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Tumor immune microenvironment dynamics and outcomes of prognosis in non-muscle-invasive bladder cancer. 非肌层浸润性膀胱癌的肿瘤免疫微环境动态和预后结果
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-10-11 DOI: 10.1111/cas.16333
Rei Kamitani, Nobuyuki Tanaka, Tadatsugu Anno, Tetsushi Murakami, Tsukasa Masuda, Yota Yasumizu, Toshikazu Takeda, Shinya Morita, Takeo Kosaka, Shuji Mikami, Kazuhiro Matsumoto, Mototsugu Oya

Agents that target PD-1 and PD-L1 have been developed in the treatment of bladder cancer (BC). However, the diversity of immune cell infiltration in non-muscle-invasive BC (NMIBC) and the dynamics of the microenvironment as it progresses to muscle-invasive/metastatic disease remains unknown. To assess tumor immune activity, hierarchical clustering was applied to 159 BC samples based on cellular positivity for the defined immune cellular markers (CD3/CD4/CD8/FOXP3/CD20/PD-1/PD-L1/LAG3/TIGIT), divided into two clusters. There was a "hot cluster" (25%) consisting of patients with a high expression of these markers and a "cold cluster" (75%) comprising those without. The expression of CD39, CD44, CD68, CD163, IDO1, and Ki67 was significantly higher in tumors in the hot cluster. Immunologically, high-grade T1 tumors were significantly hotter, whereas tumors that had progressed to muscle invasion turned cold. However, a certain number of high-grade NMIBC patients were in the cold cluster, and these patients had a significantly higher risk of disease progression. Using an externally available TCGA dataset, RB1 and TP53 alterations were more frequently observed in TCGA hot cluster; rather FGFR3, KDM6A, and KMT2A alterations were common in TCGA cold/intermediate cluster. Analyses of recurrent tumors after BCG therapy revealed that tumor immune activity was widely maintained before and after treatment, and high FGFR3 expression was detected after recurrence in tumors initially classified into the cold cluster. Collectively, we revealed the dynamics of the tumor microenvironment in BC as a whole and identified candidate molecules as therapeutic targets for recurrent NMIBC, e.g., after BCG therapy.

针对 PD-1 和 PD-L1 的药物已被开发用于治疗膀胱癌(BC)。然而,非肌层浸润性膀胱癌(NMIBC)中免疫细胞浸润的多样性以及膀胱癌发展为肌层浸润性/转移性疾病时微环境的动态变化仍然未知。为了评估肿瘤免疫活性,研究人员对 159 个 BC 样本进行了分层聚类,根据细胞对定义的免疫细胞标记物(CD3/CD4/CD8/FOXP3/CD20/PD-1/PD-L1/LAG3/TIGIT)的阳性率将其分为两个群组。一个 "热群"(25%)是这些标记物高表达的患者,另一个 "冷群"(75%)是没有这些标记物表达的患者。热群肿瘤中 CD39、CD44、CD68、CD163、IDO1 和 Ki67 的表达明显较高。从免疫学角度看,高级别 T1 肿瘤明显偏热,而进展到肌肉侵犯的肿瘤则偏冷。然而,一定数量的高级别NMIBC患者属于冷群组,这些患者的疾病进展风险明显更高。利用外部提供的TCGA数据集,RB1和TP53的改变在TCGA热群中更为常见;而FGFR3、KDM6A和KMT2A的改变则常见于TCGA冷群/中间群。对卡介苗治疗后复发肿瘤的分析表明,肿瘤免疫活性在治疗前后广泛维持,在最初归入冷簇的肿瘤中,复发后检测到了高表达的FGFR3。总之,我们揭示了整个 BC 肿瘤微环境的动态变化,并确定了候选分子作为复发性 NMIBC(如卡介苗治疗后)的治疗靶点。
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引用次数: 0
Prevalence and outcomes of germline pathogenic variants of homologous recombination repair genes in ovarian cancer. 卵巢癌中同源重组修复基因种系致病变异的发生率和结果。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-10-10 DOI: 10.1111/cas.16367
Maiko Miwa, Masakazu Kitagawa, Yuka Asami, Mayumi Kobayashi-Kato, Takafumi Watanabe, Aiko Ogasawara, Kengo Hiranuma, Hisamori Kato, Motonobu Saito, Yohei Miyagi, Tomoyasu Kato, Hiroshi Yoshida, Yukihide Momozawa, Takashi Kohno, Kouya Shiraishi, Kosei Hasegawa

Germline pathogenic variants (PVs) are pivotal in gynecological oncology. We focused on the prevalence, clinicopathological features, and survival impact of homologous recombination repair (HRR) PVs in patients with epithelial ovarian cancer (EOC). This was a multicenter retrospective cohort study, and 1248 patients with EOC were registered. Eligible patients (n = 1112) underwent germline DNA analysis for 26 cancer predisposition genes, including nine HRR-related genes, such as BRCA1/2, BRIP1, PALB2, RAD51C/D, and ATM. The associations between clinicopathological factors and HRR-related PVs were examined. Kaplan-Meier and Cox regression analyses were conducted. Among 1091 analyzed patients, 153 (14.0%) carried PVs and 140 (12.8%) were HRR-related. HRR-PV-positive status significantly correlated with serous carcinoma (22.9% vs. 4.8%, P < 0.0001) and advanced disease (18.5% vs. 5.9%, P < 0.0001). The HRR-PV-positive group exhibited higher prevalence of personal breast (12.9%) and familial breast/ovarian (29.2%) cancer history. HRR status independently improved overall survival in stage III/IV disease (P = 0.04) but not progression-free survival. HRR-related germline PVs exhibit distinct clinicopathological features with survival implications. Variants were significantly associated with serous carcinoma and advanced disease, underscoring the importance of genetic testing to develop individualized EOC treatment strategies. Considering the study period (2000-2019), the limited use of bevacizumab and poly (ADP-ribose) polymerase inhibitors as maintenance therapy should be recognized.

种系致病变异(PVs)在妇科肿瘤学中至关重要。我们重点研究了上皮性卵巢癌(EOC)患者中同源重组修复(HRR)PVs的发生率、临床病理特征和对生存的影响。这是一项多中心回顾性队列研究,共登记了 1248 例 EOC 患者。符合条件的患者(n = 1112)接受了26个癌症易感基因的种系DNA分析,其中包括9个与HRR相关的基因,如BRCA1/2、BRIP1、PALB2、RAD51C/D和ATM。研究还探讨了临床病理因素与 HRR 相关 PV 之间的关系。研究人员进行了 Kaplan-Meier 和 Cox 回归分析。在分析的1091例患者中,153例(14.0%)携带PV,140例(12.8%)与HRR相关。HRR-PV阳性状态与浆液性癌明显相关(22.9% vs. 4.8%,P
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引用次数: 0
Usefulness of multigene liquid biopsy of bile for identifying driver genes of biliary duct cancers. 胆汁多基因液体活检对确定胆管癌驱动基因的作用。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-10-08 DOI: 10.1111/cas.16365
Shin Ito, Mika Ando, Shuichi Aoki, Satoshi Soma, Jie Zhang, Naohiro Hirano, Ryosuke Kashiwagi, Keigo Murakami, Shingo Yoshimachi, Hideaki Sato, Akiko Kusaka, Masahiro Iseki, Koetsu Inoue, Masamichi Mizuma, Kiyoshi Kume, Kei Nakagawa, Atsushi Masamune, Naoki Asano, Jun Yasuda, Michiaki Unno

Liquid biopsy (LB) is an essential tool for obtaining tumor-derived materials with minimum invasion. Bile has been shown to contain much higher free nucleic acid levels than blood plasma and can be collected through endoscopic procedures. Therefore, bile possesses high potential as a source of tumor derived cell-free DNA (cfDNA) for bile duct cancers. In this study, we show that a multigene panel for plasma LB can also be applied to bile cfDNA for comparing driver gene mutation detection in other sources (plasma and tumor tissues of the corresponding patients). We collected cfDNA samples from the bile of 24 biliary tract cancer cases. These included 17 cholangiocarcinomas, three ampullary carcinoma, two pancreatic cancers, one intraductal papillary mucinous carcinoma, and one insulinoma. Seventeen plasma samples were obtained from the corresponding patients before surgical resection and subjected to the LiquidPlex multigene panel LB system. We applied a machine learning approach to classify possible tumor-derived variants among the prefiltered variant calls by a LiquidPlex analytical package with high fidelity. Among the 17 cholangiocarcinomas, we could detect cancer driver mutations in the bile of 10 cases using the LiquidPlex system. Of the biliary tract cancer cases examined with this method, 13 (54%) and 4 (17%) resulted in positive cancer driver mutation detection in the bile and plasma cfDNAs, respectively. These results suggest that bile is a more reliable source for LB than plasma for multigene panel analyses of biliary tract cancers.

液体活检(LB)是以最小侵袭获取肿瘤衍生材料的重要工具。研究表明,胆汁中的游离核酸含量远高于血浆,而且可以通过内窥镜手术收集。因此,胆汁作为胆管癌的肿瘤衍生无细胞 DNA(cfDNA)来源具有很大的潜力。在本研究中,我们发现血浆 LB 的多基因面板也可应用于胆汁 cfDNA,以比较其他来源(血浆和相应患者的肿瘤组织)的驱动基因突变检测。我们从 24 例胆道癌症患者的胆汁中采集了 cfDNA 样本。其中包括 17 例胆管癌、3 例胰腺癌、2 例胰腺癌、1 例导管内乳头状黏液癌和 1 例胰岛素瘤。在手术切除前,我们从相应的患者处获得了 17 份血浆样本,并对其进行了 LiquidPlex 多基因面板 LB 系统检测。我们采用机器学习方法,在LiquidPlex高保真分析软件包预过滤的变异调用中对可能的肿瘤衍生变异进行分类。在 17 例胆管癌中,我们利用 LiquidPlex 系统检测到了 10 例胆汁中的癌症驱动基因突变。在用这种方法检测的胆道癌病例中,分别有13例(54%)和4例(17%)在胆汁和血浆cfDNA中检测到阳性的癌症驱动基因突变。这些结果表明,与血浆相比,胆汁是进行胆道癌多基因面板分析的更可靠的 LB 来源。
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引用次数: 0
CX3CR1+CD8+ T cells: Key players in antitumor immunity. CX3CR1+CD8+ T 细胞:抗肿瘤免疫的关键角色
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-10-08 DOI: 10.1111/cas.16359
Jiajin Ma, Yue Wu, Shaoxian Wu, Zhang Fang, Lujun Chen, Jingting Jiang, Xiao Zheng

CX3CR1 functions as the specific receptor for the chemokine CX3CL1, demonstrating expression across a broad spectrum of immune cells. This underscores its pivotal role in communication and response mechanisms within the immune system. Upon engagement with CX3CL1, CX3CR1 initiates a cascade of downstream signaling pathways that regulate various biological functions. In the context of tumor progression, the intricate and inhibitory nature of the tumor microenvironment presents a significant challenge to current clinical treatment techniques. This review aims to comprehensively explore the tumor-destructive potential shown by CX3CR1+CD8+ T cells. Simultaneously, it investigates the promising prospects of utilizing CX3CR1 in future tumor immunotherapies.

CX3CR1 是趋化因子 CX3CL1 的特异性受体,在多种免疫细胞中均有表达。这突显了它在免疫系统的交流和反应机制中的关键作用。与 CX3CL1 接触后,CX3CR1 会启动一系列下游信号通路,从而调节各种生物功能。在肿瘤进展的背景下,肿瘤微环境的复杂性和抑制性对目前的临床治疗技术提出了重大挑战。本综述旨在全面探讨 CX3CR1+CD8+ T 细胞对肿瘤的破坏潜力。同时,它还探讨了在未来肿瘤免疫疗法中利用 CX3CR1 的广阔前景。
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引用次数: 0
The novel and potent CD40 agonist KHK2840 augments the antitumor efficacy of anti-PD-1 antibody and paclitaxel. 新型强效CD40激动剂KHK2840增强了抗PD-1抗体和紫杉醇的抗肿瘤疗效。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-10-08 DOI: 10.1111/cas.16366
Chiaki Kobayashi, Minami Suzuki-Imaizumi, Yasuko Sakaguchi, Toshihiko Ishii, Maiko Adachi, Ayumi Kaneda, Ritsuko Ebihara, Masato Saito, Takeshi Uemori, Kiyotoshi Mori

Lack of tumor-reactive cytotoxic T lymphocytes (CTLs) limits the antitumor efficacy of immune checkpoint inhibitors (ICIs). CD40 agonists have been expected to overcome this limitation by generating tumor-reactive CTLs. However, the clinical efficacy of CD40 agonistic antibodies is not as good as in non-clinical studies. The novel human CD40 (hCD40) agonist KHK2840 is a fully human anti-CD40 IgG2 agonistic antibody that is Fc-engineered to minimize complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Compared to other hCD40 agonists, KHK2840 exhibited the most potent hCD40 agonistic signal in tumor-bearing hCD40 transgenic mice and human peripheral blood B cells. Moreover, KHK2840 enhanced the antitumor efficacy of the antiprogrammed cell death 1 antibody and paclitaxel. Comprehensive immune profiling revealed that the antitumor immune response of the triple combination involved tumor-draining lymph nodes in addition to tumor microenvironments. This suggests that a coordinated antitumor immune response between tumors and lymph nodes may underlie the synergistic antitumor efficacy of the triple combination therapy. Finally, a toxicology study in cynomolgus monkeys demonstrated that KHK2840 activated the CD40 signal with tolerable toxicological properties. These results indicate that KHK2840 is a novel and potent hCD40 agonistic antibody for cancer immunotherapy, which is expected to augment the antitumor efficacy of ICIs and chemotherapy.

缺乏肿瘤反应性细胞毒性 T 淋巴细胞(CTLs)限制了免疫检查点抑制剂(ICIs)的抗肿瘤疗效。CD40 激动剂有望通过产生对肿瘤有反应的 CTL 来克服这一限制。然而,CD40激动剂抗体的临床疗效并不如非临床研究中那么好。新型人 CD40(hCD40)激动剂 KHK2840 是一种全人源抗 CD40 IgG2 激动剂抗体,经过 Fc 工程设计,可将补体依赖性细胞毒性和抗体依赖性细胞毒性降至最低。与其他 hCD40 激动剂相比,KHK2840 在携带 hCD40 的肿瘤转基因小鼠和人类外周血 B 细胞中表现出最有效的 hCD40 激动信号。此外,KHK2840 还能增强抗程序性细胞死亡 1 抗体和紫杉醇的抗肿瘤疗效。综合免疫分析表明,三联疗法的抗肿瘤免疫反应除涉及肿瘤微环境外,还涉及肿瘤淋巴结。这表明,肿瘤和淋巴结之间协调的抗肿瘤免疫反应可能是三联疗法协同抗肿瘤疗效的基础。最后,一项在金丝猴中进行的毒理学研究表明,KHK2840能激活CD40信号,且毒理学特性可耐受。这些结果表明,KHK2840 是一种新型、强效的 hCD40 激动剂抗体,可用于癌症免疫疗法,有望增强 ICIs 和化疗的抗肿瘤疗效。
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引用次数: 0
A combination of lymphatic drug delivery of anti-CTLA-4 antibody and local radiotherapy for solid-tumor treatment. 抗 CTLA-4 抗体淋巴给药与局部放疗相结合治疗实体瘤。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-10-08 DOI: 10.1111/cas.16369
Koki Takagi, Ariunbuyan Sukhbaatar, Yohei Inaba, Shiro Mori, Tetsuya Kodama

The combination of radiotherapy and immunotherapy is a promising approach that has been shown in clinical trials to improve significantly survival and response rates compared with monotherapy against solid tumor. Since anti-CTLA-4 antibodies block immunosuppressive signals mainly in the lymph nodes (LNs), efficient drug delivery to the lymphatic system is desirable. However, the immune checkpoint inhibitors, especially anti-CTLA-4 are currently administered intravenously (i.v.), resulting in limited efficacy in controlling solid tumor and inhibiting metastases, and the method of administration has not been optimized. Here, we show that a combination of local radiotherapy and administration of anti-CTLA-4 antibodies using a lymphatic drug delivery system (LDDS) suppresses solid tumor and metastases. We compared the efficacy of LDDS-based immunotherapy or radioimmunotherapy with i.v. administration in a solid-tumor model created by subcutaneous inoculation into LN-swollen mice with osteosarcoma cells. Tumor-bearing mice were divided into various groups (no treatment, immunotherapy [i.v. or LDDS], radiotherapy, and radioimmunotherapy [i.v. or LDDS]) and were observed for 28 days. Immunotherapy was administered with a cumulative dose of 10 mg/kg of anti-CTLA-4 monoclonal antibody, and radiotherapy was administered with a cumulative 8 Gy of fractionated X-ray irradiation. For immunotherapy alone, LDDS provided slight tumor growth inhibition but did not inhibit distant metastasis. For radioimmunotherapy, however, tumor growth was delayed and distant metastasis was suppressed compared with radiotherapy alone. In particular, the LDDS group achieved a high tumor-suppressive effect with T cell-mediated immune activity, indicating the efficacy of LDDS in radioimmunotherapy.

放疗与免疫疗法相结合是一种很有前景的方法,临床试验表明,与单一疗法相比,放疗能显著提高实体瘤患者的生存率和反应率。由于抗CTLA-4抗体主要阻断淋巴结(LNs)中的免疫抑制信号,因此需要向淋巴系统高效给药。然而,免疫检查点抑制剂,尤其是抗CTLA-4目前都是静脉给药,导致其在控制实体瘤和抑制转移方面的疗效有限,而且给药方法尚未优化。在这里,我们展示了局部放疗和使用淋巴给药系统(LDDS)给药抗CTLA-4抗体的组合能抑制实体瘤和转移。我们在一种实体瘤模型中比较了基于淋巴给药系统的免疫疗法或放射免疫疗法与静脉给药的疗效,该模型是通过将骨肉瘤细胞皮下注射到LN肿胀的小鼠体内而建立的。携带肿瘤的小鼠被分为不同的组别(无治疗组、免疫治疗组(静脉注射或 LDDS)组、放射治疗组和放射免疫治疗组(静脉注射或 LDDS)组),并观察 28 天。免疫治疗采用累积剂量为10 mg/kg的抗CTLA-4单克隆抗体,放射治疗采用累积剂量为8 Gy的分次X射线照射。单用免疫疗法时,LDDS能轻微抑制肿瘤生长,但不能抑制远处转移。然而,与单纯放射治疗相比,放射免疫治疗可延缓肿瘤生长并抑制远处转移。特别是,LDDS组在T细胞介导的免疫活性方面取得了很高的肿瘤抑制效果,这表明LDDS在放射免疫疗法中的疗效。
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引用次数: 0
Population pharmacokinetic model of ABL001/CTX-009 (anti-VEGF/DLL4) in adult cancer patients with solid tumor. ABL001/CTX-009(抗血管内皮生长因子/DLL4)在成年实体瘤癌症患者中的群体药代动力学模型。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-10-07 DOI: 10.1111/cas.16363
Joo Young Na, Juyeun Jeon, Ki Young Huh, Kyung-Sang Yu, Sangmi Lee, Jaehyun Eom, Jinhyung Ahn, Weon-Kyoo You, Jaeseong Oh

ABL001/CTX-009 is a bispecific antibody targeting delta-like ligand-4 and vascular endothelial growth factor A. In this study, we developed a population pharmacokinetic (PK) model of ABL001/CTX-009 in patients with solid tumors. A total of 712 plasma concentrations from 30 patients with relapsed or refractory solid tumors were collected from a phase 1 study (NCT03292783). A population PK model was developed using a nonlinear mixed-effect method and was evaluated by graphical and numerical methods. Using the model, the steady-state concentrations were simulated to compare weight-based and fixed-dose regimens and to find optimal dosing intervals. The PK of ABL001/CTX-009 was well described by a two-compartment model with a parallel first-order and Michaelis-Menten elimination kinetics. Body weight was selected as a significant covariate on V1. Model evaluation results suggested that the model was adequate and robust with good precision. Simulations after administrations of fixed or weight-based doses showed similar plasma concentrations. Additionally, 10 mg/kg for every other week and 15 mg/kg for every three-week administration showed comparable plasma concentrations. In conclusion, the model well described the plasma concentrations of ABL001/CTX-009 in patients with solid tumors. The simulation suggested that weight-based dose and fixed dose can provide equivalent systemic exposure.

ABL001/CTX-009是一种靶向δ样配体-4和血管内皮生长因子A的双特异性抗体。在这项研究中,我们建立了ABL001/CTX-009在实体瘤患者中的群体药代动力学(PK)模型。我们从一项1期研究(NCT03292783)中收集了30名复发或难治性实体瘤患者的712个血浆浓度。研究人员采用非线性混合效应法建立了一个群体 PK 模型,并通过图形和数值方法对该模型进行了评估。利用该模型模拟了稳态浓度,以比较基于体重和固定剂量的治疗方案,并找到最佳给药间隔。ABL001/CTX-009的PK用平行一阶和Michaelis-Menten消除动力学的两室模型进行了很好的描述。体重被选为V1的重要协变量。模型评估结果表明,该模型充分、稳健、精确度高。在服用固定剂量或基于体重的剂量后进行的模拟显示出相似的血浆浓度。此外,每隔一周给药 10 毫克/千克和每三周给药 15 毫克/千克也显示出相似的血浆浓度。总之,该模型很好地描述了ABL001/CTX-009在实体瘤患者体内的血浆浓度。模拟结果表明,基于体重的剂量和固定剂量可提供等效的全身暴露。
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引用次数: 0
Genomic and transcriptomic profiling of pre- and postneoadjuvant chemotherapy triple negative breast cancer tumors. 新辅助化疗前后三阴性乳腺癌肿瘤的基因组和转录组分析。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-10-07 DOI: 10.1111/cas.16339
Tomomi Nishimura, Ravi Velaga, Norikazu Masuda, Kosuke Kawaguchi, Shuji Kawaguchi, Masahiro Takada, Yurina Maeshima, Sunao Tanaka, Yuichiro Kikawa, Takayuki Kadoya, Hiroko Bando, Rikiya Nakamura, Yutaka Yamamoto, Takayuki Ueno, Hiroyuki Yasojima, Hiroshi Ishiguro, Satoshi Morita, Shinji Ohno, Hironori Haga, Fumihiko Matsuda, Seishi Ogawa, Masakazu Toi

Our understanding of neoadjuvant treatment with microtubule inhibitors (MTIs) for triple negative breast cancer (TNBC) remains limited. To advance our understanding of the role of breast cancer driver genes' mutational status with pathological complete response (pCR; ypT0/isypN0) prediction and to identify distinct gene sets for MTIs like eribulin and paclitaxel, we carried out targeted genomic (n = 50) and whole transcriptomic profiling (n = 64) of TNBC tumor samples from the Japan Breast Cancer Research Group 22 (JBCRG-22) clinical trial. Lower PIK3CA, PTEN, and HRAS mutations were found in homologous recombination deficiency (HRD)-high (HRD score ≥ 42) tumors with higher pCR rates. When HRD-high tumors were stratified by tumor BRCA mutation status, the pCR rates in BRCA2-mutated tumors were higher (83% vs. 36%). Transcriptomic profiling of TP53-positive tumors identified downregulation of FGFR2 (false discovery rate p value = 2.07e-7), which was also the only common gene between HRD-high and -low tumors with pCR/quasi-pCR treated with paclitaxel and eribulin combined with carboplatin, respectively. Differential enrichment analysis of the HRD-high group posttreatment tumors revealed significant correlation (p = 0.006) of the glycan degradation pathway. FGFR2 expression and the differentially enriched pathways play a role in the response and resistance to MTIs containing carboplatin treatment in TNBC patients.

我们对使用微管抑制剂(MTIs)对三阴性乳腺癌(TNBC)进行新辅助治疗的了解仍然有限。为了进一步了解乳腺癌驱动基因的突变状态对病理完全反应(pCR;ypT0/isypN0)预测的作用,并确定艾瑞布林和紫杉醇等MTIs的不同基因集,我们对日本乳腺癌研究小组22(JBCRG-22)临床试验中的TNBC肿瘤样本进行了靶向基因组(n = 50)和全转录组分析(n = 64)。同源重组缺陷(HRD)高(HRD评分≥42分)肿瘤的PIK3CA、PTEN和HRAS突变率较低,pCR率较高。当根据肿瘤 BRCA 突变状态对 HRD 高肿瘤进行分层时,BRCA2 突变肿瘤的 pCR 率更高(83% 对 36%)。TP53阳性肿瘤的转录组分析发现了FGFR2的下调(假发现率p值=2.07e-7),这也是分别接受紫杉醇和艾瑞布林联合卡铂治疗的pCR/准pCR的HRD-高和-低肿瘤之间唯一的共同基因。对HRD-高组治疗后肿瘤的差异富集分析表明,糖降解途径与HRD-高组有显著相关性(p = 0.006)。FGFR2的表达和差异富集通路在TNBC患者对含卡铂的MTIs治疗的反应和耐药性中起着作用。
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引用次数: 0
Leveraging non-coding regions to guarantee the accuracy of small-sized panel-based tumor mutational burden estimates. 利用非编码区保证基于小样本组的肿瘤突变负荷估计的准确性。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-10-01 DOI: 10.1111/cas.16342
Takahiro Nishino, Mio Yumura, Kuniko Sunami, Takashi Kubo, Hitoshi Ichikawa, Tomoyo Yasuda, Eisaku Furukawa, Momoko Nagai, Yasushi Yatabe, Mamoru Kato, Takashi Kohno

Accurate estimation of tumor mutational burden (TMB) as a predictor of responsiveness to immune checkpoint inhibitors in gene panel assays requires an adequate panel size. The current calculations of TMB only consider coding regions, while most of gene panel assays interrogate non-coding regions. Leveraging the non-coding regions is a potential solution to address this panel size limitation. However, the impact of including non-coding regions on the accuracy of TMB estimates remains unclear. This study investigated the validity of leveraging non-coding regions to supplement panel size using the OncoGuide NCC Oncopanel System (NOP). The aim of this study was to evaluate test performance against orthogonal assays and the association with responsiveness to immune checkpoint inhibitors was not included in the evaluation. We compared TMB status and values between TMB calculated only from coding regions (NOP-coding) and from both coding and non-coding regions (NOP-overall) using whole exome sequencing (WES) and FoundationOne®CDx (F1CDx) assay. Our findings revealed that NOP-overall significantly improved the overall percent agreement (OPA) with TMB status compared with NOP-coding for both WES (OPA: 96.7% vs. 73.3%, n = 30) and F1CDx (OPA: 90.0% vs. 73.3%). Additionally, the mean difference in TMB values compared with WES was lower for NOP-overall (3.55 [95% CI: 0.98-6.13]) than for NOP-coding (6.22 [95% CI: 3.73-8.70]). These results exemplify the utility of incorporating non-coding regions to maintain accurate TMB estimates in small-sized panels.

要准确估算肿瘤突变负荷(TMB),并将其作为免疫检查点抑制剂反应性的预测指标,需要足够的基因组规模。目前对 TMB 的计算只考虑编码区,而大多数基因面板检测都会询问非编码区。利用非编码区是解决面板规模限制的一个潜在解决方案。然而,纳入非编码区对 TMB 估计准确性的影响仍不清楚。本研究使用 OncoGuide NCC Oncopanel System (NOP) 调查了利用非编码区补充面板规模的有效性。本研究的目的是评估正交检测的测试性能,与免疫检查点抑制剂反应性的关联不在评估范围内。我们使用全外显子测序(WES)和FoundationOne®CDx(F1CDx)检测法比较了仅从编码区(NOP-编码)和从编码区及非编码区(NOP-overall)计算的TMB状态和数值。我们的研究结果表明,在 WES(OPA:96.7% vs. 73.3%,n = 30)和 F1CDx(OPA:90.0% vs. 73.3%)中,与 NOP 编码相比,NOP-overall 显著提高了与 TMB 状态的总体一致性百分比(OPA)。此外,与 WES 相比,NOP-整体(3.55 [95% CI: 0.98-6.13])的 TMB 值平均差异低于 NOP 编码(6.22 [95% CI: 3.73-8.70])。这些结果体现了纳入非编码区以保持小规模面板中准确的 TMB 估计值的实用性。
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引用次数: 0
SNRPB2 promotes triple-negative breast cancer progression by controlling alternative splicing of MDM4 pre-mRNA. SNRPB2通过控制MDM4前mRNA的替代剪接促进三阴性乳腺癌的进展。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-09-27 DOI: 10.1111/cas.16356
Shiyi Yu, Yue Si, Jianzhong Yu, Chengyang Jiang, Fei Cheng, Miao Xu, Zhehao Fan, Fangchen Liu, Chang Liu, Ying Wang, Ning Wang, Chenxu Liu, Caili Bi, Haibo Sun

Alternative splicing generates cancer-specific transcripts and is now recognized as a hallmark of cancer. However, the critical oncogenic spliceosome-related proteins involved in triple-negative breast cancer (TNBC) remain elusive. Here, we explored the expression pattern of spliceosome-related proteins in TNBC, non-TNBC, and normal breast tissues from The Cancer Genome Atlas breast cancer (TCGA-BRCA) cohort, revealing higher expression of nearly half of spliceosome-related proteins in TNBC than their counterparts. Among these TNBC-specific spliceosome-related proteins, the expression of SNRPB2 was associated with poor prognosis in patients with TNBC. In TNBC cells, the knockdown of SNRPB2 strongly suppressed cell proliferation and invasion and induced cell cycle arrest. Mechanistically, transcriptome data showed that SNRPB2 knockdown inactivated E2F1 signaling, which regulated the cell cycle. We further validated the downregulation of several cell cycle genes in SNRPB2 knockdown cells. Moreover, the analysis showed that SNRPB2 knockdown triggered the alteration of many alternative splicing events, most of which were skipping of exon. In TNBC cells, it was found that SNRPB2 knockdown led to the skipping of exon 6 in MDM4 pre-mRNA, generating MDM4-S transcript and downregulating MDM4 protein expression. More importantly, downregulation of MDM4 decreased retinoblastoma 1 (Rb1) protein expression, which is a target of MDM4 and a regulator of E2F1 signaling. In summary, the current study revealed an SNRPB2/MDM4/Rb axis in promoting the progression of TNBC, providing novel insights and novel targets for combating TNBC.

交替剪接产生癌症特异性转录本,现已被公认为癌症的标志。然而,三阴性乳腺癌(TNBC)中涉及的关键致癌剪接体相关蛋白仍然难以确定。在这里,我们探讨了剪接体相关蛋白在TNBC、非TNBC和正常乳腺组织中的表达模式,发现近一半的剪接体相关蛋白在TNBC中的表达高于其同类组织。在这些TNBC特异性剪接体相关蛋白中,SNRPB2的表达与TNBC患者的不良预后有关。在TNBC细胞中,敲除SNRPB2可强烈抑制细胞增殖和侵袭,并诱导细胞周期停滞。从机理上讲,转录组数据显示,SNRPB2的敲除使E2F1信号失活,而E2F1信号调控细胞周期。我们进一步验证了 SNRPB2 敲除细胞中多个细胞周期基因的下调。此外,分析表明,SNRPB2敲除引发了许多替代剪接事件的改变,其中大部分是跳过外显子。在TNBC细胞中,研究发现SNRPB2敲除会导致MDM4前mRNA第6外显子的跳过,产生MDM4-S转录本,并下调MDM4蛋白的表达。更重要的是,MDM4的下调降低了视网膜母细胞瘤1(Rb1)蛋白的表达,而Rb1是MDM4的靶标,也是E2F1信号转导的调控因子。总之,本研究揭示了促进 TNBC 进展的 SNRPB2/MDM4/Rb 轴,为抗击 TNBC 提供了新的见解和新的靶点。
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引用次数: 0
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Cancer Science
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