61Human Genome Center

Laboratory of Molecular Medicine
ゲノム医科学分野
Professor
Senior Assistant Professor
Assistant Professor

Tatsuhiro Shibata, M.D., Ph.D.
Atsushi Niida, Ph.D.
Kazuki Takahashi, Ph.D.

教
講助授
師
教

医学博士
博士（理学）
博士（農学）柴 田
新井田
高 橋龍厚数弘司
冴The Laboratory of Molecular Medicine focuses on comprehensive characterizationof currently-untreatable diseases including cancer on the basis of moleculargenomics and aims to make “breakthroughs for human health” by identifying novel
disease-related genes/pathways, including potential therapeutic or preventive
targets and biomarkers, and to understand human diseases as heterogeneous but
intervention-able “biological systems”. This group has also organized the facility forthe analysis of next-generation high-performance sequencers.

1.  Multiancestry comprehensive molecular analysis of gastric cancer

2.  Genomic analysis and evolutionary simulationof MSI-H colorectal cancer

Gastric cancer is among the most common malignancies worldwide, characterized by geographical,
epidemiological and histological heterogeneity. Here,
we report an extensive, multiancestral landscape ofdriver events in gastric cancer, involving 1,335 cases.
Seventy-seven significantly mutated genes (SMGs)
were identified, including ARHGAP5 and TRIM49C.
We also identified subtype-specific drivers, including
PIGR and SOX9, which were enriched in the diffuse
subtype of the disease. SMGs also varied according to
Epstein-Barr virus infection status and ancestry.
Non-protein-truncating CDH1 mutations, which arecharacterized by in-frame splicing alterations, targeted localized extracellular domains and uniquely occurred in sporadic diffuse-type cases. In patients withgastric cancer with East Asian ancestry, our data suggested a link between alcohol consumption or metabolism and the development of RHOA mutations.
Moreover, mutations with potential roles in immune
evasion were identified. Overall, these data provide
comprehensive insights into the molecular landscapeof gastric cancer across various subtypes and ancestries.

Intratumor heterogeneity (ITH) in microsatellite
instability-high (MSI-H) colorectal cancer (CRC) has
been poorly studied. We aimed to clarify how the ITHof MSI-H CRCs is generated in cancer evolution andhow immune selective pressure affects ITH. We reanalyzed public whole-exome sequencing data on 246
MSI-H CRCs. In addition, we performed a multi-region analysis from 6 MSI-H CRCs. To verify the process of subclonal immune escape accumulation, anovel computational model of cancer evolution under
immune pressure was developed. Our analysis presented the enrichment of functional genomic alterations in antigen-presentation machinery (APM). Associative analysis of neoantigens indicated thegeneration of immune escape mechanisms via HLAalterations. Multiregion analysis revealed the clonalacquisition of driver mutations and subclonal accumulation of APM defects in MSI-H CRCs. Examination of variant allele frequencies demonstrated that
subclonal mutations tend to be subjected to selectivesweep. Computational simulations of tumour progression with the interaction of immune cells successfully verified the subclonal accumulation of immune
escape mutations and suggested the efficacy of early

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initiation of an immune checkpoint inhibitor (ICI)-based treatment. Our results demonstrate the heterogeneous acquisition of immune escape mechanisms
in MSI-H CRCs by Darwinian selection, providing
novel insights into ICI-based treatment strategies.
3.  Evaluating selection working on intra-tumor
heterogeneity.
A tumor is defined as a population of cells that
rapidly expands from a single original cell. It is now
widely acknowledged that a tumor is composed ofgenetically diverse subclones, leading to intra-tumor
heterogeneity (ITH). Ongoing discussions center on
the impact of selection on the quality and quantity ofITH, as it directly affects the medical response of tumors, resistance to therapy, and the likelihood of recurrence and/or metastasis. The central question revolves

around the significance of Darwinian selection within
the tumor cell population. Various studies have suggested that the observed ITH patterns could be explained by non-Darwinian or neutral models, whileothers propose a role for Darwinian selection.We are
currently developing a novel and straightforward statistical test to assess the influence of Darwinian selection (or positive selection) on intratumor heterogeneity. Through this approach, we plan to analyze ITH
data across different cancer types and investigate thecontribution of Darwinian selection, examining its relationship with factors such as cancer type, age, clinical stage, and genomic background. These findings
underscore the importance of understanding Darwinian selection in shaping ITH and emphasize its potential implications for improving cancer diagnosis andtreatment strategies.

Publications
1.		Multiancestry genomic and transcriptomic analysis of gastric cancer. Totoki Y, Saito-Adachi M,
Shiraishi Y, Komura D, Nakamura H, Suzuki A,
Tatsuno K, Rokutan H, Hama N, Yamamoto S,Ono H, Arai Y, Hosoda F, Katoh H, Chiba K, IidaN, Nagae G, Ueda H, Shihang C, Sekine S, Abe H,Nomura S, Matsuura T, Sakai E, Ohshima T, RinoY, Yeoh KG, So J, Sanghvi K, Soong R, Fukagawa
A, Yachida S, Kato M, Seto Y, Ushiku T, Nakajima
A, Katai H, Tan P, Ishikawa S, Aburatani H, Shibata T. Nat Genet. 2023 Apr;55(4):581-594.
2.		Lost expression of AT-rich interaction domain 1A
in the gastric mucosa-A constituent of field cancerization in the stomach. Abe H, Rokutan H,Totoki Y, Nakamura H, Shibata T, Ushiku T,Fukayama M. Pathol Int. 2023 Jun;73(6):234-245.
3.		Convergent genomic diversity and novel BCAA
metabolism in intrahepatic cholangiocarcinoma.
Kitagawa A, Osawa T, Noda M, Kobayashi Y, AkiS, Nakano Y, Saito T, Shimizu D, Komatsu H, Sugaya M, Takahashi J, Kosai K, Takao S, Motomura
Y, Sato K, Hu Q, Fujii A, Wakiyama H, Tobo T,Uchida H, Sugimachi K, Shibata K, Utsunomiya T,
Kobayashi S, Ishii H, Hasegawa T, Masuda T, Matsui Y, Niida A, Soga T, Suzuki Y, Miyano S, Aburatani H, Doki Y, Eguchi H, Mori M, Nakayama
KI, Shimamura T, Shibata T, Mimori K. Br J Cancer. 2023 Jun;128(12):2206-2217.
4.		A new era of the Asian clinical research network: areport from the ATLAS international symposium.
Terada M, Nakamura K, Matsuda T, Okuma HS,Sudo K, Yusof A, Imasa M, Sirachainan E, Anh PT,Fujiwara Y, Yamamoto N, Voon PJ, Chokephaibulkit K, Shibata T, Inoue M, Mano H, Shimoi T,Sriuranpong V, Yonemori K, Shimada K. Jpn J Clin
Oncol. 2023 Jun 29;53(7):619-628.
5.		Genomic landscape and its prognostic significancein stage III colorectal cancer: JCOG1506A1, an ancillary of JCOG0910. Shida D, Kuchiba A, Shibata
T, Hamaguchi T, Yamasaki S, Ito M, Kobatake T,Tonooka T, Masaki T, Shiozawa M, Takii Y, Uetake
H, Okamura S, Ojima H, Kazama S, Takeyama H,Kanato K, Shimada Y, Murakami Y, Kanemitsu Y.
Cancer Sci. 2023 Aug;114(8):3352-3363.
6.		UTX inactivation in germinal center B cells promotes the development of multiple myeloma withextramedullary disease. Rizq O, Mimura N, Oshima M, Momose S, Takayama N, Itokawa N, Koide
S, Shibamiya A, Miyamoto-Nagai Y, Rizk M, Nakajima-Takagi Y, Aoyama K, Wang C, Saraya A,Ito R, Seimiya M, Watanabe M, Yamasaki S, Shibata T, Yamaguchi K, Furukawa Y, Chiba T, Sakaida
E, Nakaseko C, Tamaru JI, Tai YT, Anderson KC,Honda H, Iwama A. Leukemia. 2023 Sep;37(9):18951907.
7.		Precise characterization of somatic complex structural variations from tumor/control paired longread sequencing data with nanomonsv. Shiraishi
Y, Koya J, Chiba K, Okada A, Arai Y, Saito Y, Shibata T, Kataoka K. Nucleic Acids Res. 2023 Aug
11;51(14):e74.
8.		Oncogenic structural aberration landscape in gastric cancer genomes. Saito-Adachi M, Hama N,Totoki Y, Nakamura H, Arai Y, Hosoda F, Rokutan H, Yachida S, Kato M, Fukagawa A, Shibata T.
Nat Commun. 2023 Jun 22;14(1):3688.
9.		Tumor-infiltrating Leukocyte Profiling Defines
Three Immune Subtypes of NSCLC with Distinct
Signaling Pathways and Genetic Alterations. Aoki
K, Nishito Y, Motoi N, Arai Y, Hiraoka N, ShibataT, Sonobe Y, Kayukawa Y, Hashimoto E, Takahashi M, Fujii E, Nishizawa T, Fukuda H, Ohashi
K, Arai K, Mizoguchi Y, Yoshida Y, Watanabe SI,Yamashita M, Kitano S, Sakamoto H, Nagata Y,

63Mitsumori R, Ozaki K, Niida S, Kanai Y, Hirayama
A, Soga T, Maruyama T, Tsukada K, Yabuki N,Shimada M, Kitazawa T, Natori O, Sawada N,Kato A, Yoshida T, Yasuda K, Mizuno H, Tsunoda
H, Ochiai A. Cancer Res Commun. 2023 Jun
13;3(6):1026-1040.
10.	ICGC ARGO precision medicine: genomic profiling-informed prediction of immunotherapy response in two patients with metastatic head andneck squamous cell carcinoma. Nocini R, Tondulli
L, D’Ambrosio C, Luchini C, Biankin AV, Casolino
R, Scarpa A; ICGC-ARGO; Milella M, Lawlor RT.
Lancet Oncol. 2023 Aug;24(8):851-853.
11.	Subclonal accumulation of immune escape mechanisms in microsatellite instability-high colorectal
cancers. Kobayashi Y, Niida A, Nagayama S, SaekiK, Haeno H, Takahashi KK, Hayashi S, Ozato Y,Saito H, Hasegawa T, Nakamura H, Tobo T, Kitagawa A, Sato K, Shimizu D, Hirata H, Hisamatsu
Y, Toshima T, Yonemura Y, Masuda T, Mizuno S,Kawazu M, Kohsaka S, Ueno T, Mano H, Ishihara
S, Uemura M, Mori M, Doki Y, Eguchi H, Oshima
M, Suzuki Y, Shibata T, Mimori K. Br J Cancer.
2023 Oct;129(7):1105-1118.
12.	Sleeping Beauty transposon mutagenesis identified genes and pathways involved in inflammation-associated colon tumor development. Shimomura K, Hattori N, Iida N, Muranaka Y, Sato K,Shiraishi Y, Arai Y, Hama N, Shibata T, Narushima D, Kato M, Takamaru H, Okamoto K, Takeda
H. Nat Commun. 2023 Oct 16;14(1):6514.
13.	Genomic and epigenomic integrative subtypes ofrenal cell carcinoma in a Japanese cohort. Fukagawa A, Hama N, Totoki Y, Nakamura H, Arai Y,
Saito-Adachi M, Maeshima A, Matsui Y, Yachida
S, Ushiku T, Shibata T. Nat Commun. 2023 Dec
16;14(1):8383.
14.	Pediatric diffuse glioma with EP300::BCOR fusionmanifesting as low-grade epilepsy-associatedneuroepithelial tumor: a case presentation. Nakata S, Arai Y, Fukuoka K, Shirakura T, Yamazaki A,Osawa S, Hama N, Shibata T, Miyagishima T,
Horiguchi K, Tosaka M, Yokoo H, Yoshimoto Y,
Nobusawa S. Brain Tumor Pathol. 2024
Jan;41(1):35-39.
15.	Cell cycle-dependent gene networks for cell proliferation activated by nuclear CK2α complexes.
Kato Homma, M., Nakato, R., Niida, A., Bando,M., Fujiki, K., Yokota, N., Yamamoto, S., Shibata,T., Takagi, M., Yamaki, J., Kozuka-Hata, H.,Oyama, M., Shirahige, K., Homma, Y. Life ScienceAlliance, 7(1), 2024.
16.	The Mutographs biorepository: A unique genomic
resource to study cancer around the world. Perdomo S, Abedi-Ardekani B, Carolina de Carvalho A,
Ferreiro-Iglesias A, Gaborieau V, Cattiaux T, Renard H, Chopard P, Carreira C, Spanu A, Antwi S,
Ashton-Prolla P, Canova C, Cox R, Shibata T,Świątkowska B, Scelo G, Chanudet E, Wang J,Fitzgerald S, Latimer C, Moody S, Humphreys L,Alexandrov LB, Stratton MR, Brennan P. On behalf of the Mutographs Study. Cell Genomiocs
2024, in press.