Publications by authors named "Yoshinori Murakami"

158 Publications

Pharmacological inhibition of Mint3 attenuates tumour growth, metastasis, and endotoxic shock.

Commun Biol 2021 Oct 7;4(1):1165. Epub 2021 Oct 7.

Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.

Hypoxia-inducible factor-1 (HIF-1) plays essential roles in human diseases, though its central role in oxygen homoeostasis hinders the development of direct HIF-1-targeted pharmacological approaches. Here, we surveyed small-molecule compounds that efficiently inhibit the transcriptional activity of HIF-1 without affecting body homoeostasis. We focused on Mint3, which activates HIF-1 transcriptional activity in limited types of cells, such as cancer cells and macrophages, by suppressing the factor inhibiting HIF-1 (FIH-1). We identified naphthofluorescein, which inhibited the Mint3-FIH-1 interaction in vitro and suppressed Mint3-dependent HIF-1 activity and glycolysis in cancer cells and macrophages without evidence of cytotoxicity in vitro. In vivo naphthofluorescein administration suppressed tumour growth and metastasis without adverse effects, similar to the genetic depletion of Mint3. Naphthofluorescein attenuated inflammatory cytokine production and endotoxic shock in mice. Thus, Mint3 inhibitors may present a new targeted therapeutic option for cancer and inflammatory diseases by avoiding severe adverse effects.
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http://dx.doi.org/10.1038/s42003-021-02701-1DOI Listing
October 2021

A cross-population atlas of genetic associations for 220 human phenotypes.

Nat Genet 2021 Oct 30;53(10):1415-1424. Epub 2021 Sep 30.

National Hospital Organization Osaka National Hospital, Osaka, Japan.

Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (n = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.
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http://dx.doi.org/10.1038/s41588-021-00931-xDOI Listing
October 2021

Circulating tumor DNA harboring the V600E mutation may predict poor outcomes of primary papillary thyroid cancer patients.

Thyroid 2021 Sep 19. Epub 2021 Sep 19.

The University of Tokyo Institute of Medical Science, 26430, Division of Molecular Pathology, Minato-ku, Tokyo, Japan;

Background: The significance of circulating tumor DNA (ctDNA) in primary papillary thyroid cancer (PTC) has yet to be well established. This study aimed to clarify whether ctDNA carrying the V600E mutation in plasma from primary PTC patients before and after surgery can predict outcomes.

Methods: Twenty-two primary PTC patients without distant metastasis, who underwent surgical resection at the University of Tokyo Hospital, were eligible for this study. Genomic DNA of the primary tumor was extracted from formalin-fixed and paraffin-embedded specimens, and the V600E mutation was detected by droplet digital PCR (ddPCR). Pre- and post-surgery ctDNAs were extracted from matched plasma samples obtained from 22 patients and analyzed for the BRAF V600E mutation using ddPCR.

Results: The V600E mutation was detected in 16 of 22 (73%) primary tumors. Five of 16 (31%) cases carrying the V600E mutation in their tumors showed the identical mutation in pre-surgery plasma. Extra-thyroidal extension of the primary tumor correlated significantly with the V600E mutation in pre-surgery ctDNA (p=0.025). In the five patients carrying the V600E mutation in pre-surgery ctDNA, the fractional abundance of the V600E alleles to the total alleles in the primary tumor was significantly higher than that in the 11 patients without mutated in pre-surgery ctDNA (mean, 34% vs. 17%) (P<0.01). Moreover, one patient with the mutated V600E in the primary tumor showed the identical mutation not in pre-surgery ctDNA but in post-surgery ctDNA. This patient had regional lymph node recurrence six months after surgery.

Conclusions: Pre-surgery ctDNA with the V600E mutation was detected in 31% of cases with primary PTCs carrying the identical mutation. Detection of the V600E mutation in pre-surgery plasma can provide information on the increased fractional abundance of the mutated V600E alleles and local progression of the primary tumor. Furthermore, the fractional abundance of the mutated V600E in post-surgery ctDNA might predict PTC recurrence.
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http://dx.doi.org/10.1089/thy.2021.0267DOI Listing
September 2021

Susceptibility loci and polygenic architecture highlight population specific and common genetic features in inguinal hernias: genetics in inguinal hernias.

EBioMedicine 2021 Aug 12;70:103532. Epub 2021 Aug 12.

Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan; Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan; The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan. Electronic address:

Background: The underlying pathology of inguinal hernia is still not fully known; thus, further investigations of genetic backgrounds is needed. Here, we aimed to identify genetic factors attributing to inguinal hernias and explore the polygenic architecture of which some components are population-specific, while others are more common among populations.

Methods: We performed a genome-wide association study (GWAS) on subjects with inguinal hernias using BioBank Japan (BBJ) data with 1,983 cases and 172,507 controls, followed by a trans-ethnic meta-analysis with UK Biobank (UKBB) data. We performed downstream analyses in order to identify the mechanisms underlying inguinal hernias supported by genetic findings.

Findings: We identified a locus closest to ELN, which encodes elastin, at the GWAS significant level. The trans-ethnic meta-analysis revealed 23 additional significant loci, including five loci newly identified not significant in BBJ or UKBB GWAS: TGFB2, RNA5SP214/VGLL2, LOC646588, HMCN2, and ATP5F1CP1/CDKN3. Downstream analyses revealed the overlap of GWAS significant signals in extracellular components, including elastin fiber formation. We also found a highly shared polygenic architecture across different populations (trans-ethnic genetic-effect correlation = 0•77, standard error = 0•26) and population-specific lead variants in ELN, indicating the critical role of elastin in inguinal hernias.

Interpretation: We identified a significant locus of the ELN gene in the Japanese population and five additional loci across different populations. Downstream analyses revealed highly shared genetic architectures across populations and highlighted the important roles of extracellular components in the development of inguinal hernias. These findings deepen our understanding of the mechanisms underlying inguinal hernia.

Funding: The Japan Agency for Medical Research and Development (AMED) (Grant Number: JP19km0605001).
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http://dx.doi.org/10.1016/j.ebiom.2021.103532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374389PMC
August 2021

Combined landscape of single-nucleotide variants and copy number alterations in clonal hematopoiesis.

Nat Med 2021 07 8;27(7):1239-1249. Epub 2021 Jul 8.

Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Clonal hematopoiesis (CH) in apparently healthy individuals is implicated in the development of hematological malignancies (HM) and cardiovascular diseases. Previous studies of CH analyzed either single-nucleotide variants and indels (SNVs/indels) or copy number alterations (CNAs), but not both. Here, using a combination of targeted sequencing of 23 CH-related genes and array-based CNA detection of blood-derived DNA, we have delineated the landscape of CH-related SNVs/indels and CNAs in 11,234 individuals without HM from the BioBank Japan cohort, including 672 individuals with subsequent HM development, and studied the effects of these somatic alterations on mortality from HM and cardiovascular disease, as well as on hematological and cardiovascular phenotypes. The total number of both types of CH-related lesions and their clone size positively correlated with blood count abnormalities and mortality from HM. CH-related SNVs/indels and CNAs exhibited statistically significant co-occurrence in the same individuals. In particular, co-occurrence of SNVs/indels and CNAs affecting DNMT3A, TET2, JAK2 and TP53 resulted in biallelic alterations of these genes and was associated with higher HM mortality. Co-occurrence of SNVs/indels and CNAs also modulated risks for cardiovascular mortality. These findings highlight the importance of detecting both SNVs/indels and CNAs in the evaluation of CH.
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http://dx.doi.org/10.1038/s41591-021-01411-9DOI Listing
July 2021

Efficient Separation of Photoexcited Charge at Interface between Pure CeO and Y-Doped CeO with Heterogonous Doping Structure for Photocatalytic Overall Water Splitting.

Materials (Basel) 2021 Jan 12;14(2). Epub 2021 Jan 12.

Department of Materials Science and Technology, Nagaoka University of Technology, Nagaoka 940-2188, Japan.

Enhancement of photoexcited charge separation in semiconductor photocatalysts is one of the important subjects to improve the efficiency of energy conversion for photocatalytic overall water splitting into H and O. In this study, we report an efficient separation of photoexcited charge at the interface between non-doped pure CeO and Y-doped CeO phases on particle surfaces with heterogeneous doping structure. Neither non-doped pure CeO and homogeneously Y-doped CeO gave activities for photocatalytic H and O production under ultraviolet light irradiation, meaning that both single phases showed little activity. On the other hand, Y-heterogeneously doped CeO of which the surface was composed of non-doped pure CeO, and Y-doped CeO phases exhibited remarkable photocatalytic activities, indicating that the interfacial heterostructure between non-doped pure CeO and Y-doped CeO phases plays an important role for the activation process. The role of the interface between two different phases for activated expression was investigated by selective photo-reduction and oxidation deposition techniques of metal ion, resulting that the interface between two phases become an efficient separation site of photoexcited charge. Electronic band structures of both phases were investigated by the spectroscopic method, and then a mechanism of charge separation is discussed.
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http://dx.doi.org/10.3390/ma14020350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828182PMC
January 2021

Mint3 is dispensable for pancreatic and kidney functions in mice.

Biochem Biophys Rep 2020 Dec 8;24:100872. Epub 2020 Dec 8.

Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan.

Munc-18 interacting protein 3 (Mint3) is an activator of hypoxia-inducible factor-1 in cancer cells, macrophages, and cancer-associated fibroblasts under pathological conditions. However, exactly which cells highly express Mint3 in vivo and whether Mint3 depletion affects their physiological functions remain unclear. Here, we surveyed mouse tissues for specific expression of Mint3 by comparing Mint3 expression in wild-type and Mint3-knockout mice. Interestingly, immunohistochemical analyses revealed that Mint3 was highly expressed in islet cells of the pancreas, distal tubular epithelia of the kidney, choroid plexus ependymal cells of the cerebrum, medullary cells of the adrenal gland, and epithelial cells of the seminal gland. We also studied whether Mint3 depletion affects the physiological functions of the islets and kidneys. Mint3-knockout mice did not show any abnormalities in glucose-tolerance and urine-biochemical tests, indicating that Mint3 depletion was compensated for in these organs. Thus, loss of Mint3 might be compensated in the islets and kidneys under physiological conditions in mice.
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http://dx.doi.org/10.1016/j.bbrep.2020.100872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725678PMC
December 2020

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

CADM1 promotes malignant features of small-cell lung cancer by recruiting 4.1R to the plasma membrane.

Biochem Biophys Res Commun 2021 01 6;534:172-178. Epub 2020 Dec 6.

Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address:

Cell adhesion molecule 1 (CADM1), which mediates intercellular adhesion between epithelial cells, is shown to be highly expressed in small-cell lung cancer (SCLC) and to enhance tumorigenicity of SCLC cells in nude mice. Here, we investigated the molecular mechanism underlying the oncogenic role of CADM1 in SCLC. CADM1 promoted colony formation of SCLC cells in soft agar. Analysis of deletion and point mutants of the conserved protein-binding motifs in CADM1 revealed that the 4.1 protein-binding motif in the cytoplasmic domain is responsible for the promotion of colony formation. Among the actin-binding 4.1 proteins, 4.1R was the only protein whose localization to the plasma membrane is dependent on CADM1 expression in SCLC cells. Knockdown of 4.1R suppressed the colony formation enhanced by CADM1, suggesting that 4.1R is required for the oncogenic role of CADM1 in SCLC. In primary SCLC, CADM1 expression was correlated with membranous localization of 4.1R, as was observed in a SCLC cell line. Moreover, membranous co-localization of CADM1 and 4.1R was associated with more advanced tumor stage. These results suggest that the formation of CADM1-4.1R complex would promote malignant features of SCLC.
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http://dx.doi.org/10.1016/j.bbrc.2020.11.121DOI Listing
January 2021

Improving the trans-ancestry portability of polygenic risk scores by prioritizing variants in predicted cell-type-specific regulatory elements.

Nat Genet 2020 12 30;52(12):1346-1354. Epub 2020 Nov 30.

Center for Data Sciences, Harvard Medical School, Boston, MA, USA.

Poor trans-ancestry portability of polygenic risk scores is a consequence of Eurocentric genetic studies and limited knowledge of shared causal variants. Leveraging regulatory annotations may improve portability by prioritizing functional over tagging variants. We constructed a resource of 707 cell-type-specific IMPACT regulatory annotations by aggregating 5,345 epigenetic datasets to predict binding patterns of 142 transcription factors across 245 cell types. We then partitioned the common SNP heritability of 111 genome-wide association study summary statistics of European (average n ≈ 189,000) and East Asian (average n ≈ 157,000) origin. IMPACT annotations captured consistent SNP heritability between populations, suggesting prioritization of shared functional variants. Variant prioritization using IMPACT resulted in increased trans-ancestry portability of polygenic risk scores from Europeans to East Asians across all 21 phenotypes analyzed (49.9% mean relative increase in R). Our study identifies a crucial role for functional annotations such as IMPACT to improve the trans-ancestry portability of genetic data.
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http://dx.doi.org/10.1038/s41588-020-00740-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049522PMC
December 2020

Fine Mapping of the Major Histocompatibility Complex Region and Association of the HLA-B*52:01 Allele With Cervical Cancer in Japanese Women.

JAMA Netw Open 2020 10 1;3(10):e2023248. Epub 2020 Oct 1.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.

Importance: Understanding the genetic contribution of the major histocompatibility complex (MHC) region to the risk of cervical cancer (CC) will help understand how immune responses to infection with human papillomaviruses are associated with CC.

Objective: To determine whether the HLA-B*52:01 allele is associated with CC in Japanese women.

Design, Setting, And Participants: This was a multicenter genetic association study. Genotype and phenotype data were obtained from BioBank Japan Project. Additional patients with CC were enrolled from the Aichi Cancer Center Research Institute. An MHC fine-mapping study was conducted on CC risk in the Japanese population by applying a human leukocyte antigen (HLA) imputation method to the large-scale CC genome-wide association study data of using the Japanese population-specific HLA reference panel. Participants included 540 women in BioBank Japan Project with CC or 39 829 women without gynecologic diseases, malignant neoplasms, and MHC-related diseases as controls. An additional 168 patients with CC were recruited from Aichi Cancer Center Research Institute. Histopathological subtypes and clinical stages were not considered. Participants with low genotype call rate, closely related participants, and outliers in the principal component analysis were excluded. Data analysis was performed from August 2018 to January 2020.

Main Outcomes And Measures: Loci within the MHC region associated with CC risk, and the direction and size of association.

Results: A total of 704 CC cases and 39 556 controls were analyzed. All participants were Japanese women with a median (range) age of 67 (18 to 100) years. One of the class I HLA alleles of HLA-B*52:01 was significantly associated with CC risk (odds ratio, 1.60; 95% CI, 1.38-1.86; P = 7.4 × 10-10). Allele frequency spectra of HLA-B*52:01 are heterogeneous among worldwide populations with high frequency in Japanese populations (0.109 in controls), suggesting its population-specific risk associated with CC. The conditional analysis suggested that HLA-B*52:01 could explain most of the MHC risk associated with CC because no other HLA alleles remained significant after conditioning on the HLA-B*52:01. The HLA amino acid residue-based analysis suggested that HLA-B p.Tyr171His located in the peptide-binding groove was associated with the most significant CC risk (odds ratio, 1.47; 95% CI, 1.30-1.66; P = 1.2 × 10-9).

Conclusions And Relevance: The results of this study contribute to understanding of the genetic background of CC. The results suggest that immune responses mediated by class I HLA molecules are associated with susceptibility to CC.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.23248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596586PMC
October 2020

Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease.

Nat Genet 2020 11 5;52(11):1169-1177. Epub 2020 Oct 5.

Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.

To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study of 168,228 individuals of Japanese ancestry (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,781 CAD cases and 2,636 controls. We detected eight new susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a trans-ancestry meta-analysis and discovered 35 additional new loci. Using the meta-analysis results, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European genome-wide association studies. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improve the clinical characterization of CAD genetics and suggest the utility of trans-ancestry meta-analysis for PRS derivation in non-European populations.
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http://dx.doi.org/10.1038/s41588-020-0705-3DOI Listing
November 2020

A Mendelian randomization study identified obesity as a causal risk factor of uterine endometrial cancer in Japanese.

Cancer Sci 2020 Dec 27;111(12):4646-4651. Epub 2020 Oct 27.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.

Causal inference is one of the challenges in epidemiologic studies. Gynecologic diseases have been reported to have association with obesity, however the causality remained controversial except for uterine endometrial cancer. We conducted two-sample Mendelian randomization (MR) analysis using the large-scale genome-wide association study (GWAS) results of gynecologic diseases and body mass index (BMI) in the Japanese population to assess causal effect of BMI on gynecologic diseases. We first conducted GWAS of ovarian cancer, uterine endometrial cancer, uterine cervical cancer, endometriosis, and uterine fibroid (n = 647, 909, 538, 5236, and 645 cases, respectively, and 39 556 shared female controls), and BMI (81 610 males and non-overlapping 23 924 females). We then applied two-sample MR using 74 BMI-associated variants as instrumental variables. We observed significant causal effect of increased BMI on uterine endometrial cancer (β = 0.735, P = .0010 in inverse variance-weighted analysis), which is concordant with results of European studies. Causal effect of obesity was not apparent in the other gynecologic diseases tested. Our MR analyses provided strong evidence of the causal role of obesity in gynecologic diseases etiology, and suggested a possible preventive effect of intervention for obesity.
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http://dx.doi.org/10.1111/cas.14667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734162PMC
December 2020

Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes.

EBioMedicine 2020 Oct 24;60:103033. Epub 2020 Sep 24.

Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Electronic address:

Background: National Comprehensive Cancer Network (NCCN) recently recommended germline genetic testing for all pancreatic cancer patients. However, the genes targeted by genetic testing and the feasibility of selecting patients likely to carry pathogenic variants have not been sufficiently verified. The purpose of this study was to genetically characterize Japanese patients and examine whether the current guideline is applicable in this population.

Methods: Using targeted sequencing, we analyzed the coding regions of 27 cancer-predisposing genes in 1,005 pancreatic cancer patients and 23,705 controls in Japan. We compared the pathogenic variant frequency between cases and controls and documented the demographic and clinical characteristics of carrier patients. We then examined if it was possible to use machine learning to predict carrier status based on those characteristics.

Findings: We identified 205 pathogenic variants across the 27 genes. Pathogenic variants in BRCA2, ATM, and BRCA1 were significantly associated with pancreatic cancer. Characteristics associated with carrier status were inconsistent with previous investigations. Machine learning classifiers had a low performance in determining the carrier status of pancreatic cancer patients, while the same classifiers, when applied to breast cancer data as a positive control, had a higher performance that was comparable to that of the NCCN guideline.

Interpretation: Our findings support the clinical significance of multigene panel testing for pancreatic cancer and indicate that at least 3.4% of Japanese patients may respond to poly (ADP ribose) polymerase inhibitor treatments. The difficulty in predicting carrier status suggests that offering germline genetic testing for all pancreatic cancer patients is reasonable.

Funding: AMED under Grant Number JP19kk0305010 and Australian National Health and Medical Research funding (ID177524).
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http://dx.doi.org/10.1016/j.ebiom.2020.103033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519363PMC
October 2020

The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Cell 2020 09;182(5):1214-1231.e11

Laboratory of Epidemiology and Population Science, National Institute on Aging/NIH, Baltimore, MD, 21224, USA.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.
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http://dx.doi.org/10.1016/j.cell.2020.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482360PMC
September 2020

Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.

Cell 2020 09;182(5):1198-1213.e14

Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA 02130, USA; Department of Medicine, Division on Aging, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.
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http://dx.doi.org/10.1016/j.cell.2020.06.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480402PMC
September 2020

Short somatic alterations at the site of copy number variation in breast cancer.

Cancer Sci 2021 Jan 11;112(1):444-453. Epub 2020 Dec 11.

Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Copy number variation (CNV) is a polymorphism in the human genome involving DNA fragments larger than 1 kb. Copy number variation sites provide hotspots of somatic alterations in cancers. Herein, we examined somatic alterations at sites of CNV in DNA from 20 invasive breast cancers using a Comparative Genomic Hybridization array specifically designed to detect the genome-wide CNV status of approximately 412 000 sites. Somatic copy number alterations (CNAs) were detected in 39.9% of the CNV probes examined. The most frequently altered regions were gains of 1q21-22 (90%), 8q21-24 (85%), 1q44 (85%), and 3q11 (85%) or losses of 16q22-24 (80%). Gene ontology analyses of genes within the CNA fragments revealed that cascades related to transcription and RNA metabolism correlated significantly with human epidermal growth factor receptor 2 positivity and menopausal status. Thirteen of 20 tumors showed CNAs in more than 35% of sites examined and a high prevalence of CNAs correlated significantly with estrogen receptor (ER) negativity, higher nuclear grade (NG), and higher Ki-67 labeling index. Finally, when CNA fragments were categorized according to their size, CNAs smaller than 10 kb correlated significantly with ER positivity and lower NG, whereas CNAs exceeding 10 Mb correlated with higher NG, ER negativity, and a higher Ki-67 labeling index. Most of these findings were confirmed or supported by quantitative PCR of representative DNA fragments in 72 additional breast cancers. These results suggest that most CNAs are caused by gain or loss of large chromosomal fragments and correlate with NG and several malignant features, whereas solitary CNAs of less than 10 kb could be involved in ER-positive breast carcinogenesis.
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http://dx.doi.org/10.1111/cas.14630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780029PMC
January 2021

Mint3 depletion restricts tumor malignancy of pancreatic cancer cells by decreasing SKP2 expression via HIF-1.

Oncogene 2020 09 21;39(39):6218-6230. Epub 2020 Aug 21.

Department of System Biology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Takaramachi, Kanazawa, Ishikawa, Japan.

Pancreatic cancer is one of the most fatal cancers without druggable molecular targets. Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcriptional factor that promotes malignancy in various cancers including pancreatic cancer. Herein, we found that HIF-1 is accumulated in normoxic or moderate hypoxic areas of pancreatic cancer xenografts in vivo and is active even during normoxia in pancreatic cancer cells in vitro. This prompted us to analyze whether the HIF-1 activator Mint3 contributes to malignant features of pancreatic cancer. Mint3 depletion by shRNAs attenuated HIF-1 activity during normoxia and cell proliferation concomitantly with accumulated p21 and p27 protein in pancreatic cancer cells. Further analyses revealed that Mint3 increased transcription of the oncogenic ubiquitin ligase SKP2 in pancreatic cancer cells via HIF-1. This Mint3-HIF-1-SKP2 axis also promoted partial epithelial-mesenchymal transition, stemness features, and chemoresistance in pancreatic cancer cells. Even in vivo, Mint3 depletion attenuated tumor growth of orthotopically inoculated human pancreatic cancer AsPC-1 cells. Database and tissue microarray analyses showed that Mint3 expression is correlated with SKP2 expression in human pancreatic cancer specimens and high Mint3 expression is correlated with poor prognosis of pancreatic cancer patients. Thus, targeting Mint3 may be useful for attenuating the malignant features of pancreatic cancer.
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http://dx.doi.org/10.1038/s41388-020-01423-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515798PMC
September 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

CADM1 suppresses c-Src activation by binding with Cbp on membrane lipid rafts and intervenes colon carcinogenesis.

Biochem Biophys Res Commun 2020 08 29;529(3):854-860. Epub 2020 Jun 29.

Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address:

Cell adhesion molecules act as tumor suppressors primarily by cell attachment activity, but additional mechanisms modifying signal transduction are suggested in some cases. Cell adhesion molecule 1 (CADM1), a membrane-spanning immunoglobulin superfamily, mediates intercellular adhesion by trans-homophilic interaction and acts as a tumor suppressor. Here, we investigated CADM1-associated proteins comprehensively using proteomic analysis of immune-precipitates of CADM1 by mass spectrometry and identified a transmembrane adaptor protein, Csk-binding protein (Cbp), known to suppress Src-mediated transformation, as a binding partner of CADM1. CADM1 localizes to detergent-resistant membrane fractions and co-immunoprecipitated with Cbp and c-Src. Suppression of CADM1 expression using siRNA reduces the amount of co-immunoprecipitated c-Src with Cbp and activates c-Src in colon cancer cells expressing both CADM1 and Cbp. On the other hand, co-replacement of CADM1 and Cbp in colon cancer cells lacking CADM1 and Cbp expression suppresses c-Src activation, wound healing and tumorigenicity in nude mice. Furthermore, expression of Cbp and CADM1 was lost in 55% and 83% of human colon cancer, respectively, preferentially in tumors with larger size and/or lymph node metastasis. CADM1 would act as a colon tumor suppressor by intervening oncogenic c-Src signaling through binding with Cbp besides its authentic cell adhesion activity.
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http://dx.doi.org/10.1016/j.bbrc.2020.05.103DOI Listing
August 2020

Chromosomal alterations among age-related haematopoietic clones in Japan.

Nature 2020 08 24;584(7819):130-135. Epub 2020 Jun 24.

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

The extent to which the biology of oncogenesis and ageing are shaped by factors that distinguish human populations is unknown. Haematopoietic clones with acquired mutations become common with advancing age and can lead to blood cancers. Here we describe shared and population-specific patterns of genomic mutations and clonal selection in haematopoietic cells on the basis of 33,250 autosomal mosaic chromosomal alterations that we detected in 179,417 Japanese participants in the BioBank Japan cohort and compared with analogous data from the UK Biobank. In this long-lived Japanese population, mosaic chromosomal alterations were detected in more than 35.0% (s.e.m., 1.4%) of individuals older than 90 years, which suggests that such clones trend towards inevitability with advancing age. Japanese and European individuals exhibited key differences in the genomic locations of mutations in their respective haematopoietic clones; these differences predicted the relative rates of chronic lymphocytic leukaemia (which is more common among European individuals) and T cell leukaemia (which is more common among Japanese individuals) in these populations. Three different mutational precursors of chronic lymphocytic leukaemia (including trisomy 12, loss of chromosomes 13q and 13q, and copy-neutral loss of heterozygosity) were between two and six times less common among Japanese individuals, which suggests that the Japanese and European populations differ in selective pressures on clones long before the development of clinically apparent chronic lymphocytic leukaemia. Japanese and British populations also exhibited very different rates of clones that arose from B and T cell lineages, which predicted the relative rates of B and T cell cancers in these populations. We identified six previously undescribed loci at which inherited variants predispose to mosaic chromosomal alterations that duplicate or remove the inherited risk alleles, including large-effect rare variants at NBN, MRE11 and CTU2 (odds ratio, 28-91). We suggest that selective pressures on clones are modulated by factors that are specific to human populations. Further genomic characterization of clonal selection and cancer in populations from around the world is therefore warranted.
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http://dx.doi.org/10.1038/s41586-020-2426-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489641PMC
August 2020

Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer.

Nat Commun 2020 06 24;11(1):3175. Epub 2020 Jun 24.

Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, 464-8681, Japan.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry.
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http://dx.doi.org/10.1038/s41467-020-16711-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314803PMC
June 2020

EXOSC9 depletion attenuates P-body formation, stress resistance, and tumorigenicity of cancer cells.

Sci Rep 2020 06 9;10(1):9275. Epub 2020 Jun 9.

Department of System Biology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Takaramachi, Kanazawa, Ishikawa, Japan.

Cancer cells adapt to various stress conditions by optimizing gene expression profiles via transcriptional and translational regulation. However, whether and how EXOSC9, a component of the RNA exosome complex, regulates adaptation to stress conditions and tumorigenicity in cancer cells remain unclear. Here, we examined the effects of EXOSC9 depletion on cancer cell growth under various stress conditions. EXOSC9 depletion attenuated growth and survival under various stress conditions in cancer cells. Interestingly, this also decreased the number of P-bodies, which are messenger ribonucleoprotein particles (mRNPs) required for stress adaptation. Meanwhile, EXOSC2/EXOSC4 depletion also attenuated P-body formation and stress resistance with decreased EXOSC9 protein. EXOSC9-mediated stress resistance and P-body formation were found to depend on the intact RNA-binding motif of this protein. Further, RNA-seq analyses identified 343 EXOSC9-target genes, among which, APOBEC3G contributed to defects in stress resistance and P-body formation in MDA-MB-231 cells. Finally, EXOSC9 also promoted xenografted tumor growth of MDA-MB-231 cells in an intact RNA-binding motif-dependent manner. Database analyses further showed that higher EXOSC9 activity, estimated based on the expression of 343 target genes, was correlated with poorer prognosis in some cancer patients. Thus, drugs targeting activity of the RNA exosome complex or EXOSC9 might be useful for cancer treatment.
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http://dx.doi.org/10.1038/s41598-020-66455-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283315PMC
June 2020

Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.

Nat Genet 2020 07 8;52(7):669-679. Epub 2020 Jun 8.

Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.
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http://dx.doi.org/10.1038/s41588-020-0640-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968075PMC
July 2020

Transethnic Meta-Analysis of Genome-Wide Association Studies Identifies Three New Loci and Characterizes Population-Specific Differences for Coronary Artery Disease.

Circ Genom Precis Med 2020 06 29;13(3):e002670. Epub 2020 May 29.

Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita (S. Suna, Yasushi Sakata).

Background: Genome-wide association studies provided many biological insights into coronary artery disease (CAD), but these studies were mainly performed in Europeans. Genome-wide association studies in diverse populations have the potential to advance our understanding of CAD.

Methods: We conducted 2 genome-wide association studies for CAD in the Japanese population, which included 12 494 cases and 28 879 controls and 2808 cases and 7261 controls, respectively. Then, we performed transethnic meta-analysis using the results of the coronary artery disease genome-wide replication and meta-analysis plus the coronary artery disease 1000 Genomes meta-analysis with UK Biobank. We then explored the pathophysiological significance of these novel loci and examined the differences in CAD-susceptibility loci between Japanese and Europeans.

Results: We identified 3 new loci on chromosome 1q21 (), 10q26 (), and 11q22 (-). Quantitative trait locus analyses suggested the association of and - with atherosclerotic immune cells. Tissue/cell type enrichment analysis showed the involvement of arteries, adrenal glands, and fat tissues in the development of CAD. We next compared the odds ratios of lead variants for myocardial infarction at 76 genome-wide significant loci in the transethnic meta-analysis and a moderate correlation between Japanese and Europeans, where 8 loci showed a difference. Finally, we performed tissue/cell type enrichment analysis using East Asian-frequent and European-frequent variants according to the risk allele frequencies and identified significant enrichment of adrenal glands in the East Asian-frequent group while the enrichment of arteries and fat tissues was found in the European-frequent group. These findings indicate biological differences in CAD susceptibility between Japanese and Europeans.

Conclusions: We identified 3 new loci for CAD and highlighted the genetic differences between the Japanese and European populations. Moreover, our transethnic analyses showed both shared and unique genetic architectures between the Japanese and Europeans. While most of the underlying genetic bases for CAD are shared, further analyses in diverse populations will be needed to elucidate variations fully.
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http://dx.doi.org/10.1161/CIRCGEN.119.002670DOI Listing
June 2020

Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan.

Nat Med 2020 04 23;26(4):542-548. Epub 2020 Mar 23.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.

While polygenic risk scores (PRSs) are poised to be translated into clinical practice through prediction of inborn health risks, a strategy to utilize genetics to prioritize modifiable risk factors driving heath outcome is warranted. To this end, we investigated the association of the genetic susceptibility to complex traits with human lifespan in collaboration with three worldwide biobanks (n = 675,898; BioBank Japan (n = 179,066), UK Biobank (n = 361,194) and FinnGen (n = 135,638)). In contrast to observational studies, in which discerning the cause-and-effect can be difficult, PRSs could help to identify the driver biomarkers affecting human lifespan. A high systolic blood pressure PRS was trans-ethnically associated with a shorter lifespan (hazard ratio = 1.03[1.02-1.04], P = 3.9 × 10) and parental lifespan (hazard ratio = 1.06[1.06-1.07], P = 2.0 × 10). The obesity PRS showed distinct effects on lifespan in Japanese and European individuals (P = 9.5 × 10 for BMI). The causal effect of blood pressure and obesity on lifespan was further supported by Mendelian randomization studies. Beyond genotype-phenotype associations, our trans-biobank study offers a new value of PRSs in prioritization of risk factors that could be potential targets of medical treatment to improve population health.
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http://dx.doi.org/10.1038/s41591-020-0785-8DOI Listing
April 2020

Reciprocal expression of trefoil factor-1 and thyroid transcription factor-1 in lung adenocarcinomas.

Cancer Sci 2020 Jun 30;111(6):2183-2195. Epub 2020 Apr 30.

Division of Integrative Pathology, Jichi Medical University, Shimotsuke, Japan.

Molecular targeted therapies against EGFR and ALK have improved the quality of life of lung adenocarcinoma patients. However, targetable driver mutations are mainly found in thyroid transcription factor-1 (TTF-1)/NK2 homeobox 1 (NKX2-1)-positive terminal respiratory unit (TRU) types and rarely in non-TRU types. To elucidate the molecular characteristics of the major subtypes of non-TRU-type adenocarcinomas, we analyzed 19 lung adenocarcinoma cell lines (11 TRU types and 8 non-TRU types). A characteristic of non-TRU-type cell lines was the strong expression of TFF-1 (trefoil factor-1), a gastric mucosal protective factor. An immunohistochemical analysis of 238 primary lung adenocarcinomas resected at Jichi Medical University Hospital revealed that TFF-1 was positive in 31 cases (13%). Expression of TFF-1 was frequently detected in invasive mucinous (14/15, 93%), enteric (2/2, 100%), and colloid (1/1, 100%) adenocarcinomas, less frequent in acinar (5/24, 21%), papillary (7/120, 6%), and solid (2/43, 5%) adenocarcinomas, and negative in micropapillary (0/1, 0%), lepidic (0/23, 0%), and microinvasive adenocarcinomas or adenocarcinoma in situ (0/9, 0%). Expression of TFF-1 correlated with the expression of HNF4-α and MUC5AC (P < .0001, P < .0001, respectively) and inversely correlated with that of TTF-1/NKX2-1 (P < .0001). These results indicate that TFF-1 is characteristically expressed in non-TRU-type adenocarcinomas with gastrointestinal features. The TFF-1-positive cases harbored KRAS mutations at a high frequency, but no EGFR or ALK mutations. Expression of TFF-1 correlated with tumor spread through air spaces, and a poor prognosis in advanced stages. Moreover, the knockdown of TFF-1 inhibited cell proliferation and soft-agar colony formation and induced apoptosis in a TFF-1-high and KRAS-mutated lung adenocarcinoma cell line. These results indicate that TFF-1 is not only a biomarker, but also a potential molecular target for non-TRU-type lung adenocarcinomas.
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http://dx.doi.org/10.1111/cas.14403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293082PMC
June 2020

Dimensionality reduction reveals fine-scale structure in the Japanese population with consequences for polygenic risk prediction.

Nat Commun 2020 03 26;11(1):1569. Epub 2020 Mar 26.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan.

The diversity in our genome is crucial to understanding the demographic history of worldwide populations. However, we have yet to know whether subtle genetic differences within a population can be disentangled, or whether they have an impact on complex traits. Here we apply dimensionality reduction methods (PCA, t-SNE, PCA-t-SNE, UMAP, and PCA-UMAP) to biobank-derived genomic data of a Japanese population (n = 169,719). Dimensionality reduction reveals fine-scale population structure, conspicuously differentiating adjacent insular subpopulations. We further enluciate the demographic landscape of these Japanese subpopulations using population genetics analyses. Finally, we perform phenome-wide polygenic risk score (PRS) analyses on 67 complex traits. Differences in PRS between the deconvoluted subpopulations are not always concordant with those in the observed phenotypes, suggesting that the PRS differences might reflect biases from the uncorrected structure, in a trait-dependent manner. This study suggests that such an uncorrected structure can be a potential pitfall in the clinical application of PRS.
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http://dx.doi.org/10.1038/s41467-020-15194-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099015PMC
March 2020

Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population.

Commun Biol 2020 03 5;3(1):104. Epub 2020 Mar 5.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan.

The genetic landscape of mitochondrial DNA (mtDNA) has been elusive. By analyzing mtDNA using the whole genome sequence (WGS) of Japanese individuals (n = 1928), we identified 2023 mtDNA variants and high-resolution haplogroups. Frequency spectra of the haplogroups were population-specific and were heterogeneous among geographic regions within Japan. Application of machine learning methods could finely classify the subjects corresponding to the high-digit mtDNA sub-haplogroups. mtDNA had distinct genetic structures from that of nuclear DNA (nDNA), characterized by no distance-dependent linkage disequilibrium decay, sparse tagging of common variants, and the existence of common haplotypes spanning the entire mtDNA. We did not detect any evidence of mtDNA-nDNA (or mtDNA copy number-nDNA) genotype associations. Together with WGS-based mtDNA variant imputation, we conducted a phenome-wide association study of 147,437 Japanese individuals with 99 clinical phenotypes. We observed pleiotropy of mtDNA genetic risk on the five late-onset human complex traits including creatine kinase (P = 1.7 × 10).
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http://dx.doi.org/10.1038/s42003-020-0812-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058612PMC
March 2020
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