Published papers

BACKGROUND: Abnormalities in homologous recombination contribute to the aggressive nature of castration-resistant prostate cancer. Retinoblastoma transcriptional corepressor 1 (RB1) and breast cancer 2 (BRCA2) exist close to each other in the same chromosome, and the significance of their concurrent loss has become a hot topic in the field of cancer research. CASE PRESENTATION: A 61-year-old man presented with a chief complaint of a mass on his head and was diagnosed as multiple bone metastases from prostate cancer. He was treated with standard medication, but he died 2 years 6 months after being diagnosed with prostate cancer. Simultaneous biallelic loss of RB1 and BRCA2 as well as a truncating mutation of tumor protein p53 (TP53) were revealed by genomic analysis. CONCLUSION: To our knowledge, this is the first report of castration-resistant prostate cancer (CRPC) with BRCA2 and RB1 co-loss and TP53 mutation. To establish a treatment strategy for highly malignant cases with such multiple genetic features is important.

About 4 and a half years have passed since"Cancer Genome Medicine"was first mentioned in the Third Phase of the Basic Plan to Promote Cancer Control Programs that started in October 2017. Currently, cancer genomic medicine is being carried out by the cancer gene panel test, which is covered by public insurance, mainly at the 12 Cancer Genome Medicine Core Center Hospital designated nationwide by the Ministry of Health, Labor, and Welfare in Japan. Cancer genomic medicine has come to be positioned as a standard medical treatment. However, there are various challenges in operating an expert panel that professionally examines the results of the gene panel tests and reports treatment recommendations and secondary findings that suggest hereditary tumors. In addition, there is an urgent need to disseminate and educate healthcare professionals and patients about cancer genomic medicine. In this panel discussion on January 14, 2022, 10 panelists discussed how to solve these issues and the prospects for the future.

ゲノム解析を利用して同一患者の大腸癌原発巣と肝転移巣を比較検討し、化学療法の治療経過や転移過程における時空間的なゲノム変異の解明を試みた。その結果、臨床的に「actionable」な大腸癌ドライバー遺伝子が大腸癌と転移巣間では異なり、原発巣の病理結果から再発・転移巣に対する化学療法を選択しても、再発・転移巣には化学療法が奏功しない可能性が考えられた。また、ドライバー遺伝子の相違は原発巣から転移巣における治療過程でのclonal evolutionによって引き起こされることから、治療経過における転移巣切除や肝生検、リキッドバイオプシーを積極的に行うことで、より正確な真の癌個別化医療が進んでいくものと示唆された。

「がん遺伝子診断部」を開設し、専門の遺伝外来、診療(医療面接)、患者採血、DNA抽出、ライブラリー調整、シークエンス、ゲノム解析、カンファレンス、遺伝カウンセリング、結果報告をすべてインハウスで行う院内完結型クリニカルシークエンス(CLHURC検査)を開始した。次に腫瘍センター内にゲノム医療ユニットを設置し、CLHURC検査と同様に次世代シークエンサー(NGS)を用いてパネル化したがんドライバー遺伝子160種類を解析する網羅的がん遺伝子パネル検査「PleSSision検査」を実施した。従来までの臨床検査とは異なり、専門としている検査分野のみの知識や技術、経験だけでは、がんゲノム医療に携わることは困難で、他職種の医療従事者や専門家との連携が非常に重要であった。臨床検査技師がゲノム医療における多くの役割を求められることによるデメリットは、新しい分野の検査が導入され、臨床検査技師の役割が増すことで人手や環境、設備が不足し、現場が混乱する可能性が高いことであった。メリットは「専門分野の検査」についての知識や技術、経験以外にも、様々な知識や技術を得ることができることであった。

Human DOCK180, which was originally identified as a major protein bound to the Crk oncogene product, is an archetype of the CDM family of proteins, including Ced-5 of Caenorhabditis elegans and Mbc of Drosophila melanogaster. After DOCK180, at least three putative human proteins that manifest high amino acid sequence similarity to DOCK180 have been registered in the GenBank/EMBL database. We have designated one of them, KIAA0209, as DOCK2 and characterize here. DOCK2 mRNA was expressed mostly in peripheral blood cells, followed by slight expression in the spleen and thymus, whereas DOCK180 was expressed in all tissues tested except in peripheral blood cells. Immunostaining of human cadaver tissues revealed that the expression of DOCK2 was limited to the lymphocytes and macrophages of various organs. DOCK2 bound to and activated Rac1, as did DOCK180 however, DOCK2 did not bind to CrkII, which transduces signals at focal adhesions. Thus, DOCK180 and DOCK2 are regulators of Rac and function in adherent and non-adherent cells, respectively.

We report a rare case of colonic metastasis from primary carcinoma of the lung. A 59-year-old man who underwent pulmonary surgery for lung cancer was referred to our hospital in June 2007. The patient complained of abdominal pain, and barium enema examination at another hospital had demonstrated a descending colon tumor. Postoperative histopathological and immunohistochemical findings indicated that the tumor was a colonic metastasis of lung cancer. Three months postoperatively, the cancer had metastasized to the brain, and the patient underwent radiotherapy. He survived for more than 1 year after colonic surgery. Clinically apparent metastases from lung cancer to the colon are rare, and in the 50 Japanese cases retrospectively investigated here, the prognosis was poor. © 2008 Springer.

Cyclin-dependent kinase 12 (CDK12), one of the key factors associated with DNA damage response pathways, is located on chromosome 17 proximal to Erb-B2 receptor tyrosine kinase 2 (ERBB2). In this report, CDK12 and ERBB2 coamplification was detected by targeted next-generation sequencing in two urothelial carcinomas. The staining intensity of the CDK12 and human epidermal growth factor receptor-2 proteins was associated with the prognosis of each urothelial carcinoma case. Our results suggest that CDK12 coamplification with ERBB2 might be associated with tumor aggressiveness and contribution to cancer pathogenesis. Therapies targeting CDK12 should be developed for these patients.

Cyclin-dependent kinase 12 (CDK12), one of the key factors associated with DNA damage response pathways, is located on chromosome 17 proximal to Erb-B2 receptor tyrosine kinase 2 (ERBB2). In this report,CDK12andERBB2coamplification was detected by targeted next-generation sequencing in two urothelial carcinomas. The staining intensity of the CDK12 and human epidermal growth factor receptor-2 proteins was associated with the prognosis of each urothelial carcinoma case. Our results suggest thatCDK12coamplification withERBB2might be associated with tumor aggressiveness and contribution to cancer pathogenesis. Therapies targeting CDK12 should be developed for these patients.

Mix and more than match: Relative to the catalytic activity of pure Rh nanoparticles in a dendrimer cage, Rh/Fe bimetallic nanoparticles in dendrimers have improved catalytic activity towards the hydrogenation of olefins, and unlike Wilkinson catalyst could catalyze nitroarene hydrogenation (see scheme, G4=4th generation dendrimer). © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

We report a rare case of granulomatosis with polyangiitis (GPA) presenting with hypertrophic cranial pachymeningitis (HCP), abducens nerve palsy, and stenosis of the internal carotid artery (ICA). A 59-year-old Japanese man presented with a year history of nasal obstruction and a 2-month history of slight headache. Histopathological examination of the granulomatous mucosa in the ethmoid sinuses resected by endoscopic sinus surgery revealed necrotizing vasculitis with multinucleated giant cells. The patient was diagnosed with the limited form of GPA as a result of the systemic examination. He declined immunosuppressive treatment. Eighteen months after the diagnosis of GPA, he presented with diplopia and severe headache. Though nasal findings indicating GPA were not observed in the nasal cavity, CT scan revealed a lesion of the right sphenoid sinus eroding the bone of the clivus. Gadolinium-enhanced MRI of the brain showed thickening of the dura mater around the right cavernous sinus and clivus. Magnetic resonance angiography and cerebral angiography revealed narrowing at the C5 portion of the ICA. Intravenous methylprednisolone pulse therapy followed by oral prednisolone and cyclophosphamide resolved headache and dramatically improved HCP and stenosis of the ICA.

The development of genomic medicine has enabled us to perform contemporary clinical sequencing, while the acquisition of high-quality biospecimens and the appropriate handling of these materials are indispensable. We started Clinical Biobank, a novel system for on-demand-type banking, in 2014. During the 22 months from August 2014, we stored around 6,000 biospecimens from 1,700 patients, and most of them were obtained for diverse clinical research. The quality and amount of extracted DNA and RNA from PFPE samples were markedly high; thus, these samples are adequate for targeted amplicon sequencing using MiSeq (Illumina). In addition, we recently established the Division of Clinical Cancer Genetics for personalized cancer medicine. We obtain biospecimens including blood and tissue fixed using the PAXgene Tissue system, and the samples are immediately analyzed for targeted amplicon sequencing using MiSeq. The rest of the samples are stored after adequate procedures in a -80 degree freezer. We obtain DNA and RNA from PAX-fixed paraffin- embedded samples with a high quality and sufficient amounts for clinical sequencing after pathological evalua- tion. For three months, we examined 40 cancer patients and performed targeted exome sequencing. As a result, detection rates of actionable and druggable gene mutations were around 85 and 50%, respectively. We have also established the Clinical Biobank Study Group in Japan, collaborating with several universities and cancer centers. We believe that this novel biospecimen repository system will help to effectively estab- lish cancer clinical sequencing throughout Japan.