy number amplifications at (), (), and () and deletions at () were identified. Overall, these multi-dimensional view of genomic alterations improve the understanding of the ESCC development at molecular level and provides future prognosis and therapeutic implications for ESCC in Japan.
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http://dx.doi.org/10.7717/peerj.9294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323713PMC
June 2020
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