Annual Report 2017

Nobuyoshi Hiraoka, Shigeki Sekine, Yoshinori Ino, Taisuke Mori, Kosei Nakajima, Reiko Ogawa, Chie Naito, Eijitsu Ryo, Naoko Minematsu

Introduction

 Three members of the Molecular Pathology Division are also working as staff pathologists at the Pathology Division of the National Cancer Center Hospital (NCCH). On the basis of the knowledge and experience in diagnostic situations, we are exploring molecular backgrounds of tumors, particularly focusing on the molecular mechanisms of carcinogenesis and the tumor microenvironment. Many of our projects are based on precise histopathological analyses, taking advantage of the participation of pathologists.

Research activities

 To investigate how the antitumor immune microenvironment is formed, we screened IL-12 family and IL-12 receptor family molecules to be prognostic in human pancreatic cancer using three different cohorts and obtained one molecule. This molecule dimerized with a different molecule and acted in cancer tissue. That heterodimer molecule was involved in the antitumor microenvironment in two in vivo systems; 1) stable transfectants transplanted to syngeneic mice, and 2) chemical carcinogenesis using transgenic mice with expressing dominant negative form of that heterodimer molecule.

 We have been working on the genetic backgrounds of colorectal cancer precursors and their correlations with morphology. Approximately 20-30% of colorectal cancers develop through the serrated pathway, which is distinct from the classical adenoma-carcinoma sequence. We identified RNF43 mutations and RSPO fusions as WNT pathway gene alterations specific to the serrated pathway and are exploring how these genetic alterations are involved during colorectal tumorigenesis. We are also working on colorectal tumorigenesis in Lynch syndrome, which is the most common hereditary cancer syndrome. Our analysis revealed that, in contrast to the current understanding, mismatch repair deficiency is the

initial molecular abnormality in Lynch syndrome-

associated tumorigenesis. This suggests the importance of mismatch repair deficient foci as important precursors of Lynch syndrome-associated colorectal cancer.

 Adenocarcinoma and adenoma derived from pigmented ciliary epithelium (APCE) are rare ocular neoplasms. The distinction between APCE and uveal melanoma is often difficult but critical because of their different therapeutic strategies. We showed that the lack of SOX10 expression and the presence of the BRAF V600E mutation are characteristic and distinguishing features of APCE. Head and neck squamous cell carcinoma (HNSCC) is known to have TP53 mutations at high frequency. We performed detailed analysis of TP53 mutations and p53 protein expression in 326 HNSCCs and analyzed their prognostic significance in surgically treated HNSCCs. The result showed that TP53 mutation and p53 expression statuses are significantly associated with disease free survival as well as overall survival, suggesting their potential use as a prognostic factor.

Future prospects

 On the basis of the experience in clinical diagnostic situations, we are hoping to develop novel diagnostic methods that are useful in clinical situations and to identify candidate therapeutic targets.

List of papers published in January 2017 - March 2018

Journal

 1. Mori T, Sukeda A, Sekine S, Shibata S, Ryo E, Okano H, Suzuki S, Hiraoka N. SOX10 Expression as Well as BRAF and GNAQ/11 Mutations Distinguish Pigmented Ciliary Epithelium Neoplasms From Uveal Melanomas. Invest Ophthalmol Vis Sci, 58:5445-5451, 2017

 2. Yoshida A, Kobayashi E, Kubo T, Kodaira M, Motoi T, Motoi N, Yonemori K, Ohe Y, Watanabe SI, Kawai A, Kohno T, Kishimoto H, Ichikawa H, Hiraoka N. Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities. Mod Pathol, 30:797-809, 2017

 3. Asano N, Yoshida A, Ichikawa H, Mori T, Nakamura M, Kawai A, Hiraoka N. Immunohistochemistry for trimethylated H3K27 in the diagnosis of malignant peripheral nerve sheath tumours. Histopathology, 70:385-393, 2017

 4. Nagasato M, Rin Y, Yamamoto Y, Henmi M, Hiraoka N, Chiwaki F, Matsusaki K, Tagawa M, Sasaki H, Aoki K. A Tumor-targeting Adenovirus with High Gene-transduction Efficiency for Primary Pancreatic Cancer and Ascites Cells. Anticancer Res, 37:3599-3605, 2017

 5. Nakajima K, Heilbrun LK, Smith D, Hogan V, Raz A, Heath E. The influence of PSA autoantibodies in prostate cancer patients: a prospective clinical study-II. Oncotarget, 8:17643-17650, 2017

 6. Iwao Y, Ojima H, Kobayashi T, Kishi Y, Nara S, Esaki M, Shimada K, Hiraoka N, Tanabe M, Kanai Y. Liver atrophy after percutaneous transhepatic portal embolization occurs in two histological phases: Hepatocellular atrophy followed by apoptosis. World journal of hepatology, 9:1227-1238, 2017

 7. Kojima M, Shimazaki H, Iwaya K, Nakamura T, Kawachi H, Ichikawa K, Sekine S, Ishiguro S, Shimoda T, Kushima R, Yao T, Fujimori T, Hase K, Watanabe T, Sugihara K, Lauwers GY, Ochiai A. Intramucosal colorectal carcinoma with invasion of the lamina propria: a study by the Japanese Society for Cancer of the Colon and Rectum. Hum Pathol, 66:230-237, 2017

 8. Makise N, Yoshida A, Komiyama M, Nakatani F, Yonemori K, Kawai A, Fukayama M, Hiraoka N. Dedifferentiated Liposarcoma With Epithelioid/Epithelial Features. Am J Surg Pathol, 41:1523-1531, 2017

 9. Nakamura Y, Mori T, Takae Y, Tsutsumida A, Takahashi A, Namikawa K, Hirai I, Yamazaki N. Rapidly developed BRAF inhibitor-induced verrucous keratosis. J Dermatol, 44:e274-e275, 2017

10. Shoji H, Tada K, Kitano S, Nishimura T, Shimada Y, Nagashima K, Aoki K, Hiraoka N, Honma Y, Iwasa S, Takashima A, Kato K, Boku N, Honda K, Yamada T, Heike Y, Hamaguchi T. The peripheral immune status of granulocytic myeloid-derived suppressor cells correlates the survival in advanced gastric cancer patients receiving cisplatin-based chemotherapy. Oncotarget, 8:95083-95094, 2017

11. Maki D, Mori T, Teshima M, Kobayashi K, Matsumoto F, Sakai A, Okami K, Yoshimoto S. Chondrosarcoma of the hyoid bone - Report of a case and a literature review of the suitable treatment strategy. Auris Nasus Larynx, 44:629-634, 2017

12. Iwasaki T, Nara S, Kishi Y, Esaki M, Shimada K, Hiraoka N. Surgical treatment of neuroendocrine tumors in the second portion of the duodenum: a single center experience and systematic review of the literature. Langenbecks Arch Surg, 402:925-933, 2017

13. Cui L, Nakano K, Obchoei S, Setoguchi K, Matsumoto M, Yamamoto T, Obika S, Shimada K, Hiraoka N. Small Nucleolar Noncoding RNA SNORA23, Up-Regulated in Human Pancreatic Ductal Adenocarcinoma, Regulates Expression of Spectrin Repeat-Containing Nuclear Envelope 2 to Promote Growth and Metastasis of Xenograft Tumors in Mice. Gastroenterology, 153:292-306.e2, 2017

14. Shimada Y, Kohno T, Ueno H, Ino Y, Hayashi H, Nakaoku T, Sakamoto Y, Kondo S, Morizane C, Shimada K, Okusaka T, Hiraoka N. An Oncogenic ALK Fusion and an RRAS Mutation in KRAS Mutation-Negative Pancreatic Ductal Adenocarcinoma. Oncologist, 22:158-164, 2017

15. Kihara A, Yoshida H, Watanabe R, Takahashi K, Kato T, Ino Y, Kitagawa M, Hiraoka N. Clinicopathologic Association and Prognostic Value of Microcystic, Elongated, and Fragmented (MELF) Pattern in Endometrial Endometrioid Carcinoma. Am J Surg Pathol, 41:896-905, 2017

16. Hayashi H, Kohno T, Ueno H, Hiraoka N, Kondo S, Saito M, Shimada Y, Ichikawa H, Kato M, Shibata T, Morizane C, Sakamoto Y, Shimada K, Komatsu Y, Sakamoto N, Okusaka T. Utility of Assessing the Number of Mutated KRAS, CDKN2A, TP53, and SMAD4 Genes Using a Targeted Deep Sequencing Assay as a Prognostic Biomarker for Pancreatic Cancer. Pancreas, 46:335-340, 2017

17. Nakajima K, Nangia-Makker P, Hogan V, Raz A. Cancer Self-Defense: An Immune Stealth. Cancer Res, 77:5441-5444, 2017

18. Matsumoto F, Mori T, Matsumura S, Matsumoto Y, Fukasawa M, Teshima M, Kobayashi K, Yoshimoto S. Prognostic significance of surgical extranodal extension in head and neck squamous cell carcinoma patients. Jpn J Clin Oncol, 47:699-704, 2017

19. Sekine S, Ogawa R, Saito S, Ushiama M, Shida D, Nakajima T, Taniguchi H, Hiraoka N, Yoshida T, Sugano K. Cytoplasmic MSH2 immunoreactivity in a patient with Lynch syndrome with an EPCAM-MSH2 fusion. Histopathology, 70:664-669, 2017

20. Yamada M, Saito Y, Takamaru H, Sasaki H, Yokota T, Matsuyama Y, Sato Y, Sakamoto T, Nakajima T, Taniguchi H, Sekine S, Matsuda T. Long-term clinical outcomes of endoscopic submucosal dissection for colorectal neoplasms in 423 cases: a retrospective study. Endoscopy, 49:233-242, 2017

21. Nakamura K, Nonaka S, Nakajima T, Yachida T, Abe S, Sakamoto T, Suzuki H, Yoshinaga S, Oda I, Matsuda T, Sekine S, Kanemitsu Y, Katai H, Saito Y, Hirota S. Clinical outcomes of gastric polyps and neoplasms in patients with familial adenomatous polyposis. Endosc Int Open, 5:E137-E145, 2017

22. Kishi Y, Nara S, Esaki M, Hiraoka N, Shimada K. Salvage hepatectomy for local recurrence of hepatocellular carcinomas offers survival comparable to that of matched patients who undergo primary hepatectomies. Eur J Surg Oncol, 43:1076-1082, 2017

23. Ueno H, Kanemitsu Y, Sekine S, Ishiguro M, Ito E, Hashiguchi Y, Kondo F, Shimazaki H, Mochizuki S, Kajiwara Y, Shinto E, Yamamoto J. Desmoplastic Pattern at the Tumor Front Defines Poor-prognosis Subtypes of Colorectal Cancer. Am J Surg Pathol, 41:1506-1512, 2017

24. Masai K, Sakurai H, Sukeda A, Suzuki S, Asakura K, Nakagawa K, Asamura H, Watanabe SI, Motoi N, Hiraoka N. Prognostic Impact of Margin Distance and Tumor Spread Through Air Spaces in Limited Resection for Primary Lung Cancer. J Thorac Oncol, 12:1788-1797, 2017

25. Shiokawa D, Sato A, Ohata H, Mutoh M, Sekine S, Kato M, Shibata T, Nakagama H, Okamoto K. The Induction of Selected Wnt Target Genes by Tcf1 Mediates Generation of Tumorigenic Colon Stem Cells. Cell Rep, 19:981-994, 2017

26. Kobayashi K, Mori T, Matsumoto F, Murakami N, Teshima M, Fukasawa M, Matsumoto Y, Matsumura S, Itami J, Asai M, Yoshimoto S. Impact of microscopic orbital periosteum invasion in orbital preservation surgery. Jpn J Clin Oncol, 47:321-327, 2017

27. Yoshida A, Arai Y, Kobayashi E, Yonemori K, Ogura K, Hama N, Mukai W, Motoi T, Kawai A, Shibata T, Hiraoka N. CIC break-apart fluorescence in-situ hybridization misses a subset of CIC-DUX4 sarcomas: a clinicopathological and molecular study. Histopathology, 71:461-469, 2017

28. Hironaka-Mitsuhashi A, Matsuzaki J, Takahashi RU, Yoshida M, Nezu Y, Yamamoto Y, Shiino S, Kinoshita T, Ushijima T, Hiraoka N, Shimizu C, Tamura K, Ochiya T. A tissue microRNA signature that predicts the prognosis of breast cancer in young women. PLoS One, 12:e0187638, 2017

29. Hashimoto T, Yamashita S, Yoshida H, Taniguchi H, Ushijima T, Yamada T, Saito Y, Ochiai A, Sekine S, Hiraoka N. WNT Pathway Gene Mutations Are Associated With the Presence of Dysplasia in Colorectal Sessile Serrated Adenoma/Polyps. Am J Surg Pathol, 41:1188-1197, 2017

30. Yamada M, Oda I, Tanaka H, Abe S, Nonaka S, Suzuki H, Yoshinaga S, Kuchiba A, Koyanagi K, Igaki H, Taniguchi H, Sekine S, Saito Y, Tachimori Y. Tumor location is a risk factor for lymph node metastasis in superficial Barrett's adenocarcinoma. Endoscopy international open, 5:E868-E874, 2017

31. Furukawa D, Chijiwa T, Matsuyama M, Mukai M, Matsuo EI, Nishimura O, Kawai K, Suemizu H, Nakagohri T, Ozawa S, Shimada K, Hiraoka N, Nakamura M. Plasma membrane expression of ZNF185 is a prognostic factor in pancreatic ductal carcinoma. Oncology letters, 14:3633-3640, 2017

32. Yamamoto Y, Nagasato M, Rin Y, Henmi M, Ino Y, Yachida S, Ohki R, Hiraoka N, Tagawa M, Aoki K. Strong antitumor efficacy of a pancreatic tumor-targeting oncolytic adenovirus for neuroendocrine tumors. Cancer Med, 6:2385-2397, 2017

33. Sekine S, Ogawa R, Hashimoto T, Motohiro K, Yoshida H, Taniguchi H, Saito Y, Yasuhiro O, Ochiai A, Hiraoka N. Comprehensive characterization of RSPO fusions in colorectal traditional serrated adenomas. Histopathology, 71:601-609, 2017

34. Sekine S, Mori T, Ogawa R, Tanaka M, Yoshida H, Taniguchi H, Nakajima T, Sugano K, Yoshida T, Kato M, Furukawa E, Ochiai A, Hiraoka N. Mismatch repair deficiency commonly precedes adenoma formation in Lynch Syndrome-Associated colorectal tumorigenesis. Mod Pathol, 30:1144-1151, 2017