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Human Genome Center

Laboratory of Genome Technology
シークエンス技術開発分野
Project Professor

Koichi Matsuda, M.D., Ph.D.

特任教授

博士（医学）

松田浩

一The major goal of our group is to identify genes of medical importance, and todevelop new diagnostic and therapeutic tools. We have been attempting to isolate
genes involving in carcinogenesis and also those causing or predisposing tovarious diseases as well as those related to drug efficacies and adverse reactions.
By means of technologies developed through the genome project including a highresolution SNP map, a large-scale DNA sequencing, and proteome/metabolome
analysis, we have isolated a number of biologically and/or medically important
genes, and are developing novel diagnostic and therapeutic tools.

1.  Functional analysis of p53 signaling pathway
Regulation of the innate immune response andgut microbiome by p53
p53 is a key tumor suppressor mutated in half ofhuman cancers. In recent years, p53 was shown toregulate a wide variety of functions. From the transcriptome analysis of 24 tissues of irradiated mice, weidentified 553 genes markedly induced by p53. Gene
Ontology (GO) enrichment analysis found that themost associated biological process was innate immunity. 16S rRNA-seq analysis revealed that Akkermansia, which has anti-inflammatory properties and isinvolved in the regulation of intestinal barrier integrity, was decreased in p53-knockout (p53-/- ) mice afterradiation. p53-/- mice were susceptible to radiation-induced GI toxicity and had a significantly shorter survival time than p53-wild-type (p53+/+ ) mice following
radiation. However, administration of antibiotics resulted in a significant improvement in survival andprotection against GI toxicity. Mbl2 and Lcn2, whichhave antimicrobial activity, were identified to be directly transactivated by p53 and secreted by liver into
the circulatory system. We also found the expressionof MBL2 and LCN2 was decreased in liver cancer tissues with p53 mutations compared with those without p53 mutations. These results indicate that p53 isinvolved in shaping the gut microbiome through its

downstream targets related to the innate immune
system, thus protecting the intestinal barrier.
2.  Analysis of host genetic factors of various diseases
Helicobacter pylori, homologous-recombination genes, and gastric cancer
Background: Helicobacter pylori infection is awell-known risk factor for gastric cancer. However,the contribution of germline pathogenic variants incancer-predisposing genes and their effect, whencombined with H. pylori infection, on the risk of gastric cancer has not been widely evaluated.
Methods: We evaluated the association between
germline pathogenic variants in 27 cancer-predisposing genes and the risk of gastric cancer in a sample of
10,426 patients with gastric cancer and 38,153 controls
from BioBank Japan. We also assessed the combined
effect of pathogenic variants and H. pylori infection
status on the risk of gastric cancer and calculated thecumulative risk in 1433 patients with gastric cancer
and 5997 controls from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC).
Results: Germline pathogenic variants in nine
genes (APC, ATM, BRCA1, BRCA2, CDH1, MLH1,MSH2, MSH6, and PALB2) were associated with the65
risk of gastric cancer. We found an interaction between H. pylori infection and pathogenic variants inhomologous-recombination genes with respect to therisk of gastric cancer in the sample from HERPACC(relative excess risk due to the interaction, 16.01; 95%
confidence interval [CI], 2.22 to 29.81; P = 0.02). At 85
years of age, persons with H. pylori infection and apathogenic variant had a higher cumulative risk ofgastric cancer than noncarriers infected with H. pylori(45.5% [95% CI, 20.7 to 62.6] vs. 14.4% [95% CI, 12.2 to16.6]).
Conclusions: H. pylori infection modified the riskof gastric cancer associated with germline pathogenic
variants in homologous-recombination genes. (Funded by the Japan Agency for Medical Research and Development and others.).
East Asian-specific and cross-ancestry genomewide meta-analyses provide mechanistic insights
into peptic ulcer disease,
Peptic ulcer disease (PUD) refers to acid-induced

injury of the digestive tract, occurring mainly in thestomach (gastric ulcer (GU)) or duodenum (duodenalulcer (DU)). In the present study, we conducted alarge-scale, cross-ancestry meta-analysis of PUD combining genome-wide association studies with Japanese and European studies (52,032 cases and 905,344controls), and discovered 25 new loci highly concordant across ancestries. An examination of GU and DU
genetic architecture demonstrated that GUs shared
the same risk loci as DUs, although with smaller genetic effect sizes and higher polygenicity than DUs,
indicating higher heterogeneity of GUs. Helicobacter
pylori (HP)-stratified analysis found an HP-related
host genetic locus. Integrative analyses using bulkand single-cell transcriptome profiles highlighted thegenetic factors of PUD being enriched in the highly
expressed genes in stomach tissues, especially in somatostatin-producing D cells. Our results provide genetic evidence that gastrointestinal cell differentiations and hormone regulations are critical in PUD
etiology.

Publications
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 .H.P. Khor, T. Koguchi, H. Liu, M. Kakuta, D.
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Matsubara, R. Wen, Y. Sagiya, S. Imoto, H. Nakagawa, K. Matsuda, C. Tanikawa. Regulationof the innate immune response and gut microbiome by p53, Cancer Science, (2023).
Y. Usui, Y. Taniyama, M. Endo, Y.N. Koyanagi,
Y. Kasugai, I. Oze, H. Ito, I. Imoto, T. Tanaka,
M. Tajika, K. Matsuda, Y. Momozawa et al. Helicobacter pylori, homologous-recombination
genes, and gastric cancer, New England Journal of Medicine, 388 (2023) 1181-1190.
Y. He, M. Koido, Y. Sutoh, M. Shi, Y. Otsuka-Yamasaki, H.M. Munter, T. Morisaki, A. Nagai, Y. Murakami, K. Matsuda, Y. Kamatani etal. East Asian-specific and cross-ancestry genome-wide meta-analyses provide mechanistic
insights into peptic ulcer disease, Nature Genetics, (2023) 1-10.
M. Akiyama, S. Sakaue, A. Takahashi, K. Ishigaki, M. Hirata, K. Matsuda, Y. Momozawa, Y.
Okada, T. Ninomiya, K. Matsuda, et al. Genome-wide association study reveals BET1L
associated with survival time in the 137,693
Japanese individuals, Communications Biology, 6 (2023) 143.
Y. Akiyama, K. Sonehara, D. Maeda, H. Katoh,
T. Naito, K. Yamamoto, K. Matsuda, Y.
Yamanashi, Y. Furukawa, T. Morisaki, K. Matsuda, et al. enome-wide association study identifies risk loci within the major histocompatibility complex region for Hunner-type interstitial
cystitis, Cell Reports Medicine, 4 (2023).
S. Dofuku, K. Sonehara, S. Miyawaki, S. Sakaue,

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H. Imai, M. Shimizu, H. Hongo, Y. Shinya, K.
Ohara, Y. Teranishi, K. Matsuda, et al. Genome-wide association study of intracranialartery stenosis followed by phenome-wide association study, Translational Stroke Research,
14 (2023) 322-333.
C. Fernandez-Rozadilla, M. Timofeeva, Z. Chen,P. Law, M. Thomas, S. Schmit, V. Díez-Obrero,L. Hsu, J. Fernandez-Tajes, C. Palles, K. Matsuda, et al. Deciphering colorectal cancer genetics
through multi-omic analysis of 100,204 cases
and 154,587 controls of European and east
Asian ancestries, Nature genetics, 55 (2023) 8999.
K. Miyazawa, K. Ito, M. Ito, Z. Zou, M. Kubota,
S. Nomura, H. Matsunaga, S. Koyama, H. Ieki,
M. Akiyama, Cross-ancestry genome-wide
analysis of atrial fibrillation unveils disease biology and enables cardioembolic risk prediction, Nature genetics, 55 (2023) 187-197.
K. Yamazaki, C. Terao, A. Takahashi, Y.
Kamatani, K. Matsuda, S. Asai, Y. Takahashi,
Genome‐wide association studies categorized
by class of anti‐hypertensive drugs reveal complex pathogenesis of hypertension with drugresistance, Clinical Pharmacology & Therapeutics, (2023).
N. Nishida, J. Ohashi, G. Suda, T. Chiyoda, N.
Tamaki, T. Tomiyama, S. Ogasawara, M. Sugiyama, Y. Kawai, S.-S. Khor, K. Matsuda, et al.
Prediction Model with HLA-A* 33: 03 Reveals
Number of Days to Develop Liver Cancer from
Blood Test, International journal of molecular

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sciences, 24 (2023) 4761.
Y. Okawa, Y. Iwasaki, T.A. Johnson, N. Ebata, C.
Inai, M. Endo, K. Maejima, S. Sasagawa, M. Fujita, K. Matsuda, H. Nakagawa, et al. Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer, Journalof Hepatology, 78 (2023) 333-342.
G. Sato, Y. Shirai, S. Namba, R. Edahiro, K.
Sonehara, T. Hata, M. Uemura, K. Matsuda, Y.
Doki, Y. Okada et al. Pan-cancer and cross-population genome-wide association studies dissect shared genetic backgrounds underlying
carcinogenesis, Nature Communications, 14(2023) 3671.
J. Shi, K. Shiraishi, J. Choi, K. Matsuo, T.-Y.
Chen, J. Dai, R.J. Hung, K. Chen, X.-O. Shu, Y.T.
Kim, K. Matsuda, et al. Genome-wide association study of lung adenocarcinoma in East Asiaand comparison with a European population,
Nature communications, 14 (2023) 3043.
Y. Shima, S. Sasagawa, N. Ota, R. Oyama, M.
Tanaka, M. Kubota-Sakashita, H. Kawakami,M. Kobayashi, N. Takubo, A.N. Ozeki, K. Matsuda, et al. Increased PDGFRB and NF-κB signaling caused by highly prevalent somatic mutations in intracranial aneurysms, Science
Translational Medicine, 15 (2023) eabq7721.
L. Stolarova, P. Kleiblova, P. Zemankova, B.
Stastna, M. Janatova, J. Soukupova, M.I. Achatz,
C. Ambrosone, P. Apostolou, B.K. Arun, K.
Matsuda, et al. ENIGMA CHEK2 gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense

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Variants Associated with Increased Breast Cancer Risk, Clinical Cancer Research, 29 (2023)
3037-3050.
Y. Tomofuji, K. Suzuki, T. Kishikawa, N. Shojima, J. Hosoe, K. Inagaki, S. Matsubayashi, H.
Ishihara, H. Watada, Y. Ishigaki, K. Matsuda, etal. Identification of serum metabolome signatures associated with retinal and renal complications of type 2 diabetes, Communications
Medicine, 3 (2023) 5.
A. Wang, J. Shen, A.A. Rodriguez, E.J. Saunders,F. Chen, R. Janivara, B.F. Darst, X. Sheng, Y. Xu,A.J. Chou, K. Matsuda, et al. Characterizing
prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants,
Nature genetics, (2023) 1-10.
G. Jia, Y. Li, X. Zhong, K. Wang, M. Pividori, R.
Alomairy, A. Esposito, H. Ltaief, C. Terao, M.
Akiyama, K. Matsuda, et al. The high-dimensional space of human diseases built from diagnosis records and mapped to genetic loci, Nature Computational Science, (2023) 1-15.
A. Kawamura, K. Matsuda, Y. Murakami, M.
Saruta, T. Kohno, K. Shiraishi, et al. Contribution of an Asian-prevalent HLA haplotype tothe risk of HBV-related hepatocellular carcinoma, (2023).
Y. Wang, S. Namba, E. Lopera, S. Kerminen, K.
Tsuo, K. Läll, M. Kanai, W. Zhou, K.-H. Wu, M.J. Favé, K. Matsuda, et al. Global Biobank analyses provide lessons for developing polygenic
risk scores across diverse cohorts, Cell Genomics, 3 (2023).