Annual Report 2022

Division of Innovative Pathology and Laboratory Medicine (Tsukiji Campus)

Nobuyoshi Hiraoka, Kosei Nakajima, Sachiyo Hasegawa

Introduction

 In the Division of Innovative Pathology and Laboratory Medicine, we develop and improve new evaluation methods to analyze the pathobiological and clinicopathological characteristics of useful molecules for clinical studies in EPOC projects.

Research Activities

 The tumor immune microenvironment in intractable cancers, including pancreatic and biliary tract cancer, is studied clinicopathologically and pathobiologically. We examined 261 intrahepatic cholangiocarcinoma (iCCA) cases and demonstrated that the tertiary lymphoid structure (TLS) is prognostic only in the large-duct type, the tumor microenvironment of TLS-rich iCCA shows a significantly high vein density with an active immune-responsive microenvironment, and the vein density is prognostic in patients with iCCA. Thus, a TLS-rich microenvironment has a high vein density, which represents the antitumor direction of the tumor microenvironment with a favorable patient outcome. We report new diagnostic markers, carboxypeptidase A2 (CPA2) and carboxypeptidase A1 (CPA1), for pancreatic acinar cell neoplasms with very high sensitivity and specificity, which are useful for surgical and EUS-FNA/B specimens. The clinicopathological characteristics of hepatoid carcinoma and its related entities in the extrahepatic bile duct have been reported.

Education

 Teaching analytical techniques to technicians and researchers in several departments of the National Cancer Center was performed.

Future Prospects

 We will answer the requests from the selected project in various types of studies, including basic, preclinical, and clinical studies, and assess the clinicopathological or pathobiological significance of the target molecules. We will develop methods of quantitative analysis to evaluate morphological findings that are currently analyzed qualitatively.

List of papers published in 2022

Journal

1. Ikeda G, Hijioka S, Nagashio Y, Maruki Y, Ohba A, Hisada Y, Yoshinari M, Harai S, Kitamura H, Koga T, Murashima Y, Maehara K, Okada M, Yamashige D, Okamoto K, Hara H, Hagiwara Y, Agarie D, Takasaki T, Takeshita K, Kawasaki Y, Kondo S, Morizane C, Ueno H, Hiraoka N, Yatabe Y, Saito Y, Iwakiri K, Okusaka T. Fine-needle biopsy with 19G needle is effective in combination with endoscopic ultrasound-guided tissue acquisition for genomic profiling of unresectable pancreatic cancer. Digestive endoscopy, 35:124-133, 2023

2. Fukuta T, Tanaka T, Hashimoto T, Isahaya K, Kubo Y, Yamano Y, Satomi K, Hiraoka N, Shirakawa N, Arakawa A, Ogawa C, Nishimura N, Aoki J, Ito A, Inamoto Y, Kim SW, Fukuda T. Nelarabine-induced myelopathy in patients undergoing allogeneic hematopoietic cell transplantation: a report of three cases. International journal of hematology, 117:933-940, 2023

3. Furuya G, Katoh H, Atsumi S, Hashimoto I, Komura D, Hatanaka R, Senga S, Hayashi S, Akita S, Matsumura H, Miura A, Mita H, Nakakido M, Nagatoishi S, Sugiyama A, Suzuki R, Konishi H, Yamamoto A, Abe H, Hiraoka N, Aoki K, Kato Y, Seto Y, Yoshimura C, Miyadera K, Tsumoto K, Ushiku T, Ishikawa S. Nucleic acid-triggered tumoral immunity propagates pH-selective therapeutic antibodies through tumor-driven epitope spreading. Cancer science, 114:321-338, 2023

4. Ishimoto-Namiki U, Ino Y, Esaki M, Shimada K, Saruta M, Hiraoka N. Novel Insights Into Immunohistochemical Analysis For Acinar Cell Neoplasm of The Pancreas: Carboxypeptidase A2, Carboxypeptidase A1, and Glycoprotein 2. The American journal of surgical pathology, 47:525-534, 2023

5. Kometani T, Kamo K, Kido T, Hiraoka N, Chibazakura T, Unno K, Sekine K. Development of a novel co-culture system using human pancreatic cancer cells and human iPSC-derived stellate cells to mimic the characteristics of pancreatic ductal adenocarcinoma in vitro. Biochemical and biophysical research communications, 658:1-9, 2023

6. Ohba A, Morizane C, Ueno M, Kobayashi S, Kawamoto Y, Komatsu Y, Ikeda M, Sasaki M, Okano N, Furuse J, Hiraoka N, Yoshida H, Kuchiba A, Sadachi R, Nakamura K, Matsui N, Nakamura Y, Okamoto W, Yoshino T, Okusaka T. Multicenter phase II trial of trastuzumab deruxtecan for HER2-positive unresectable or recurrent biliary tract cancer: HERB trial. Future oncology (London, England), 18:2351-2360, 2022

7. Morizane C, Machida N, Honma Y, Okusaka T, Boku N, Kato K, Nomura S, Hiraoka N, Sekine S, Taniguchi H, Okano N, Yamaguchi K, Sato T, Ikeda M, Mizuno N, Ozaka M, Kataoka T, Ueno M, Kitagawa Y, Terashima M, Furuse J. Effectiveness of Etoposide and Cisplatin vs Irinotecan and Cisplatin Therapy for Patients With Advanced Neuroendocrine Carcinoma of the Digestive System: The TOPIC-NEC Phase 3 Randomized Clinical Trial. JAMA oncology, 8:1447-1455, 2022

8. Okura K, Esaki M, Nara S, Ban D, Takamoto T, Shimada K, Hiraoka N. Hepatoid carcinoma and related entities of the extrahepatic bile duct: A clinicopathological study of four cases. Pathology international, 72:332-342, 2022

9. Kitamura K, Esaki M, Sone M, Sugawara S, Hiraoka N, Nara S, Ban D, Takamoto T, Mizui T, Shimada K. Prognostic Impact of Radiological Splenic Artery Involvement in Pancreatic Ductal Adenocarcinoma of the Body and Tail. Annals of surgical oncology, 29:7047-7058, 2022

10. Tsuda N, Tian Y, Fujimoto M, Kuramoto J, Makiuchi S, Ojima H, Gotoh M, Hiraoka N, Yoshida T, Kanai Y, Arai E. DNA methylation status of the SPHK1 and LTB genes underlies the clinicopathological diversity of non-alcoholic steatohepatitis-related hepatocellular carcinomas. Journal of cancer research and clinical oncology, 2022

11. Sawada J, Hiraoka N, Qi R, Jiang L, Fournier-Goss AE, Yoshida M, Kawashima H, Komatsu M. Molecular Signature of Tumor-Associated High Endothelial Venules That Can Predict Breast Cancer Survival. Cancer immunology research, 10:468-481, 2022

12. Mafficini A, Simbolo M, Shibata T, Hong SM, Pea A, Brosens LA, Cheng L, Antonello D, Sciammarella C, Cantù C, Mattiolo P, Taormina SV, Malleo G, Marchegiani G, Sereni E, Corbo V, Paolino G, Ciaparrone C, Hiraoka N, Pallaoro D, Jansen C, Milella M, Salvia R, Lawlor RT, Adsay V, Scarpa A, Luchini C. Integrative characterization of intraductal tubulopapillary neoplasm (ITPN) of the pancreas and associated invasive adenocarcinoma. Modern pathology, 35:1929-1943, 2022

13. Sieverling L, Hong C, Koser SD, Ginsbach P, Kleinheinz K, Hutter B, Braun DM, Cortés-Ciriano I, Xi R, Kabbe R, Park PJ, Eils R, Schlesner M, Brors B, Rippe K, Jones DTW, Feuerbach L. Genomic footprints of activated telomere maintenance mechanisms in cancer. Nature communications, 11:733, 2020

14. Shuai S, Gallinger S, Stein LD. Combined burden and functional impact tests for cancer driver discovery using DriverPower. Nature communications, 11:734, 2020

15. Bhandari V, Li CH, Bristow RG, Boutros PC. Divergent mutational processes distinguish hypoxic and normoxic tumours. Nature communications, 11:737, 2020

16. Zhang Y, Chen F, Fonseca NA, He Y, Fujita M, Nakagawa H, Zhang Z, Brazma A, Creighton CJ. High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations. Nature communications, 11:736, 2020

17. Rubanova Y, Shi R, Harrigan CF, Li R, Wintersinger J, Sahin N, Deshwar AG, Morris QD. Reconstructing evolutionary trajectories of mutation signature activities in cancer using TrackSig. Nature communications, 11:731, 2020

18. Cmero M, Yuan K, Ong CS, Schröder J, Corcoran NM, Papenfuss T, Hovens CM, Markowetz F, Macintyre G. Inferring structural variant cancer cell fraction. Nature communications, 11:730, 2020

19. Paczkowska M, Barenboim J, Sintupisut N, Fox NS, Zhu H, Abd-Rabbo D, Mee MW, Boutros PC, Reimand J. Integrative pathway enrichment analysis of multivariate omics data. Nature communications, 11:735, 2020

20. Jiao W, Atwal G, Polak P, Karlic R, Cuppen E, Danyi A, de Ridder J, van Herpen C, Lolkema MP, Steeghs N, Getz G, Morris QD, Stein LD. A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns. Nature communications, 11:728, 2020

21. Reyna MA, Haan D, Paczkowska M, Verbeke LPC, Vazquez M, Kahraman A, Pulido-Tamayo S, Barenboim J, Wadi L, Dhingra P, Shrestha R, Getz G, Lawrence MS, Pedersen JS, Rubin MA, Wheeler DA, Brunak S, Izarzugaza JMG, Khurana E, Marchal K, von Mering C, Sahinalp SC, Valencia A, Reimand J, Stuart JM, Raphael BJ. Pathway and network analysis of more than 2500 whole cancer genomes. Nature communications, 11:729, 2020

22. Yakneen S, Waszak SM, Gertz M, Korbel JO. Butler enables rapid cloud-based analysis of thousands of human genomes. Nature biotechnology, 38:288-292, 2020

23. Carlevaro-Fita J, Lanzós A, Feuerbach L, Hong C, Mas-Ponte D, Pedersen JS, Johnson R. Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis. Communications biology, 3:56, 2020

24. Yuan Y, Ju YS, Kim Y, Li J, Wang Y, Yoon CJ, Yang Y, Martincorena I, Creighton CJ, Weinstein JN, Xu Y, Han L, Kim HL, Nakagawa H, Park K, Campbell PJ, Liang H. Comprehensive molecular characterization of mitochondrial genomes in human cancers. Nature genetics, 52:342-352, 2020

25. Rodriguez-Martin B, Alvarez EG, Baez-Ortega A, Zamora J, Supek F, Demeulemeester J, Santamarina M, Ju YS, Temes J, Garcia-Souto D, Detering H, Li Y, Rodriguez-Castro J, Dueso-Barroso A, Bruzos AL, Dentro SC, Blanco MG, Contino G, Ardeljan D, Tojo M, Roberts ND, Zumalave S, Edwards PA, Weischenfeldt J, Puiggròs M, Chong Z, Chen K, Lee EA, Wala JA, Raine KM, Butler A, Waszak SM, Navarro FCP, Schumacher SE, Monlong J, Maura F, Bolli N, Bourque G, Gerstein M, Park PJ, Wedge DC, Beroukhim R, Torrents D, Korbel JO, Martincorena I, Fitzgerald RC, Van Loo P, Kazazian HH, Burns KH, Campbell PJ, Tubio JMC. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. Nature genetics, 52:306-319, 2020

26. Akdemir KC, Le VT, Chandran S, Li Y, Verhaak RG, Beroukhim R, Campbell PJ, Chin L, Dixon JR, Futreal PA. Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer. Nature genetics, 52:294-305, 2020

27. Zapatka M, Borozan I, Brewer DS, Iskar M, Grundhoff A, Alawi M, Desai N, Sültmann H, Moch H, Cooper CS, Eils R, Ferretti V, Lichter P. The landscape of viral associations in human cancers. Nature genetics, 52:320-330, 2020

28. Li Y, Roberts ND, Wala JA, Shapira O, Schumacher SE, Kumar K, Khurana E, Waszak S, Korbel JO, Haber JE, Imielinski M, Weischenfeldt J, Beroukhim R, Campbell PJ. Patterns of somatic structural variation in human cancer genomes. Nature, 578:112-121, 2020

29. Gerstung M, Jolly C, Leshchiner I, Dentro SC, Gonzalez S, Rosebrock D, Mitchell TJ, Rubanova Y, Anur P, Yu K, Tarabichi M, Deshwar A, Wintersinger J, Kleinheinz K, Vázquez-García I, Haase K, Jerman L, Sengupta S, Macintyre G, Malikic S, Donmez N, Livitz DG, Cmero M, Demeulemeester J, Schumacher S, Fan Y, Yao X, Lee J, Schlesner M, Boutros PC, Bowtell DD, Zhu H, Getz G, Imielinski M, Beroukhim R, Sahinalp SC, Ji Y, Peifer M, Markowetz F, Mustonen V, Yuan K, Wang W, Morris QD, Spellman PT, Wedge DC, Van Loo P. The evolutionary history of 2,658 cancers. Nature, 578:122-128, 2020

30. Rheinbay E, Nielsen MM, Abascal F, Wala JA, Shapira O, Tiao G, Hornshøj H, Hess JM, Juul RI, Lin Z, Feuerbach L, Sabarinathan R, Madsen T, Kim J, Mularoni L, Shuai S, Lanzós A, Herrmann C, Maruvka YE, Shen C, Amin SB, Bandopadhayay P, Bertl J, Boroevich KA, Busanovich J, Carlevaro-Fita J, Chakravarty D, Chan CWY, Craft D, Dhingra P, Diamanti K, Fonseca NA, Gonzalez-Perez A, Guo Q, Hamilton MP, Haradhvala NJ, Hong C, Isaev K, Johnson TA, Juul M, Kahles A, Kahraman A, Kim Y, Komorowski J, Kumar K, Kumar S, Lee D, Lehmann KV, Li Y, Liu EM, Lochovsky L, Park K, Pich O, Roberts ND, Saksena G, Schumacher SE, Sidiropoulos N, Sieverling L, Sinnott-Armstrong N, Stewart C, Tamborero D, Tubio JMC, Umer HM, Uusküla-Reimand L, Wadelius C, Wadi L, Yao X, Zhang CZ, Zhang J, Haber JE, Hobolth A, Imielinski M, Kellis M, Lawrence MS, von Mering C, Nakagawa H, Raphael BJ, Rubin MA, Sander C, Stein LD, Stuart JM, Tsunoda T, Wheeler DA, Johnson R, Reimand J, Gerstein M, Khurana E, Campbell PJ, López-Bigas N, Weischenfeldt J, Beroukhim R, Martincorena I, Pedersen JS, Getz G. Analyses of non-coding somatic drivers in 2,658 cancer whole genomes. Nature, 578:102-111, 2020

31. Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, Tian Ng AW, Wu Y, Boot A, Covington KR, Gordenin DA, Bergstrom EN, Islam SMA, Lopez-Bigas N, Klimczak LJ, McPherson JR, Morganella S, Sabarinathan R, Wheeler DA, Mustonen V, Getz G, Rozen SG, Stratton MR. The repertoire of mutational signatures in human cancer. Nature, 578:94-101, 2020

32. Calabrese C, Davidson NR, Demircioğlu D, Fonseca NA, He Y, Kahles A, Lehmann KV, Liu F, Shiraishi Y, Soulette CM, Urban L, Greger L, Li S, Liu D, Perry MD, Xiang Q, Zhang F, Zhang J, Bailey P, Erkek S, Hoadley KA, Hou Y, Huska MR, Kilpinen H, Korbel JO, Marin MG, Markowski J, Nandi T, Pan-Hammarström Q, Pedamallu CS, Siebert R, Stark SG, Su H, Tan P, Waszak SM, Yung C, Zhu S, Awadalla P, Creighton CJ, Meyerson M, Ouellette BFF, Wu K, Yang H, Brazma A, Brooks AN, Göke J, Rätsch G, Schwarz RF, Stegle O, Zhang Z. Genomic basis for RNA alterations in cancer. Nature, 578:129-136, 2020

33. Li CH, Prokopec SD, Sun RX, Yousif F, Schmitz N, Boutros PC. Sex differences in oncogenic mutational processes. Nature communications, 11:4330, 2020