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Construction and validation of a novel forecasting nomogram to the risk of colorectal adenomas: preventing colorectal cancer at its origin 构建和验证新型结直肠腺瘤风险预测提名图:从源头预防结直肠癌
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-09-17 DOI: 10.1158/1940-6207.capr-24-0066
Mao Li, Mingyu Cui, Xiaobin Zhou, Ying Song
Colorectal adenomas are responsible for the origin of most colorectal cancers (CRC). Early detection together with active intervention of colorectal adenomas plays a crucial role in the prevention of colorectal cancer. This study aimed to construct and validate a new nomogram for the forecasting of the risk of colorectal adenomas based on lifestyle risk factors that could offer potential benefits for CRC prevention. Colonoscopy reports, pathology reports, physical factors, family history, personal history of disease, diet, and lifestyle habits were collected from 1133 subjects who underwent complete colonoscopy. All subjects were divided into the training cohort (n = 792) and the validation cohort (n = 341). A nomogram predicting the risk of colorectal adenoma development was constructed using the training cohort and the C-index was calculated. The predictive accuracy and clinical applicability of the nomogram were verified in the validation cohort. The nomogram was constructed by 6 statistically significant variables selected from 18 health factors, including advanced age, male, smoking, drinking, pickles, and irregular defecation. The C-index of the training cohort was 0.778 and the C-index of the validation cohort was 0.754. The calibration curve and decision curve analysis (DCA) also confirmed that the model has good predictive ability and high profit. The nomogram constructed in this study was validated and can be applied to predicting the occurrence risk of colorectal adenoma. The model can guide the identification of patients with non-symptomatic colorectal adenomas and the recognition of high-risk individuals for whom a colonoscopy is advisable.
大肠腺瘤是大多数大肠癌(CRC)的起源。早期发现并积极干预结直肠腺瘤对预防结直肠癌起着至关重要的作用。本研究旨在根据生活方式风险因素构建并验证一种新的大肠腺瘤风险预测提名图,该提名图可为预防 CRC 带来潜在益处。研究收集了 1133 名接受过完整结肠镜检查的受试者的结肠镜检查报告、病理报告、身体因素、家族史、个人病史、饮食和生活习惯。所有受试者被分为训练队列(792 人)和验证队列(341 人)。利用训练队列构建了预测结直肠腺瘤发病风险的提名图,并计算了 C 指数。在验证队列中验证了提名图的预测准确性和临床适用性。从高龄、男性、吸烟、饮酒、腌制咸菜和排便不规律等 18 个健康因素中选出 6 个具有统计学意义的变量构建了提名图。训练队列的 C 指数为 0.778,验证队列的 C 指数为 0.754。校准曲线和决策曲线分析(DCA)也证实了该模型具有良好的预测能力和较高的收益。本研究构建的提名图经过验证,可用于预测结直肠腺瘤的发生风险。该模型可指导识别无症状结直肠腺瘤患者,并识别建议进行结肠镜检查的高危人群。
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引用次数: 0
Effect of Clonal Hematopoiesis Mutations and Canakinumab Treatment on Incidence of Solid Tumors in the CANTOS Randomized Clinical Trial 克隆性造血突变和卡那单抗治疗对 CANTOS 随机临床试验中实体瘤发病率的影响
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-05-03 DOI: 10.1158/1940-6207.capr-23-0342
Janghee Woo, Tingting Zhai, Fang Yang, Huilei Xu, Margaret L. Healey, Denise P. Yates, Michael T. Beste, David P. Steensma
Clonal hematopoiesis (CH) is more common in older persons and has been associated with an increased risk of hematological cancers and cardiovascular diseases. The most common CH mutations occur in the DNMT3A and TET2 genes and result in increased pro-inflammatory signaling. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS, NCT01327846) evaluated the neutralizing anti-IL-1β antibody canakinumab in 10,061 randomized patients with a history of myocardial infarction and persistent inflammation; DNA samples were available from 3,923 patients for targeted genomic sequencing. We examined the incidence of non-hematological malignancy by treatment assignment and CH mutations and estimated the cumulative incidence of malignancy events during trial follow-up. Patients with TET2 mutations treated with canakinumab had the lowest incidence of non-hematological malignancy across cancer types. The cumulative incidence of at least one reported malignancy was lower for patients with TET2 mutations treated with canakinumab vs those treated with placebo. These findings support a potential role for canakinumab in cancer prevention and provide evidence of IL-1β blockade cooperating with CH mutations to modify the disease course.
克隆性造血(CH)在老年人中更为常见,与罹患血癌和心血管疾病的风险增加有关。最常见的克隆性造血突变发生在 DNMT3A 和 TET2 基因中,会导致促炎信号的增加。卡那单抗抗炎血栓形成结果研究(CANTOS,NCT01327846)评估了中和抗IL-1β抗体卡那单抗在10061名有心肌梗死和持续炎症病史的随机患者中的应用情况;3923名患者的DNA样本可用于靶向基因组测序。我们根据治疗分配和CH突变研究了非血液恶性肿瘤的发生率,并估算了试验随访期间恶性肿瘤事件的累积发生率。在所有癌症类型中,接受卡那单抗治疗的TET2突变患者的非血液恶性肿瘤发病率最低。接受卡纳库单抗治疗的TET2突变患者与接受安慰剂治疗的患者相比,至少一种恶性肿瘤的累计发生率较低。这些发现支持了卡那单抗在癌症预防中的潜在作用,并提供了IL-1β阻断与CH基因突变合作改变病程的证据。
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引用次数: 0
Diet modulates the gut microbiome, metabolism, and mammary gland inflammation to influence breast cancer risk 饮食调节肠道微生物组、新陈代谢和乳腺炎症,从而影响乳腺癌风险
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-05-03 DOI: 10.1158/1940-6207.capr-24-0055
Alana A. Arnone, Adam S. Wilson, David R. Soto-Pantoja, Katherine L. Cook
Several studies have indicated a strong link between obesity and the risk of breast cancer. Obesity decreases gut microbial biodiversity and modulates Bacteroidetes-to-Firmicutes proportional abundance, suggesting that increased energy-harvesting capacity from indigestible dietary fibers and elevated lipopolysaccharide bioavailability may promote inflammation. To address the limited evidence linking diet-mediated changes in the gut microbiota to breast cancer risk, we aimed to determine how diet affects the microbiome and breast cancer risk. Female 3-week-old BALB/c mice were fed six different diets (control, high-sugar, lard, coconut oil, lard+flaxseed oil, and lard+safflower oil) for 10 weeks. Fecal 16s sequencing was performed for each group. Diet shifted fecal microbiome populations and modulated mammary gland macrophage infiltration. Fecal conditioned media shifted macrophage polarity and inflammation. In our DMBA-induced breast cancer model, diet differentially modulated tumor and mammary gland metabolism. We demonstrated how dietary patterns change metabolic outcomes, and gut microbiota, which may contribute to breast tumor risk. Furthermore, we showed the influence of diet on metabolism, inflammation, and macrophage polarity. This study suggests that dietary-microbiome interactions are key mediators of breast cancer risk.
多项研究表明,肥胖与乳腺癌风险之间存在密切联系。肥胖降低了肠道微生物的生物多样性,并调节了类杆菌与固着菌的丰度比例,这表明从难以消化的膳食纤维中获取能量的能力增加以及脂多糖生物利用率的提高可能会促进炎症。针对将饮食介导的肠道微生物群变化与乳腺癌风险联系起来的有限证据,我们旨在确定饮食如何影响微生物群和乳腺癌风险。给 3 周大的雌性 BALB/c 小鼠喂食六种不同的饮食(对照组、高糖、猪油、椰子油、猪油+亚麻籽油和猪油+红花油),为期 10 周。每组都进行了粪便 16s 测序。饮食改变了粪便微生物组群并调节了乳腺巨噬细胞浸润。粪便条件培养基改变了巨噬细胞的极性和炎症。在我们的 DMBA 诱导的乳腺癌模型中,饮食对肿瘤和乳腺的新陈代谢起着不同的调节作用。我们展示了饮食模式如何改变代谢结果和肠道微生物群,这可能会导致乳腺肿瘤风险。此外,我们还展示了饮食对新陈代谢、炎症和巨噬细胞极性的影响。这项研究表明,饮食与微生物组之间的相互作用是乳腺癌风险的关键介质。
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引用次数: 0
On the Hunt for the Missed Genetic Causes of Multiple Primary Tumors 寻找多发性原发性肿瘤被遗漏的遗传原因
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-05-02 DOI: 10.1158/1940-6207.capr-24-0115
Fiona Chan-Pak-Choon, William D. Foulkes
Improved cancer screening and treatment programs have led to an increased survivorship of patients with cancer, but consequently also to the rise in number of individuals with multiple primary tumors (MPT). Germline testing is the first approach investigating the cause of MPT, as a positive result provides a diagnosis and proper clinical management to the affected individual and their family. Negative or inconclusive genetic results could suggest non-genetic causes, but are negative genetic results truly negative? Herein, we discuss the potential sources of missed genetic causes and highlight the trove of knowledge MPT can provide. See related article by Borja et al., p. 209
癌症筛查和治疗计划的改进提高了癌症患者的存活率,但同时也导致了多发性原发性肿瘤(MPT)患者人数的增加。种系检测是调查多发性原发性肿瘤病因的首要方法,因为阳性结果可为患者及其家人提供诊断和适当的临床治疗。阴性或不确定的基因检测结果可能提示非遗传原因,但阴性基因检测结果真的是阴性的吗?在此,我们将讨论遗漏遗传病因的潜在来源,并强调 MPT 可以提供的知识宝库。参见 Borja 等人的相关文章,第 209 页
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引用次数: 0
Economic Considerations for Implementing Tobacco Cessation Programs in Cancer Care Settings 在癌症护理机构实施戒烟计划的经济考虑因素
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-05-02 DOI: 10.1158/1940-6207.capr-24-0122
Ramzi G. Salloum, Kimberly A. Shoenbill, Adam O. Goldstein
Increasingly, research demonstrates economic benefits of tobacco cessation in cancer care, as seen in a new study by Kypriotakis and colleagues of the MD Anderson cessation program, demonstrating median health care cost savings of $1,095 per patient over 3 months. While the cost-effectiveness of tobacco cessation programs from a hospital perspective is important, implementation decisions in a predominantly fee-for-service system, such as in the United States, too often insufficiently value this outcome. Economic barriers, stakeholder disincentives, and payment models all impact program implementation. Combining economic evaluation with implementation research, including assessment of return-on-investment, may enhance sustainability and inform decision-making in cancer care settings. See related article by Kypriotakis et al., p. 217
Kypriotakis及其同事对MD安德森戒烟项目进行了一项新研究,结果显示每位患者3个月内节省的医疗成本中位数为1095美元。虽然从医院角度看戒烟项目的成本效益非常重要,但在美国这样一个以收费服务为主的系统中,实施决策往往对这一结果重视不够。经济障碍、利益相关者的抑制因素以及支付模式都会影响项目的实施。将经济评估与实施研究相结合,包括对投资回报的评估,可以提高可持续性,并为癌症护理机构的决策提供参考。参见 Kypriotakis 等人的相关文章,第 217 页
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引用次数: 0
Stool protein mass spectrometry identifies biomarkers for the early detection of diffuse-type gastric cancer 粪便蛋白质谱法确定早期检测弥漫型胃癌的生物标记物
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-04-26 DOI: 10.1158/1940-6207.capr-23-0449
Chi-Lee C. Ho, Michael B. Gilbert, Guillaume Urtecho, Hyoungjoo Lee, David A. Drew, Samuel J. Klempner, Jin S. Cho, Thomas J. Ryan, Naryan Rustgi, Hyuk Lee, Jeeyun Lee, Alexander Caraballo, Marina V. Magicheva-Gupta, Carmen Rios, Alice E. Shin, Yuen-Yi Tseng, Jeremy L. Davis, Daniel C. Chung, Andrew T. Chan, Harris H. Wang, Sandra Ryeom
There is a high unmet need for early detection approaches for diffuse gastric cancer (DGC). We examined whether the stool proteome of mouse models of GC or individuals with hereditary diffuse GC (HDGC) have utility as biomarkers for early detection. Proteomic mass spectrometry of stool from a genetically engineered mouse model driven by oncogenic KrasG12D and loss of p53 and Cdh1 in gastric parietal cells (known as TCON mice) identified differentially abundant proteins compared to littermate controls. Immunoblot assays validated a panel of proteins including actinin alpha 4 (ACTN4), N-acylsphingosine amidohydrolase 2 (ASAH2), dipeptidyl peptidase 4 (DPP4), and valosin-containing protein (VCP) as enriched in TCON stool compared to littermate control stool. Immunofluorescence analysis of these proteins in TCON stomach sections revealed increased protein expression as compared to littermate controls. Proteomic mass spectrometry of stool obtained from HDGC patients with CDH1 mutations identified increased expression of ASAH2, DPP4, VCP, lactotransferrin (LTF), and tropomyosin-2 (TPM2) relative to stool from healthy sex and age-matched donors. Chemical inhibition of ASAH2 using C6-urea ceramide was toxic to GC cell lines and patient derived-GC organoids. This toxicity was reversed by adding downstream products of the S1P synthesis pathway, suggesting a dependency on ASAH2 activity in GC. An exploratory analysis of the HDGC stool microbiome identified features which correlated with patient tumors. Here we provide evidence supporting the potential of analyzing stool biomarkers for the early detection of DGC.
弥漫性胃癌(DGC)早期检测方法的需求尚未得到满足。我们研究了胃癌小鼠模型或遗传性弥漫性胃癌(HDGC)患者的粪便蛋白质组是否可作为早期检测的生物标记物。我们对一种由致癌基因 KrasG12D 和胃顶细胞中 p53 和 Cdh1 缺失驱动的基因工程小鼠模型(称为 TCON 小鼠)的粪便进行了蛋白质组质谱分析,发现了与同窝对照组相比不同的丰富蛋白质。免疫印迹检测验证了一组蛋白质,包括肌动蛋白α4 (ACTN4)、N-酰鞘苷酸酰胺水解酶 2 (ASAH2)、二肽基肽酶 4 (DPP4) 和含缬氨酸蛋白 (VCP),与同卵对照组相比,TCON 小鼠粪便中富含这些蛋白质。对 TCON 胃切片中这些蛋白质的免疫荧光分析表明,与同窝对照组相比,这些蛋白质的表达量有所增加。对 CDH1 基因突变的 HDGC 患者的粪便进行蛋白质组质谱分析发现,与性别和年龄匹配的健康供体的粪便相比,ASAH2、DPP4、VCP、乳转铁蛋白 (LTF) 和肌球蛋白-2 (TPM2) 的表达量增加。使用 C6-urea 神经酰胺对 ASAH2 进行化学抑制会对 GC 细胞系和患者衍生的 GC 器官组织产生毒性。加入 S1P 合成途径的下游产物可逆转这种毒性,这表明 GC 对 ASAH2 活性有依赖性。对 HDGC 粪便微生物组的探索性分析发现了与患者肿瘤相关的特征。我们在此提供的证据支持了分析粪便生物标记物以早期检测 DGC 的潜力。
{"title":"Stool protein mass spectrometry identifies biomarkers for the early detection of diffuse-type gastric cancer","authors":"Chi-Lee C. Ho, Michael B. Gilbert, Guillaume Urtecho, Hyoungjoo Lee, David A. Drew, Samuel J. Klempner, Jin S. Cho, Thomas J. Ryan, Naryan Rustgi, Hyuk Lee, Jeeyun Lee, Alexander Caraballo, Marina V. Magicheva-Gupta, Carmen Rios, Alice E. Shin, Yuen-Yi Tseng, Jeremy L. Davis, Daniel C. Chung, Andrew T. Chan, Harris H. Wang, Sandra Ryeom","doi":"10.1158/1940-6207.capr-23-0449","DOIUrl":"https://doi.org/10.1158/1940-6207.capr-23-0449","url":null,"abstract":"There is a high unmet need for early detection approaches for diffuse gastric cancer (DGC). We examined whether the stool proteome of mouse models of GC or individuals with hereditary diffuse GC (HDGC) have utility as biomarkers for early detection. Proteomic mass spectrometry of stool from a genetically engineered mouse model driven by oncogenic KrasG12D and loss of p53 and Cdh1 in gastric parietal cells (known as TCON mice) identified differentially abundant proteins compared to littermate controls. Immunoblot assays validated a panel of proteins including actinin alpha 4 (ACTN4), N-acylsphingosine amidohydrolase 2 (ASAH2), dipeptidyl peptidase 4 (DPP4), and valosin-containing protein (VCP) as enriched in TCON stool compared to littermate control stool. Immunofluorescence analysis of these proteins in TCON stomach sections revealed increased protein expression as compared to littermate controls. Proteomic mass spectrometry of stool obtained from HDGC patients with CDH1 mutations identified increased expression of ASAH2, DPP4, VCP, lactotransferrin (LTF), and tropomyosin-2 (TPM2) relative to stool from healthy sex and age-matched donors. Chemical inhibition of ASAH2 using C6-urea ceramide was toxic to GC cell lines and patient derived-GC organoids. This toxicity was reversed by adding downstream products of the S1P synthesis pathway, suggesting a dependency on ASAH2 activity in GC. An exploratory analysis of the HDGC stool microbiome identified features which correlated with patient tumors. Here we provide evidence supporting the potential of analyzing stool biomarkers for the early detection of DGC.","PeriodicalId":9373,"journal":{"name":"Cancer Prevention Research","volume":"1 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140802262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Prevalence of H. pylori and gastric intestinal metaplasia in BRCA1 and BRCA2 carriers BRCA1 和 BRCA2 携带者中幽门螺杆菌和胃肠化生的发病率
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-04-20 DOI: 10.1158/1940-6207.capr-24-0039
Blake A. Niccum, Sarah Coughlin, Daniel Clay, Jordan Heiman, Kole H. Buckley, Michaela Dungan, Michael G. Daniel, Jose Ruiz, Kara N. Maxwell, Susan M. Domchek, Galen Leung, Nuzhat A. Ahmad, Gregory G. Ginsberg, Michael L. Kochman, Bryson W. Katona
BRCA1 and BRCA2 carriers may be at increased risk for gastric cancer (GC), however the mechanisms of gastric carcinogenesis remain poorly understood. We sought to determine the prevalence of GC risk factors Helicobacter pylori (H. pylori) infection and gastric intestinal metaplasia (GIM) among BRCA1/2 carriers to gain insight into the pathogenesis of GC in this population. 100 unselected BRCA1/2 carriers undergoing endoscopic ultrasound from 3/2022-3/2023 underwent concomitant upper endoscopy with non-targeted gastric antrum and body biopsies. The study population (70% women; mean age: 60.1) included 66% BRCA2 carriers. H. pylori was detected in one (1%) individual, 7 (7%) had GIM, 2 (2%) had autoimmune atrophic gastritis, and no GCs were diagnosed. Among BRCA1/2 carriers, H. pylori prevalence was low and GIM prevalence was similar to the general population, however identification of H. pylori or GIM may help inform future GC risk management strategies in BRCA1/2 carriers.
BRCA1 和 BRCA2 携带者罹患胃癌(GC)的风险可能会增加,但人们对胃癌发生的机制仍然知之甚少。我们试图确定 BRCA1/2 携带者中 GC 危险因素幽门螺旋杆菌(H. pylori)感染和胃肠化生(GIM)的发生率,以深入了解该人群中 GC 的发病机制。在 2022 年 3 月至 2023 年 3 月期间,100 名未经筛选的 BRCA1/2 携带者接受了内镜超声检查,并同时接受了上内镜检查和非靶向胃窦及胃体活检。研究对象(70% 为女性;平均年龄:60.1 岁)中有 66% 为 BRCA2 携带者。其中1人(1%)检测出幽门螺杆菌,7人(7%)患有GIM,2人(2%)患有自身免疫性萎缩性胃炎,未确诊GC。在 BRCA1/2 基因携带者中,幽门螺杆菌的感染率较低,GIM 的感染率与普通人群相似,但是幽门螺杆菌或 GIM 的鉴定可能有助于为 BRCA1/2 基因携带者未来的 GC 风险管理策略提供依据。
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引用次数: 0
Evaluating the Reach of a Patient Navigation Program for Follow-up Colonoscopy in a Large Federally Qualified Health Center 评估大型联邦合格医疗中心结肠镜检查随访患者导航计划的覆盖范围
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-04-20 DOI: 10.1158/1940-6207.capr-23-0498
Priyanka Gautom, A. Gabriela Rosales, Amanda F. Petrik, Jamie H. Thompson, Matthew T. Slaughter, Leslie Mosso, Syed Akmal. Hussain, Ricardo Jimenez, Gloria D. Coronado
Patient navigation (PN) has been shown to improve participation in cancer screening, including colorectal cancer screening, and the Community Preventive Services Task Force now recommends the practice. Despite the effectiveness of PN programs, little is known about the number of contacts needed to successfully reach patients or about the demographic and healthcare utilization factors associated with reach. PRECISE was an individual randomized study of PN vs. usual care conducted as a partnership between two large health systems in the Pacific Northwest. The navigation program was a six topic-area telephonic program designed to support patients with an abnormal fecal test result to obtain a follow-up colonoscopy. We report the number of contact attempts needed to successfully reach navigated patients. We used logistic regression to report the demographic and healthcare utilization characteristics associated with patients allocated to PN who were successfully reached. We identified 1200 patients with an abnormal FIT result, among whom 970 were randomized into the study (45.7% were female, 17.5% were Spanish-speaking, mean age was 60.8). Of the 479 patients allocated to the PN intervention, 382 (79.7%) were reached within 18 call attempts and nearly all (n = 356; 93.2%) were reached within six contact attempts. Patient characteristics associated with reach were race, county of residence, and body mass index. Our findings can guide future efforts to optimize the reach of PN programs.
患者指导(PN)已被证明可提高癌症筛查(包括结直肠癌筛查)的参与率,社区预防服务工作组现在也推荐这种做法。尽管患者指导项目很有效,但人们对成功接触患者所需的接触次数或与接触患者相关的人口统计学和医疗保健利用率因素知之甚少。PRECISE 是西北太平洋地区两家大型医疗系统合作开展的一项关于 PN 与常规护理的个人随机研究。该导航计划是一项六个主题区域的电话计划,旨在帮助粪便检查结果异常的患者获得后续结肠镜检查。我们报告了成功联系导航患者所需的联系次数。我们使用逻辑回归法报告了被分配到 PN 并成功联系到的患者的相关人口统计学特征和医疗保健使用特征。我们确定了 1200 名 FIT 结果异常的患者,其中 970 人被随机纳入研究(45.7% 为女性,17.5% 讲西班牙语,平均年龄为 60.8 岁)。在被分配到 PN 干预的 479 名患者中,有 382 人(79.7%)在 18 次呼叫尝试内被联系到,几乎所有患者(n = 356;93.2%)都在 6 次呼叫尝试内被联系到。与联系成功率相关的患者特征包括种族、居住地和体重指数。我们的研究结果可以指导未来优化 PN 项目覆盖范围的工作。
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引用次数: 0
Germline and Somatic Fumarate Hydratase Testing in Atypical Uterine Leiomyomata 非典型子宫纵隔肌瘤的种系和体细胞富马酸氢化酶检测
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-04-18 DOI: 10.1158/1940-6207.capr-23-0535
Lindsay M. Kipnis, Katelyn M. Breen, Diane R. Koeller, Alison Schwartz Levine, Zelei Yang, Hyeji Jun, Nabihah Tayob, Samantha M. Stokes, Connor P. Hayes, Arezou A. Ghazani, Sarah J. Hill, Huma Q. Rana
Women with germline pathogenic variants (PV) in the fumarate hydratase (FH) gene develop cutaneous and uterine leiomyomata and have an increased risk of developing aggressive renal cell carcinomas. Many of these women are unaware of their cancer predisposition until an atypical uterine leiomyoma is diagnosed during a myomectomy or hysterectomy, making a streamlined genetic counseling process after a pathology-based atypical uterine leiomyoma diagnosis critical. However, the prevalence of germline pathogenic/likely PVs in FH among atypical uterine leiomyomata cases is unknown. To better understand FH germline PV prevalence and current patterns of genetic counseling and germline genetic testing, we undertook a retrospective review of atypical uterine leiomyomata cases at a single large center. We compared clinical characteristics between the FH PV, FH wild-type (WT), and unknown genetic testing cohorts. Of the 144 cases with atypical uterine leiomyomata with evaluable clinical data, only 49 (34%) had documented genetic test results, and 12 (8.3%) had a germline FH PV. There were 48 IHC-defined FH-deficient cases, of which 41 (85%) had FH testing and nine had a germline FH PV, representing 22% of the tested cohort and 18.8% of the FH-deficient cohort. Germline FH PVs were present in 8.3% of evaluable patients, representing 24.5% of the cohort that completed genetic testing. These data highlight the disconnect between pathology and genetic counseling, and help to refine risk estimates that can be used when counseling patients with atypical uterine leiomyomata. Prevention Relevance: Women diagnosed with fumarate hydratase (FH)-deficient uterine leiomyomata are at increased risk of renal cancer. This work suggests a more standardized pathology-genetic counseling referral pathway for these patients, and that research on underlying causes of FH-deficient uterine leiomyomata in the absence of germline FH pathogenic/likely pathogenic variants is needed.
富马酸氢化酶(FH)基因中存在种系致病变异(PV)的女性会患上皮肤和子宫白肌瘤,并增加患侵袭性肾细胞癌的风险。在子宫肌瘤切除术或子宫切除术中诊断出非典型子宫肌瘤之前,这些妇女中的许多人并不知道自己有患癌症的倾向,因此在病理诊断出非典型子宫肌瘤后,简化遗传咨询流程至关重要。然而,在非典型子宫肌瘤病例中,FH 的种系致病基因/可能 PV 的发病率尚不清楚。为了更好地了解 FH 种系 PV 的患病率以及目前遗传咨询和种系基因检测的模式,我们对一个大型中心的非典型子宫白肌瘤病例进行了回顾性研究。我们比较了FH PV、FH野生型(WT)和未知基因检测队列的临床特征。在144例临床数据可评估的非典型子宫白肌瘤病例中,只有49例(34%)有记录的基因检测结果,12例(8.3%)有种系FH PV。有 48 例 IHC 定义的 FH 缺乏病例,其中 41 例(85%)进行了 FH 检测,9 例具有种系 FH PV,分别占检测病例群的 22% 和 FH 缺乏病例群的 18.8%。8.3%的可评估患者存在种系 FH PV,占完成基因检测人群的 24.5%。这些数据凸显了病理学与遗传咨询之间的脱节,有助于完善风险评估,从而为非典型子宫肌瘤患者提供咨询。预防相关性:被诊断患有富马酸氢化酶(FH)缺陷型子宫纵膈肌瘤的妇女罹患肾癌的风险会增加。这项工作建议为这些患者提供更标准化的病理-遗传咨询转诊途径,并建议在没有出现种系FH致病变体/可能致病变体的情况下,需要对FH缺陷性子宫纵隔肌瘤的潜在病因进行研究。
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引用次数: 0
High-Fat Diet Induced PPARδ Promotes Self-renewal of Preleukemic Progenitors in Development of Acute Promyelocytic Leukemia 高脂饮食诱导的 PPARδ 在急性早幼粒细胞白血病的发展过程中促进白血病前祖细胞的自我更新
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-02-02 DOI: 10.1158/1940-6207.capr-23-0469
Hiroshi Y. Yamada, Chinthalapally V. Rao
From risk association between acute promyelocytic leukemia (APL) and obese-overweight individuals, Mazzarella and colleagues hypothesized that a high-fat diet (HFD) promotes development of APL. Using mouse APL model (PML-RARα knock-in), the authors demonstrated that linoleic acid drives activation of PPARδ in hematopoietic progenitors, and that activation of PPARδ increases proliferation of progenitor cells with PML-RARA expression toward APL. Involvements of PPARδ on regulation of stem cell renewal and proliferation were shown in colorectal cancers earlier, but this study newly demonstrates in hematopoietic progenitors, while suggesting use of diet rich in linoleic acid with caution. See related article by Mazzarella et al., p. 59
根据急性早幼粒细胞白血病(APL)与肥胖超重者之间的风险关联,Mazzarella 及其同事假设高脂饮食(HFD)会促进 APL 的发展。作者利用小鼠 APL 模型(PML-RARα 基因敲入)证明,亚油酸能驱动造血祖细胞中 PPARδ 的活化,PPARδ 的活化能增加有 PML-RARA 表达的祖细胞向 APL 的增殖。PPARδ参与干细胞更新和增殖的调控早先在结直肠癌中得到证实,但本研究在造血祖细胞中得到了新的证实,同时建议谨慎使用富含亚油酸的饮食。参见 Mazzarella 等人的相关文章,第 59 页。
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Cancer Prevention Research
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