Cancer Genetics最新文献_第8页

11. Developing a robust bioinformatics workflow to support personalized neoantigen vaccine clinical trials 11.开发强大的生物信息学工作流程以支持个性化新抗原疫苗临床试验

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.013

Kartik Singhal , Susanna Kiwala , Peter S. Goedegebuure , Christopher Miller , Evelyn Schmidt , Huiming Xia , My Hoang , Mariam Khanfar , Shelly O'Laughlin , Nancy Myers , Tammi Vickery , Kelsy C. Cotto , Sherri Davies , Feiyu Du , Thomas B. Mooney , Gue Su Chang , Jasreet Hundal , John Garza , Mike D. McLellan , Joshua McMichael , Malachi Griffith

Personalized cancer vaccines (PCVs) leverage immunogenomics strategies to combat cancer. Somatic mutations in tumor cells generate neoantigens that may get presented on the tumor cell's surface by MHC molecules. Immunotherapies target neoantigens to stimulate tumor-specific immune responses. Our bioinformatics workflow has designed vaccines for over 170 patients across 11 of the 180 neoantigen vaccine trials on clinicaltrials.gov.

Despite the rise in PCV-related interventions, gaps in established protocols addressing the complexities associated with the design of PCVs still remain. Here, we summarize our bioinformatics pipeline and describe measures taken to ensure robust support for clinical trials at Washington University. Our Google Cloud immunotherapy pipeline (open MIT license) to predict neoantigen epitopes is implemented in Workflow Definition Language and containerized using Docker to ensure portability and reliability. The pVACtools software suite (pvactools.org) that carries out neoantigen identification and prioritization, is developed and updated following industry best practices including version control (Git), formal code review, automated unit and integration tests, and benchmark tests. The final steps of the bioinformatics workflow generate files recording the analysis parameters and QC results tailored to the FDA's requests. Candidates generated by the pipeline are reviewed at an Immunogenomics Tumor Board using the pVACview tool. Prioritized candidates undergo a rigorous examination of data QC metrics, variant support at genomic and transcriptomic levels, MHC binding prediction algorithms, and HLA allele concordance between the clinical data and in-silico prediction tools. Finally, a long-peptide order form generated by the pipeline is sent to the vaccine manufacturer for synthesis.

个性化癌症疫苗（PCV）利用免疫基因组学策略抗击癌症。肿瘤细胞中的体细胞突变会产生新抗原，这些新抗原可通过 MHC 分子呈现在肿瘤细胞表面。免疫疗法以新抗原为目标，刺激肿瘤特异性免疫反应。我们的生物信息学工作流程已为临床试验网（clinicaltrials.gov）上 180 项新抗原疫苗试验中 11 项试验的 170 多名患者设计了疫苗。尽管 PCV 相关干预措施不断增加，但在解决 PCV 设计相关复杂性的既定方案方面仍存在差距。在此，我们总结了我们的生物信息学管道，并介绍了华盛顿大学为确保为临床试验提供有力支持而采取的措施。我们预测新抗原表位的谷歌云免疫疗法管道（开放 MIT 许可）是用工作流定义语言实现的，并使用 Docker 进行了容器化，以确保可移植性和可靠性。进行新抗原鉴定和优先排序的 pVACtools 软件套件（pvactools.org）的开发和更新遵循行业最佳实践，包括版本控制（Git）、正式代码审查、自动单元测试和集成测试以及基准测试。生物信息学工作流程的最后步骤是生成文件，记录分析参数和符合 FDA 要求的质量控制结果。免疫组学肿瘤委员会使用 pVACview 工具对管道生成的候选样本进行审查。排序优先的候选者将接受严格的数据质量控制指标、基因组和转录组水平的变异支持、MHC 结合预测算法以及临床数据与实验室内预测工具之间的 HLA 等位基因一致性检查。最后，流水线生成的长肽订购单将发送给疫苗制造商进行合成。

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引用次数: 0

72. What's under VarCat's hat: Modeling variant oncogenicity classifications with GA4GH Standards 72.VarCat 帽下有什么？利用 GA4GH 标准建立变体致癌性分类模型

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.074

Kathryn Stahl, Wesley Goar, Kori Kuzma, Alex Wagner

The Variation Categorizer (VarCat) is a tool for classifying variant oncogenicity for variant-disease pairings in a clinical laboratory workflow. VarCat implements the ClinGen/CGC/VICC oncogenicity guidelines to assist in the classification of a variant's capability for driving cancer formation and growth. VarCat provides an intuitive interface for structured data sharing and produces classification assessments compliant with genomic knowledge standards specified by the Global Alliance for Genomics and Health (GA4GH).

Here, we present the models, structures, and capabilities provided by VarCat's API and demonstrate its ability to create standardized assessments. VarCat leverages harmonized data from several genomic knowledge sources collated by the VICC MetaKB service. VarCat ensures comprehensive analysis by incorporating standardized gene, variant, therapeutic, disease, and evidence data, and it is driving the development of GA4GH genomic knowledge formats for oncogenicity data. We also describe the suite of normalization microservices used by MetaKB and VarCat to harmonize genomic knowledge concepts. We illustrate how VarCat reduces barriers to interoperable variant-associated evidence through the adoption of the GA4GH Variation Representation Specification (VRS). We also present standardized evidence data using the AMP/ASCO/CAP guidelines for clinical actionability. Overall, our work illustrates how GA4GH Genomic Knowledge Standards drive data interoperability and successful knowledge exchange, ultimately enhancing genetic disease comprehension and advancing patient care.

变异分类器（VarCat）是一种在临床实验室工作流程中对变异-疾病配对进行变异致癌性分类的工具。VarCat 执行 ClinGen/CGC/VICC 致癌性指南，以协助对变异推动癌症形成和生长的能力进行分类。VarCat为结构化数据共享提供了直观的界面，并根据全球基因组学与健康联盟（GA4GH）规定的基因组知识标准进行分类评估。在此，我们介绍了VarCat应用程序接口提供的模型、结构和功能，并展示了其创建标准化评估的能力。VarCat利用VICC MetaKB服务整理的多个基因组知识源的统一数据。VarCat 通过整合标准化的基因、变异体、治疗、疾病和证据数据来确保全面的分析，并推动了 GA4GH 致癌性数据基因组知识格式的开发。我们还介绍了 MetaKB 和 VarCat 用于统一基因组知识概念的规范化微服务套件。我们说明了 VarCat 如何通过采用 GA4GH 变异表示规范 (VRS) 减少可互操作变异相关证据的障碍。我们还利用 AMP/ASCO/CAP 指南介绍了标准化证据数据的临床可操作性。总之，我们的工作说明了 GA4GH 基因组知识标准如何推动数据互操作性和成功的知识交流，最终提高遗传疾病的理解能力并促进患者护理。

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引用次数: 0

12. Contextualizing clinical significance using FDA label supplemented DGI data 12.利用 FDA 标签补充 DGI 数据确定临床意义的内涵

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.014

Matthew Cannon , James Stevenson , Kathryn Stahl , Rohit Basu , Adam Coffman , Susanna Kiwala , Joshua McMichael , Elaine Mardis , Obi Griffith , Malachi Griffith , Alex Wagner

The drug-gene interaction database (DGIdb) is a resource that aggregates interaction data from over 40 different resources into one platform with the primary goal of making the druggable genome accessible to clinicians and researchers. By providing a public, computationally accessible database, the DGIdb enables therapeutic insights through broad aggregation of DGI data.

As part of our aggregation process, DGIdb preserves data regarding interaction types, directionality, and other attributes that enable filtering or biochemical insight. However, source data are often incomplete and may not contain the original physiological context of the interaction. Without this context, the therapeutic relevance of an interaction may be compromised or lost. In this report, we address these missing data and extract therapeutic context from free-text sources. We apply existing large language models (LLMs) that have been fine-tuned on additional medical corpuses to tag and extract indications, cancer types, and relevant pharmacogenomics from free-text, FDA approved labels. We are then able to utilize our in-house normalization services to link extracted data back to formally grouped concepts.

In a preliminary test set of 355 FDA labels, we were able to normalize 59.4%, 49.8%, and 49.1% of extracted chemical, disease, and genetic entities back to harmonized concepts. Extracting this data allows us to supplement our existing interactions with relevant context that may inform the therapeutic relevance of a particular interaction. Inclusion of these data will be particularly invaluable for variant interpretation pipelines where mutational status can lead to the identification of a lifesaving therapeutic and a positive patient outcome.

药物基因相互作用数据库（DGIdb）是一种资源，它将40多种不同资源中的相互作用数据聚合到一个平台上，其主要目的是让临床医生和研究人员能够访问药物基因组。作为我们聚合过程的一部分，DGIdb 保留了有关相互作用类型、方向性和其他属性的数据，这些数据有助于筛选或生化研究。然而，源数据往往是不完整的，可能不包含相互作用的原始生理背景。没有这种背景，相互作用的治疗相关性可能会受到影响或丧失。在本报告中，我们解决了这些数据缺失的问题，并从自由文本源中提取了治疗背景。我们应用现有的大型语言模型 (LLM)，这些模型已在其他医疗语料库中进行过微调，可从自由文本、FDA 批准的标签中标记并提取适应症、癌症类型和相关药物基因组学。在 355 个 FDA 标签的初步测试集中，我们能够将 59.4%、49.8% 和 49.1% 的提取化学、疾病和基因实体归一化为统一的概念。通过提取这些数据，我们可以用相关的上下文来补充现有的相互作用，从而为特定相互作用的治疗相关性提供信息。纳入这些数据对于变异解释管道尤其有价值，因为变异状态可以帮助确定拯救生命的疗法和积极的患者预后。

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引用次数: 0

30. Current next generation sequencing reporting practices: A GOAL Consortium report 30.下一代测序报告的现行做法：GOAL 联合会报告

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.032

Celeste Eno , Rama Sompallae , T. Niroshi Senaratne

Molecular testing by next generation sequencing (NGS) panels are widely used for oncology specimens; however, the reporting of the results vary greatly across institutions. A 70-question survey was sent to member laboratories in the Genomics Organization for Academic Laboratories (GOAL) consortium to assess current reporting practices to assess the potential for standardization. GOAL is a non-profit organization with aims of cross-institutional collaborations, including shared assay content and interpretative frameworks, to allow for academic laboratory success. Each laboratory had the opportunity to fill out the survey for hematological and solid tumor-based panels or a combined survey for both types of tumors. A total of 28 surveys were received from 21 academic tertiary-care laboratories regarding NGS reporting practices. Only a few practices differed significantly between heme and solid tumor panels, including repeat testing. Most notably, the survey respondents noted the time and review process for testing was formidable, including review of previous results, care in reporting potential germline findings, and integrating other ancillary testing. Through these efforts, GOAL seeks to bridge the gap in result reporting, ultimately improving consistency and accuracy of NGS-based molecular testing for cancer. We anticipate the results of this study will help serve as a benchmark for clinical laboratories looking to compare practices with their peers and reveal potential areas for standardization or improvement of clinical reporting.

下一代测序 (NGS) 面板分子检测广泛用于肿瘤标本；然而，不同机构对结果的报告却大相径庭。我们向学术实验室基因组学组织（GOAL）联盟的成员实验室发送了一份包含 70 个问题的调查问卷，以评估当前的报告实践，从而评估标准化的潜力。GOAL 是一个非营利性组织，其宗旨是开展跨机构合作，包括共享检测内容和解释框架，从而使学术实验室取得成功。每个实验室都有机会填写血液肿瘤和实体瘤样本的调查表，或同时填写两类肿瘤的调查表。21 家三级医疗学术实验室共收到 28 份有关 NGS 报告实践的调查问卷。只有少数几个实验室在血红素样本和实体瘤样本（包括重复检测）方面有明显差异。最值得注意的是，调查对象指出检测的时间和审查过程非常繁琐，包括审查以前的结果、谨慎报告潜在的种系发现以及整合其他辅助检测。通过这些努力，GOAL 试图缩小结果报告方面的差距，最终提高基于 NGS 的癌症分子检测的一致性和准确性。我们预计，这项研究的结果将有助于为临床实验室提供一个基准，帮助他们与同行进行比较，并揭示临床报告标准化或改进的潜在领域。

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引用次数: 0

35. Integrated comprehensive genomic profiling of meningiomas: A single institutional study 35.脑膜瘤的综合全面基因组图谱分析：单一机构研究

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.037

Mohana Priya Jayavel, Ha Nguyen, Madina Sukhanova, Lucas Santana dos Santos, Behtash Nezami, Juehua Gao, Erica Vormittag-Nocito, Lawrence Jennings, Xinyan Lu

Meningioma is the most common central nervous system tumor and understudied because of its benign nature. High-grade meningiomas often show poorer outcome and enriched with high-risk copy-number-aberrations (CNAs) including losses/segmental-losses of chromosomes 1p, 3p, 4p/q, 6p/q, 10p/q, 14q, 18p/q and 19p/q, CDKN2A/B homozygous-deletion (CDKN2A/B-homo) and TERT promoter-mutation (TERTp) detected by comprehensive genomic profiling (CGP) including SNP-microarray, next generation sequencing (NGS) and DNA-methylation. In this study, we performed CGP on a large series of meningioma.

We identified 122 (45.2%) cases with high-risk CNAs in 270 cases assessed, including 33 WHO-grade-I, 67 WHO-grade-II and 22 WHO-grade-III. Fifty-one (41.8%) cases had hypodiploidy characterized by losses of 22, 14, 10, X/Y, 6 and 8; Eighteen (14.8%) showed polyploidy with relative losses of 1p, 14, 18, 6 and 10. In 53 (43.4%) cases with near-diploidy, half showed complex CNAs with losses/segmental-losses involving 1p, 3p, 19p,14q and 6q. Five cases (4.1%) showed CDKN2A/B-homo. NGS performed in 30 cases revealed mutations in NF2 (n=20), ARID1A (n=7), MSH6 (n=4). Seven (6.6%, 7/106) had TERTp mutation. Methylation profiling matched classifier for meningioma in 92% (79/86) of cases tested. CGP upgraded 58% WHO-grade-I and 67.2% WHO-grade-II tumors to WHO-grade-II and III, respectively. Although follow-up data is limited, 51 patients (41.8%) had tumor recurrence.

Our study showed that meningiomas are enriched by high-risk CNAs even in low-grade tumors, less frequent TERTp mutation or CDKN2A/B-homo. CGP is of clinical importance for tumor molecular characterizations. CGP should be utilized clinically and integrated in future WHO classifications for tumor grading and risk stratification.

脑膜瘤是最常见的中枢神经系统肿瘤，因其良性而研究不足。高级别脑膜瘤通常预后较差，富含高风险的拷贝数异常（CNAs），包括染色体1p、3p、4p/q、6p/q、10p/q、14q、18p/q和19p/q的缺失/片段缺失、CDKN2A/B同源染色体缺失（CDKN2A/B-homo）和TERT启动子突变（TERTp）是通过包括SNP微阵列、新一代测序（NGS）和DNA甲基化在内的全面基因组分析（CGP）检测到的。在这项研究中，我们对大量脑膜瘤病例进行了CGP分析。在评估的270个病例中，我们发现了122个（45.2%）病例具有高风险CNA，其中包括33个WHO-I级病例、67个WHO-II级病例和22个WHO-III级病例。51例（41.8%）为低二倍体，其特征为22、14、10、X/Y、6和8的丢失；18例（14.8%）为多倍体，其特征为1p、14、18、6和10的相对丢失。在 53 例（43.4%）近二倍体病例中，半数显示出复杂的 CNA，涉及 1p、3p、19p、14q 和 6q 的缺失/片段缺失。5个病例（4.1%）表现为CDKN2A/B-homo。在 30 个病例中进行的 NGS 发现了 NF2（n=20）、ARID1A（n=7）和 MSH6（n=4）的突变。7例（6.6%，7/106）有TERTp突变。在所检测的病例中，92%（79/86）的甲基化图谱与脑膜瘤分类器相匹配。CGP分别将58%的WHO-Ⅰ级和67.2%的WHO-Ⅱ级肿瘤升级为WHO-Ⅱ级和Ⅲ级。虽然随访数据有限，但有51名患者（41.8%）肿瘤复发。我们的研究表明，即使在低分级肿瘤中，脑膜瘤也富含高风险的CNAs，而TERTp突变或CDKN2A/B-homo的发生率较低。CGP对肿瘤的分子特征描述具有重要的临床意义。CGP应在临床上加以利用，并纳入未来的WHO肿瘤分级和风险分层分类中。

{"title":"35. Integrated comprehensive genomic profiling of meningiomas: A single institutional study","authors":"Mohana Priya Jayavel, Ha Nguyen, Madina Sukhanova, Lucas Santana dos Santos, Behtash Nezami, Juehua Gao, Erica Vormittag-Nocito, Lawrence Jennings, Xinyan Lu","doi":"10.1016/j.cancergen.2024.08.037","DOIUrl":"10.1016/j.cancergen.2024.08.037","url":null,"abstract":"<div><div>Meningioma is the most common central nervous system tumor and understudied because of its benign nature. High-grade meningiomas often show poorer outcome and enriched with high-risk copy-number-aberrations (CNAs) including losses/segmental-losses of chromosomes 1p, 3p, 4p/q, 6p/q, 10p/q, 14q, 18p/q and 19p/q, CDKN2A/B homozygous-deletion (CDKN2A/B-homo) and TERT promoter-mutation (TERTp) detected by comprehensive genomic profiling (CGP) including SNP-microarray, next generation sequencing (NGS) and DNA-methylation. In this study, we performed CGP on a large series of meningioma.</div><div>We identified 122 (45.2%) cases with high-risk CNAs in 270 cases assessed, including 33 WHO-grade-I, 67 WHO-grade-II and 22 WHO-grade-III. Fifty-one (41.8%) cases had hypodiploidy characterized by losses of 22, 14, 10, X/Y, 6 and 8; Eighteen (14.8%) showed polyploidy with relative losses of 1p, 14, 18, 6 and 10. In 53 (43.4%) cases with near-diploidy, half showed complex CNAs with losses/segmental-losses involving 1p, 3p, 19p,14q and 6q. Five cases (4.1%) showed CDKN2A/B-homo. NGS performed in 30 cases revealed mutations in NF2 (n=20), ARID1A (n=7), MSH6 (n=4). Seven (6.6%, 7/106) had TERTp mutation. Methylation profiling matched classifier for meningioma in 92% (79/86) of cases tested. CGP upgraded 58% WHO-grade-I and 67.2% WHO-grade-II tumors to WHO-grade-II and III, respectively. Although follow-up data is limited, 51 patients (41.8%) had tumor recurrence.</div><div>Our study showed that meningiomas are enriched by high-risk CNAs even in low-grade tumors, less frequent TERTp mutation or CDKN2A/B-homo. CGP is of clinical importance for tumor molecular characterizations. CGP should be utilized clinically and integrated in future WHO classifications for tumor grading and risk stratification.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S11"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

55. Advancing bladder carcinoma diagnosis: The innovative potential of the BCDx multi-omics approach 55.推进膀胱癌诊断：BCDx 多组学方法的创新潜力

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.057

Thakshila Habarakada Liyanage, Asel Habarakada Liyanage

The use of multi-omic biomarkers in liquid biopsies is emerging as a promising method for enhancing disease detection accuracy. However, it faces significant challenges, such as the complexity of integrating and interpreting data from various omic layers, which is time-consuming, low-throughput, and costly. Additionally, there is currently no simple instrument capable of detecting all the omics simultaneously. Early Is Good (EIG) has developed the Multi-Omic Integration Platform (MIP) to tackle these challenges in early disease detection. MIP can detect DNA, RNA, and proteins simultaneously using a standard plate reader, employing localized surface plasmon resonance (LSPR) of gold nanoparticles to enhance the bioluminescence resonance energy transfer (BRET) readout signal.

The novel MIP assay technology is applied to early bladder cancer recurrence monitoring using a multi-omic biomarker panel that includes miRNA, mRNA, lncRNA, and proteins. Current methods for identifying bladder cancer (BC) involve cystoscopy and urinary cytology. Cystoscopy, with 97% sensitivity for high-grade tumors, is invasive, operator-dependent, and costly. It often misses small or carcinoma in situ tumors, which can progress to muscle-invasive bladder cancer (MIBC) in about half of the patients. It also causes side effects like dysuria (50%), hematuria (19%), and urinary tract infections (3%), leading to discomfort, anxiety, and embarrassment. Urinary cytology, with 80-90% sensitivity and 98-100% specificity for high-grade tumors, struggles with low sensitivity (4-31%) for low-grade tumors and has a higher rate of false positives. This highlights the need for innovative approaches like the MIP, which offers non-invasive, highly sensitive, and comprehensive detection capabilities, potentially transforming the clinical management of bladder cancer. MIP has shown 100% sensitivity and 100% NPV for bladder cancer recurrence monitoring by combining the multi-omic biomarkers.

在液体活检中使用多组学生物标记物正在成为提高疾病检测准确性的一种有前途的方法。然而，它也面临着巨大的挑战，例如整合和解释来自不同奥米克层的数据非常复杂，耗时长、通量低、成本高。此外，目前还没有一种简单的仪器能够同时检测所有的 omics。Early Is Good (EIG) 开发了多微米集成平台 (MIP)，以应对早期疾病检测中的这些挑战。MIP 可以使用标准平板阅读器同时检测 DNA、RNA 和蛋白质，并利用金纳米粒子的局部表面等离子体共振 (LSPR) 来增强生物发光共振能量转移 (BRET) 读出信号。新颖的 MIP 检测技术应用于早期膀胱癌复发监测，使用的多组学生物标记物面板包括 miRNA、mRNA、lncRNA 和蛋白质。目前鉴定膀胱癌（BC）的方法包括膀胱镜检查和尿液细胞学检查。膀胱镜检查对高级别肿瘤的灵敏度为 97%，但具有侵入性、依赖操作者且成本高昂。它经常会漏诊小肿瘤或原位癌，约有一半的患者会发展为肌肉浸润性膀胱癌（MIBC）。它还会引起排尿困难（50%）、血尿（19%）和尿路感染（3%）等副作用，导致不适、焦虑和尴尬。尿液细胞学检查对高级别肿瘤的敏感性为 80-90%，特异性为 98-100%，但对低级别肿瘤的敏感性较低（4-31%），假阳性率也较高。这凸显了对 MIP 等创新方法的需求，MIP 具有无创、高灵敏度和全面的检测能力，有可能改变膀胱癌的临床治疗。通过结合多组学生物标记物，MIP 对膀胱癌复发监测的灵敏度和 NPV 分别达到了 100%和 100%。

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引用次数: 0

46. Clinical SNP-array adds value to diagnosis and surveillance of bone marrow failure syndromes 46.临床 SNP 阵列为骨髓衰竭综合征的诊断和监测增添价值

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.048

Lucilla Pizzo , Jian Zhao , Akiko Shimamura , Sara Lewis , Marcin Wlodarski , Bo Hong , Erica Andersen

Cytogenomic SNP microarray (SNP-A) utilization for diagnosis and monitoring of bone marrow failure syndromes (BMFS) is increasing. Understanding the biology of these heterogeneous diseases is required to appropriately identify, interpret, and track prognostically significant clones, some of which may represent revertant somatic genetic rescue (SGR) events. We reviewed SNP-A findings from our encounter of over 100 BMFS cases tested at our institution. Abnormal results were reported in 30 cases, including nine aplastic anemia (AA, 30%), eleven Shwachman-Diamond syndrome (SDS, 37%), six SAMD9/SAMD9L-related syndrome (20%), and four Diamond-Blackfan anemia (DBA, 13%) cases. In 15 (50%) cases, the SNP-A profile was consistent with SGR and acquired correction of the disease-causing variant. Isolated CN-LOH of the chromosome containing the disease-causing gene was observed in 12 (40%) cases, including CN-LOH 7q in two individuals with SDS (SBDS gene) and three individuals with SAMD9/SAMD9L-associated syndromes, and CN-LOH 2p and 19q in two individuals with RPS7 and RPS19-associated DBA, respectively. SGR-associated CNVs included isochromosome 7q (SBDS) and 20q deletion (EIF6 gene) in three cases of SDS. Malignant transformation SNP-A findings were observed in 4/30 (13%) cases, including CN-LOH 17p with TP53 Tier 1 variant in an SDS case and monosomy 7 in three cases of SAMD9/SAMD9L-related syndromes. Concurrent review of cytogenetic/FISH, NGS, and/or germline BMFS results, where available; identification of low-level, complex and/or coexisting clones; and accurate clonal estimation for sequential tracking are essential, and add value to clinical management. Our results emphasize the value of SNP-A in the diagnosis, prognosis, and monitoring of BMFS.

细胞基因组 SNP 芯片（SNP-A）在骨髓衰竭综合征（BMFS）诊断和监测中的应用越来越广泛。了解这些异质性疾病的生物学特性是适当识别、解释和跟踪具有预后意义的克隆的必要条件，其中一些克隆可能代表体细胞基因挽救（SGR）事件。我们回顾了本机构检测的 100 多例 BMFS 病例的 SNP-A 结果。有 30 例报告结果异常，包括 9 例再生障碍性贫血（AA，30%）、11 例 Shwachman-Diamond 综合征（SDS，37%）、6 例 SAMD9/SAMD9L 相关综合征（20%）和 4 例钻石-贝克范贫血（DBA，13%）。在 15 个病例（50%）中，SNP-A 特征与 SGR 和获得性致病变体校正一致。在 12 个病例（40%）中观察到了含有致病基因的染色体的孤立 CN-LOH，其中包括两个 SDS（SBDS 基因）患者和三个 SAMD9/SAMD9L 相关综合征患者的 CN-LOH 7q，以及两个 RPS7 和 RPS19 相关 DBA 患者的 CN-LOH 2p 和 19q。与 SGR 相关的 CNV 包括同染色体 7q（SBDS）和 3 例 SDS 中的 20q 缺失（EIF6 基因）。在 4/30 例（13%）病例中观察到恶性转化 SNP-A，包括一例 SDS 病例中带有 TP53 第 1 层变异的 CN-LOH 17p，以及三例 SAMD9/SAMD9L 相关综合征病例中的 7 号单体。同时审查细胞遗传学/FISH、NGS 和/或种系 BMFS 结果（如果有的话）；识别低水平、复杂和/或共存的克隆；以及为序列追踪进行准确的克隆估计是至关重要的，这也为临床管理增添了价值。我们的研究结果强调了 SNP-A 在 BMFS 诊断、预后和监测中的价值。

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引用次数: 0

77. dic(7;9):A distinct entity in B-ALL with multiple genomic aberrations including IKAROS and PAX5 DIC(7;9)：B-ALL 中的一个独特实体，具有多种基因组畸变，包括 IKAROS 和 PAX5

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.079

Ashwini Yenamandra, Rebecca Smith, Kun Zhao, Yingda Wang, Brianna Smith, Christine Smith, Meng-Chang Hsiao, Debra Friedman

dic(7;9) is a rare (<1%) and recurrent abnormality in both pediatric and adult B-ALL, resulting in partial monosomy of chromosomes 7p and 9p. Co-occurrence of dic(7;9) with PAX5 gene alterations including deletions, mutations and amplification have been reported. PAX5 encodes the B lymphoid transcription factor gene that is important in regulating B cell lineage differentiation, leading to B-cell development and may play a crucial role in B lymphoid leukemogenesis.

Here, we present two cases of pediatric B-ALL with dic(7;9) with complex genomic aberrations.

Case 1: is a four year old female who presented in 2024 with orbital and left sinus maxillary masses, anemia, fever and leukocytosis with peripheral blasts. Karyotype and fish were complex with 45,XX,der(7)dic(7;9)(p11.2;p13)del(7)(p13p11.2)t(7;20)(p13;q11.2),der(20)t(7;20)(p13;q11.2)[13]/46,XX[7]. SNP array revealed loss of 7p and 9p including IKAROS and PAX5, respectively.

Cerebral sinus fluid demonstrated a leukocytosis with leukemic blasts, resulting in a CNS3b classification. She had negative minimal residual disease at the end of induction on a very high-risk standard of care protocol and on consolidation therapy.

Case 2: is a 10 year old male referred in 2022 for a month of fever and fatigue.. karyotype was complex with several rearrangements. 45,XY,dic(7)t(7;9)(p13;p13),-9,der(10)t(9;10)(q34.1;q22),der(12)t(7;12)(p13;p13),der(13)t(10;13)(q22;q34)[11]/46,XY[9].

The patient was treated on a standard risk standard of care protocol and had negative minimal residual disease at the end of induction. He remains in remission during maintenance therapy.

Given the two dic (7;9) cases described here have complex karyotypes, it is possible that PAX5 and IKZF1 alterations may be contributing to this complex cytogenetic entity.

dic(7;9)是小儿和成人 B-ALL 中的一种罕见（<1%）和复发性异常，导致 7p 和 9p 染色体部分单体。有报道称，dic(7;9)与PAX5基因改变（包括缺失、突变和扩增）同时存在。PAX5编码B淋巴转录因子基因，在调控B细胞系分化、导致B细胞发育方面具有重要作用，并可能在B淋巴白血病发生中发挥关键作用。在此，我们介绍了两例伴有复杂基因组畸变的dic（7;9）的小儿B-ALL病例。病例1：是一名四岁女性，于2024年出现眼眶和左上颌窦肿块、贫血、发热和白细胞增多伴外周血块。核型和鱼形图为 45,XX,der(7)dic(7;9)(p11.2;p13)del(7)(p13p11.2)t(7;20)(p13;q11.2),der(20)t(7;20)(p13;q11.2)[13]/46,XX[7] 的复杂组合。SNP阵列显示7p和9p分别缺失，其中包括IKAROS和PAX5。脑窦液显示白细胞增多，并伴有白血病血泡，结果被分为CNS3b。病例 2：男性，10 岁，因发热和乏力一个月于 2022 年转诊，核型复杂，有多个重排。45,XY,dic(7)t(7;9)(p13;p13),-9,der(10)t(9;10)(q34.1;q22),der(12)t(7;12)(p13;p13),der(13)t(10;13)(q22;q34)[11]/46,XY[9]。鉴于本文描述的两例双(7;9)染色体病例具有复杂的核型，PAX5和IKZF1的改变可能是导致这种复杂细胞遗传实体的原因。

{"title":"77. dic(7;9):A distinct entity in B-ALL with multiple genomic aberrations including IKAROS and PAX5","authors":"Ashwini Yenamandra, Rebecca Smith, Kun Zhao, Yingda Wang, Brianna Smith, Christine Smith, Meng-Chang Hsiao, Debra Friedman","doi":"10.1016/j.cancergen.2024.08.079","DOIUrl":"10.1016/j.cancergen.2024.08.079","url":null,"abstract":"<div><div>dic(7;9) is a rare (<1%) and recurrent abnormality in both pediatric and adult B-ALL, resulting in partial monosomy of chromosomes 7p and 9p. Co-occurrence of dic(7;9) with <em>PAX5</em> gene alterations including deletions, mutations and amplification have been reported. <em>PAX5</em> encodes the B lymphoid transcription factor gene that is important in regulating B cell lineage differentiation, leading to B-cell development and may play a crucial role in B lymphoid leukemogenesis.</div><div>Here, we present two cases of pediatric B-ALL with dic(7;9) with complex genomic aberrations.</div><div>Case 1: is a four year old female who presented in 2024 with orbital and left sinus maxillary masses, anemia, fever and leukocytosis with peripheral blasts. Karyotype and fish were complex with 45,XX,der(7)dic(7;9)(p11.2;p13)del(7)(p13p11.2)t(7;20)(p13;q11.2),der(20)t(7;20)(p13;q11.2)[13]/46,XX[7]. SNP array revealed loss of 7p and 9p including <em>IKAROS</em> and <em>PAX5</em>, respectively.</div><div>Cerebral sinus fluid demonstrated a leukocytosis with leukemic blasts, resulting in a CNS3b classification. She had negative minimal residual disease at the end of induction on a very high-risk standard of care protocol and on consolidation therapy.</div><div>Case 2: is a 10 year old male referred in 2022 for a month of fever and fatigue.. karyotype was complex with several rearrangements. 45,XY,dic(7)t(7;9)(p13;p13),-9,der(10)t(9;10)(q34.1;q22),der(12)t(7;12)(p13;p13),der(13)t(10;13)(q22;q34)[11]/46,XY[9].</div><div>The patient was treated on a standard risk standard of care protocol and had negative minimal residual disease at the end of induction. He remains in remission during maintenance therapy.</div><div>Given the two dic (7;9) cases described here have complex karyotypes, it is possible that <em>PAX5</em> and <em>IKZF1</em> alterations may be contributing to this complex cytogenetic entity.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Pages S24-S25"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

6. Hot-spot D816 KIT has different clinical outcome compared to non-D816 KIT variants in myeloid neoplasms 6.与非 D816 KIT 变体相比，骨髓性肿瘤中的热点 D816 KIT 具有不同的临床结果

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.008

Barina Aqil , Lucas Santana-Santos , Juehua Gao , Xinyan Lu , Amandeep Kaur , Erica Vormittag-Nocito , Lawrence Jennings , Yasmin Abaza , Madina Sukhanova

KIT (proto-oncogene) plays significant role in diagnosis and prognosis of myeloid neoplasms (MNs). The hot-spot KIT D816 mutation in exon 17 is recognized by WHO classification as poor prognostic marker for acute myeloid leukemia (AML) with RUNX1::RUNX1T1 and as one of diagnostic and prognostic criteria for systemic mastocytosis (SM), a MN characterized by clonal proliferation of mast cells. The role of activating KIT mutations outside of codon 816 was recognized, resulting in addition of few critical KIT regions in updated consensus proposal for SM diagnosis. However, information on prognostic weight of these 'non-hot-spot' changes is limited. Here we present results of comparative analysis of clinicopathological and survival parameters for patients diagnosed with MNs with activating KIT changes outside of codon 816 (N=14) using patients with MNs with KIT D816 (N=26) as comparative group. Most of study patients had AML (65%) followed by MDS and MDS/MPN (35% combined). Both study groups had same representation of normal, non-complex and complex karyotypes, and karyotypes with diagnostic t(8;21) and inv(16). IHC staining for c-KIT (CD117) detected significantly lower percentage of mast cells with c-Kit protein expression in non-D816 group in contrast to patients with D816 KIT (p<0.0076). Consistent with that, none of the non-D816 group patients developed SM compared to 31% of D816 group patients who developed SM. Notably, the group with non-D816 KIT showed better OS compared to patients with D816 change (p<0.016). Our results support the hypothesis of weaker prognostic impact of non-D816 KIT mutations compared to D816 hot-spot.

KIT（原癌基因）在髓系肿瘤（MNs）的诊断和预后中发挥着重要作用。世卫组织认为，外显子 17 中的热点 KIT D816 突变是伴有 RUNX1::RUNX1T1 的急性髓性白血病（AML）的不良预后标志，也是以肥大细胞克隆性增殖为特征的系统性肥大细胞增多症（SM）的诊断和预后标准之一。人们认识到密码子 816 以外的活化 KIT 突变的作用，因此在最新的 SM 诊断共识建议中增加了几个关键的 KIT 区域。然而，有关这些 "非热点 "变化对预后影响的信息却很有限。在此，我们以KIT D816的MNs患者（N=26）为对比组，比较分析了被诊断为KIT 816密码子外激活性变化的MNs患者（N=14）的临床病理和生存参数。大多数研究对象为急性髓细胞性白血病患者（65%），其次为骨髓增生异常综合症和骨髓增生异常综合症/骨髓增生异常性白血病患者（35%）。两个研究组的正常、非复杂和复杂核型以及诊断性 t(8;21) 和 inv(16) 核型的代表性相同。对 c-KIT (CD117) 进行 IHC 染色发现，非 D816 组肥大细胞中表达 c-Kit 蛋白的比例明显低于 D816 KIT 患者（p<0.0076）。与此相一致的是，非 D816 组患者中没有人发展为 SM，而 D816 组患者中有 31% 发展为 SM。值得注意的是，与 D816 变化的患者相比，非 D816 KIT 组患者的 OS 更好（p<0.016）。我们的结果支持了非D816 KIT突变对预后的影响弱于D816热点的假设。

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引用次数: 0

A complex t(15;22;17)(q22;q11.2;q21) variant of APL APL 的复杂 t(15;22;17)(q22;q11.2;q21)变体

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.07.003

Bilgesu Ak , Özge Güngör , Emin Karaca , Burak Durmaz , Denis S. Bozer , Mahmut Töbü , Haluk Akın

The present study described an extremely rare case of acute promyelocytic leukemia (APL) characterized by a complex three‑way (15;22;17)(q22;q11.2;q21) translocation. Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia with distinctive clinical and therapeutic characteristics. Besides being characterized by the t(15;17)(q22;q12) translocation, this subtype is also notable for its response to all-trans-retinoic acid (ATRA) treatment. APL is highly responsive to a combination of ATRA and chemotherapeutic agents, achieving over 90 % complete remission rates and over 80 % long-term remission rates. In this case, a 79-year-old male patient presented with complaints of weakness, fatigue, and petechial rash, with no other significant medical history except for diabetes mellitus and hypertension. Conventional cytogenetic methods, dual-color dual-fusion, and dual-color break-apart fluorescent in situ hybridization techniques together identified the t(15;22;17) translocation. RT-PCR analysis was performed for expression of PML/RARA fusion transcripts. The patient, diagnosed with APL, exhibited a complete response to all-trans retinoic acid (ATRA) and idarubicin treatment. In this paper, we present the second documented case of t(15;22;17) and explore the remarkable remission observed following treatment with All-Trans Retinoic Acid (ATRA).

本研究描述了一例极其罕见的急性早幼粒细胞白血病（APL）病例，其特征是复杂的三向（15;22;17）（q22;q11.2;q21）易位。急性早幼粒细胞白血病（APL）是急性髓细胞白血病的一种特殊亚型，具有独特的临床和治疗特点。除了以t(15;17)(q22;q12)易位为特征外，该亚型对全反式维甲酸（ATRA）治疗的反应也很显著。APL 对 ATRA 和化疗药物的联合治疗反应强烈，完全缓解率超过 90%，长期缓解率超过 80%。在本病例中，一名79岁的男性患者主诉虚弱、乏力和瘀斑皮疹，除糖尿病和高血压外无其他重要病史。常规细胞遗传学方法、双色双融合和双色断裂荧光原位杂交技术共同确定了t（15;22;17）易位。对PML/RARA融合转录本的表达进行了RT-PCR分析。该患者被诊断为 APL，对全反式维甲酸（ATRA）和依达比星治疗有完全反应。在本文中，我们介绍了第二例记录在案的t(15;22;17)病例，并探讨了使用全反式维甲酸（ATRA）治疗后观察到的显著缓解。

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引用次数: 0