【背景・目的】リンチ症候群はミスマッチ修復遺伝子（MLH1、MSH2、MSH6、PMS2）の生殖細胞系列変異を原因とする常染色体優性遺伝性疾患である。いずれかの修復機構が損なわれて腫瘍が発生し表現型としてマイクロサテライト不安定性(MSI)を呈するが、ミスマッチ修復酵素異常から下流に生じるドライバー遺伝子変異やパスウェイについては明らかにされていない。
【対象・方法】遺伝性リンチ症候群FFPE検体37例分についてTOP (Todai OncoPanel)を用いて解析を行った。TOPパネルには体細胞変異の検出が可能な478遺伝子搭載のDNA用パネル(DNA v4 panel)と、発現量解析と高精度に融合遺伝子の検出も可能な677遺伝子搭載のRNA用パネル(RNA v5 panel)とがある。まず我々は、DNA用パネルを用いて、生殖細胞系列変異から解析した。
【経過報告】37例より集積したDNA 45検体は、十分なリード数が得られることを確認した。MSIの判定は、通常5つのベセスダマーカーを用いるが、本研究ではDNA v4 panel上ゲノム領域のうち、microsatellite markerを用いてMSI scoreを判定した。判定方法としては、非癌部に比べて癌部において反復配列数に変化があったsiteの割合をMSI scoreとし、MSI score 3.5%以上をMSI陽性とした。MSI score陽性の割合は肺腺癌症例(LUAD) 11例/114例(9.7%)、肉腫(SARC) 11例/87例(12.6%)に対して、リンチ症候群37例では37検体/45検体(83%)と高値であった。また、体細胞変異プロファイル解析は終えており、ドライバー変異とアリル頻度、アミノ酸置換パターンは集積済みである。RNAについても、43検体を対象にTOPパネルで解析済みであり、腫瘍免疫応答を中心に数理統計学的解析を進めている状況である。
【今後の方針】MSI陽性大腸がんの進化解析を進めるために、凍結検体での多領域（5か所）シーケンス（Target Seq/RNA seq）を進めていく。最終的にはこれまでの成果と今後の進化解析の統合により、リンチ症候群が免疫寛容を獲得して大腸における発癌または癌進展に寄与する機構を明らかにしたい。

Publisher：Proceedings of the National Academy of Sciences of the United States of America  

Elevated levels of miR-155 in solid and liquid malignancies correlate with aggressiveness of the disease. In this manuscript, we show that miR-155 targets transcripts encoding IcosL, the ligand for Inducible T-cell costimulator (Icos), thus impairing the ability of T cells to recognize and eliminate malignant cells. We specifically found that overexpression of miR-155 in B cells of Eµ-miR-155 mice causes loss of IcosL expression as they progress toward malignancy. Similarly, in mice where miR-155 expression is controlled by a Cre-Tet-OFF system, miR-155 induction led to malignant infiltrates lacking IcosL expression. Conversely, turning miR-155 OFF led to tumor regression and emergence of infiltrates composed of IcosL-positive B cells and Icos-positive T cells forming immunological synapses. Therefore, we next engineered malignant cells to express IcosL, in order to determine whether IcosL expression would increase tumor infiltration by cytotoxic T cells and reduce tumor progression. Indeed, overexpressing an IcosL-encoding cDNA in MC38 murine colon cancer cells before injection into syngeneic C57BL6 mice reduced tumor size and increased intratumor CD8+ T cell infiltration, that formed synapses with IcosL-expressing MC38 cells. Our results underscore the fact that by targeting IcosL transcripts, miR-155 impairs the infiltration of tumors by cytotoxic T cells, as well as the importance of IcosL on enhancing the immune response against malignant cells. These findings should lead to the development of more effective anticancer treatments based on maintaining, increasing, or restoring IcosL expression by malignant cells, along with impairing miR-155 activity.

DOI： 10.1073/pnas.2408649121

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Language：English   Publisher：Heliyon  

Hot springs have long been used for medical purposes throughout the world. Recently, the positive effects of hot spa-bathing on circulatory diseases have been reported, while there are few reports on the mental effects of hot spa-bathing. Therefore, the purpose of this study was to clarify the relationship between hot spa-bathing habits and mental health throughout Japan. We conducted a nationwide online survey, including questions on bathing behavior, subjective satisfaction, lifestyle, and illness. The results showed a significant positive correlation between hot spa-bathing habits and multiple subjective satisfaction levels regarding mental health effects. The factor analysis results indicated that hot spa-bathing habits tended to be associated with good mental health, high health consciousness, and disease. Our study revealed that subjective satisfaction was higher among individuals with hot spa-bathing habits, suggesting that the hot spring spa-bathing habit may have a positive influence on mental health.

DOI： 10.1016/j.heliyon.2023.e19631

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

本研究の目的は、血中マイクロRNA(miRNA)をバイオマーカーとして検出することで、胃癌リスクの高い症例を同定することである。スクリーニングを行った1206名のうち、血清抗体検査でヘリコバクター・ピロリ(H.pylori)陽性で、内視鏡検査を受けた144名を本研究の対象とした。粘膜炎症の肉眼的評価には、正常粘膜をグレード0、萎縮をグレード1(C-1、C-2)、グレード2(C-3、O-1)、グレード3(O-2、O-3)に分類する木村・竹本分類を適用した。血清サンプルは2相に分け、miRNAマイクロアレイプロファイリングに使用した。グレード3の粘膜とその他のグレードの粘膜におけるmiRNAの発現を比較した。胃癌における発現は、TCGAのデータで確認した。miR-196b-3pは有意に増加し、miR-92a-2-5pは減少していた(P<0.05、q<0.2)。TCGAのデータでは、胃癌症例においてmiR-196b-3pの発現が高いことが示された(P<0.001)。グレード3とそれ以外を比較すると、検出されたmiRNAを用いた受信者動作特性曲線下面積は0.7であった。さらに、miRNAを組み合わせることで、より高い精度が得られた。miRNAを組み合わせる場合、3種類のmiRNA(miR-196b-3p、miR-92a-2-5p、miR-6791-3p)の組み合わせが高い感度と特異性を示し、曲線下面積は0.8を超えていた。ここに示されたmiRNAの組み合わせは、胃癌の前癌病変のバイオマーカーとして有望である可能性がある。

Language：English   Publisher：Annals of Gastroenterological Surgery  

Aim: Gastric mucosal changes associated with chronic gastritis are known to be precancerous lesions of gastric cancer. We aimed to identify individuals with a high risk of gastric cancer by detection of microRNAs (miRNA) in the blood as biomarkers. Methods: Of 1206 individuals screened, 144 who were positive for Helicobacter pylori (H. pylori) by the serum antibody test and who underwent endoscopy were the subjects of this study. For the gross assessment of mucosal inflammation, we applied the Kimura–Takemoto classification, in which normal mucosa was defined as grade 0, and atrophy was categorized as grade 1 (C-1 and C-2), grade 2 (C-3 and O-1), and grade 3 (O-2 and O-3). Serum samples were divided into two phases and used for miRNA microarray profiling. We compared the expression of miRNAs in grade 3 mucosa and other grades. Expression in gastric cancer was confirmed with TCGA data. Results: miR-196b-3p was significantly upregulated, and miR-92a-2-5p was downregulated (P <.05 and q < 0.2). TCGA data showed a high expression of miR-196b-3p in gastric cancer cases (P <.001). Comparing grade 3 and the others, the area under the receiver operating characteristic curve using the detected miRNAs was as high as about 0.7. Furthermore, the combination of miRNAs resulted in higher accuracy. In terms of the significance of the combinatory mRNAs, the combination of three miRNAs (miR-196b-3p, miR-92a-2-5p, and miR-6791-3p) revealed high sensitivity and specificity, with the area under the curve exceeding 0.8. Conclusion: The identified combinatory miRNAs may represent promising biomarkers of precancerous lesions in gastric cancer.

DOI： 10.1002/ags3.12610

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Language：English   Publisher：European Journal of Cancer  

Background: The mainstream first-line chemotherapy for advanced/recurrent gastric cancer (ARGC) is combination therapy including platinum-based agents. With the progressive aging of the society, the incidence of gastric cancer in elderly patients is increasing. However, elderly patients cannot tolerate these agents because of renal dysfunction or low quality of life. The KSCC1701 study explored the efficacy and safety of S-1 + ramucirumab in elderly patients with ARGC. Patients and methods: Chemotherapy-naive patients aged ≥70 years with ARGC were eligible. Patients received S-1 (40–60 mg twice daily for 4 weeks in 6-week cycles) and ramucirumab (8 mg/kg every 2 weeks) until disease progression. The primary end-point was the 1-year overall survival (OS) rate. The anticipated lower threshold of 1-year survival was set at 40% in light of previous S-1–based regimens. The secondary end-points included progression-free survival (PFS), OS, the overall response rate (ORR) and safety. Results: Between September 2017 and November 2019, 48 patients (34 men and 14 women) were enrolled in this study. The median patient age was 77.5 years, and all patients had a performance status of 0 (n = 20) or 1 (n = 28). The 1-year OS rate was 65.2%, which met the primary end-point. The median survival time and median PFS were 16.4 and 5.8 months, respectively. The ORR was 41.9%. The most frequent grade 3/4 (≥15%) adverse events were neutropenia, anorexia and anaemia. Conclusion: Considering these findings, S-1 + ramucirumab appears to be an excellent treatment option for elderly patients with ARGC. (250 words). This trial has been registered with the Japan Registry of Clinical Trials Registry under the number jRCTs071180066.

DOI： 10.1016/j.ejca.2022.02.028

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Event date： 2019.2

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：佐賀   Country：Japan  

Event date： 2018.12

Language：Japanese  

Venue：福岡   Country：Japan  

Event date： 2018.11

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2018.9

Language：Japanese  

Venue：大阪   Country：Japan  

Event date： 2018.9

Language：Japanese  

Venue：大阪   Country：Japan  

Language：Japanese  

食道癌の個別治療標的あるいは診断法の選択のために、がんゲノム領域の理解と研究成果が望まれている。今日までに生殖細胞系列変異の解析では食道癌罹患の遺伝的要因、環境的要因が明らかであり、体細胞変異解析では高頻度の変異を来すドライバー変異が報告されている。コピー数変異についても食道がん特異的な染色体レベルの増幅・欠損が明らかである。さらにゲノム研究成果の臨床応用としてcfDNAにおける体細胞変異検出が超早期再発や治療効果診断に有用と考えられる結果も示されている。本稿ではそれらを中心に述べ、今後の食道がんの診断や治療に有用な標的変異について考察する。

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

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