Cancer Genetics最新文献_第10页

25. Enhancing precision oncology: The value of open-source knowledgebase integration 25.加强精准肿瘤学：开源知识库整合的价值

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.027

Cameron Grisdale , Erin Pleasance , Connor Frey , Caralyn Reisle , Laura Williamson , Jing Xu , Veronika Csizmok , John Dupuis , Kathleen Wee , Yaoqing Shen , Zakhar Krekhno , Melika Bonakdar , Greg Taylor , Asmita Jain , Melissa McConechy , Kilannin Krysiak , Jason Saliba , Arpad Danos , Adam Coffman , Susanna Kiwala , Steven Jones

Precision oncology relies on advanced sequencing technologies to guide treatment strategies, yet effectively translating genomic data into actionable insights remains a critical challenge. The Personalized OncoGenomics (POG) program at BC Cancer utilizes whole genome and transcriptome analysis (WGTA), providing a comprehensive view of the molecular biology of advanced cancer patient tumours, with over 1200 patients enrolled to-date. This analysis relies on curated clinical knowledgebases linking cancer variants and their clinical relevance, but the breadth and utility of these can be limited by access restrictions or missing information. CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is an open-access, expert moderated, crowd-sourced knowledgebase of clinically relevant cancer variants that aims to address these limitations and is one of several sources used for variant interpretation in POG. Based on a retrospective cohort of POG cases, we evaluated the knowledgebase coverage of genes and variants involved in treatment recommendations from the molecular tumour board (MTB) as well as those suggested by genome analysts. We also considered the impact of quality of evidence on MTB recommendations and patient treatments. We found more than 95% of patients had an alteration considered clinically actionable by the MTB, demonstrating the benefit of WGTA paired with open-source automated variant matching and reporting software. Clinical interpretations derived from CIViC represented nearly 50% of therapeutic evidence reported at the MTB, emphasizing the role of open-access knowledge in precision oncology. Additionally, we identified genome signatures as a critical area with clinical implications requiring further curation efforts and evidence model development.

精准肿瘤学依赖于先进的测序技术来指导治疗策略，但有效地将基因组数据转化为可操作的见解仍是一项严峻的挑战。不列颠哥伦比亚癌症中心的个性化肿瘤基因组学（POG）计划利用全基因组和转录组分析（WGTA），提供晚期癌症患者肿瘤分子生物学的全面视图，迄今已有超过1200名患者加入该计划。这种分析依赖于将癌症变异及其临床相关性联系起来的临床知识库，但这些知识库的广度和实用性可能会受到访问限制或信息缺失的限制。CIViC（Clinical Interpretation of Variants in Cancer; civicdb.org，癌症变异临床解读；civicdb.org）是一个开放存取、专家主持、群众参与的临床相关癌症变异知识库，旨在解决这些局限性，是用于 POG 变异解读的几个来源之一。基于一组回顾性 POG 病例，我们评估了分子肿瘤委员会（MTB）治疗建议中涉及的基因和变异的知识库覆盖范围，以及基因组分析师提出的建议。我们还考虑了证据质量对 MTB 建议和患者治疗的影响。我们发现 95% 以上的患者有 MTB 认为在临床上可采取行动的变异，这证明了 WGTA 与开源自动变异匹配和报告软件搭配使用的好处。CIViC得出的临床解释占MTB报告的治疗证据的近50%，强调了开放获取知识在精准肿瘤学中的作用。此外，我们还发现基因组特征是一个具有临床影响的关键领域，需要进一步的整理工作和证据模型的开发。

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引用次数: 0

67. An undiagnosed chronic myeloid leukemia (CML) with p190 BCR::ABL1 transcript, an extra Philadelphia chromosome, and IKARO 67.未确诊的慢性髓性白血病（CML），伴有 p190 BCR::ABL1转录本、额外的费城染色体和 IKARO

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.069

Fabiola Quintero-Rivera, Sumayya Aslam, Lynn Yang, Johnson Tso, Melissa Lyon, Katherine Dang, Ying Zhang, Kiran Naqvi, Sherif Rezk

Chronic myeloid leukemia (CML) with p190 BCR::ABL1 transcript is rare but when present, it is usually associated with increased monocytes. IKZF1, a gene that encodes the lymphoid transcription factor IKAROS, is commonly deleted in B-lymphoblastic leukemia (B-ALL). Here, we describe a 66-year-old male with 2-weeks history of myalgias, night sweats, malaise, and fatigue, and white blood cells of 177K with 90% circulating blasts. At our institute, bone marrow examination showed ∼56% B-lymphoblasts, ∼3% myeloblasts, and increased monocytes (21%). Aberrant CD13 and CD25 expression was noted, which can be seen in B-ALL with BCR::ABL1 fusion (BAF). FISH leukemia panels detected 2-3 BAF, in 94.5% and 4% of the cells, consistent with an extra Ph+, and loss of IKZF1 locus in 91% of cells. RT-PCR showed BAF p190 breakpoint. The initial diagnosis was a B-ALL with BAF but given the presence of increased monocytes and left-shifted granulocytes, a preceding CML could not be ruled out. Subsequently, an abnormal karyotype with two clones was detected; one with an interstitial deletion of 7p leading to IKZF1 deletion, and t(9;22). Clone two, exhibited an extra Ph+, plus t(9;22); both clones were consistent with the proportion of abnormal cells detected by FISH 46,XY,del(7)(p15p11.2),t(9;22)(q34;q11.2)[19]/47,XY,t(9;22),+der(22)t(9;22)[1]. The immunophenotype obtained by flow cytometry/immunohistochemistry and RT-PCR was supportive of B-ALL. The morphologic picture along with the correlation of the karyotype, which detected two distinct cell populations, supported by FISH IKZF1/ BCR::ABL1 results led to a diagnosis of a preceding CML presenting in lymphoid blast crisis. Patient is undergoing initial

带有 p190 BCR::ABL1 转录本的慢性髓性白血病（CML）非常罕见，但一旦出现，通常与单核细胞增多有关。IKZF1是一种编码淋巴细胞转录因子IKAROS的基因，在B淋巴细胞白血病（B-ALL）中常见缺失。在此，我们描述了一名 66 岁男性患者的病史，该患者两周前出现肌痛、盗汗、乏力和疲劳，白细胞为 177K，90% 为循环型白细胞。在我院进行的骨髓检查显示，B淋巴细胞占 56%，骨髓母细胞占 3%，单核细胞增多（21%）。发现CD13和CD25表达异常，这可能见于BCR::ABL1融合（BAF）的B-ALL。FISH 白血病检测板分别在 94.5% 和 4% 的细胞中检测到 2-3 个 BAF，这与额外的 Ph+ 一致，91% 的细胞中存在 IKZF1 基因座缺失。RT-PCR显示BAF p190断点。初步诊断为伴有BAF的B-ALL，但考虑到存在单核细胞增多和粒细胞左移的情况，不能排除患者曾患CML。随后，发现了两个克隆的异常核型；一个是7p间质缺失导致IKZF1缺失，另一个是t(9;22)。克隆二显示出一个额外的 Ph+，外加 t(9;22)；这两个克隆与 FISH 46,XY,del(7)(p15p11.2),t(9;22)(q34;q11.2)[19]/47,XY,t(9;22),+der(22)t(9;22)[1]检测到的异常细胞比例一致。通过流式细胞术/免疫组化和 RT-PCR 获得的免疫表型支持 B-ALL。形态学图像与核型的相关性（核型检测出两个不同的细胞群）以及 FISH IKZF1/ BCR::ABL1 检测结果的支持，导致诊断为出现淋巴细胞暴发危象的先期 CML。患者正在接受初步

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引用次数: 0

10. Standardizing fusion calls in a computable format with FUSOR for downstream clinical assessment 10.利用 FUSOR 将融合调用标准化为可计算格式，用于下游临床评估

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.012

Jeremy A. Arbesfeld , James S. Stevenson , Kathryn Stahl , Kori Kuzma , Alex H. Wagner

The detection of gene fusion events, in which two or more genes interact to drive aberrant expression of a gene product, plays a key role in clinical diagnostics. Although advances in sequencing technology have strengthened gene fusion data availability, there are limitations in the way such knowledge is interpreted in a clinical context. Specifically, current standards are imprecise for representing the complexity of fusions that are observed from biological specimens. To address this challenge, experts from VICC, CGC, and other clinical genomics communities developed a consensus, unified framework for the description of fusion events. We developed the FUSOR package, a Python library containing modeling and validation tools that implements this standard for use with gene fusion data.

We tested use of FUSOR on patient sample data through development of a Translator module (http://tinyurl.com/FUSOR-Translator) that standardizes fusion calls from eight widely-used fusion detection algorithms including CICERO and Arriba and fusion calls from the AACR Project GENIE cohort. We assessed application of the VICC Gene Fusion Specification using FUSOR to evaluate the completeness of the specification for representing fusion variant calls. We demonstrate how application of the tool to real-world data identified gaps in the nascent specification, including the use of gene concepts not covered by the HUGO Gene Nomenclature committee and the improved alignment of evidence between assayed and categorical fusion concepts, that we were able to fill to improve the standard. We conclude with applications of the FUSOR tool for use with clinical variant curation workflows.

基因融合是指两个或两个以上的基因相互作用，导致基因产物的异常表达，基因融合事件的检测在临床诊断中起着关键作用。虽然测序技术的进步提高了基因融合数据的可用性，但在临床环境中解释这些知识的方式还存在局限性。具体来说，目前的标准并不精确，无法体现从生物标本中观察到的基因融合的复杂性。为了应对这一挑战，来自 VICC、CGC 和其他临床基因组学团体的专家们开发了一个用于描述融合事件的共识性统一框架。我们开发了 FUSOR 软件包，这是一个 Python 库，其中包含建模和验证工具，用于实现基因融合数据的这一标准。我们通过开发翻译模块 (http://tinyurl.com/FUSOR-Translator) 测试了 FUSOR 在患者样本数据上的使用情况，该模块可标准化来自 CICERO 和 Arriba 等八种广泛使用的融合检测算法的融合调用，以及来自 AACR Project GENIE 队列的融合调用。我们使用 FUSOR 评估了 VICC 基因融合规范的应用情况，以评价该规范在表示融合变异调用方面的完整性。我们展示了如何将该工具应用于真实世界的数据，从而发现新生规范中的不足，包括使用 HUGO 基因命名委员会未涵盖的基因概念，以及改进化验和分类融合概念之间的证据一致性。最后，我们将介绍 FUSOR 工具在临床变异体整理工作流中的应用。

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引用次数: 0

76. Automating immunogenomic tumor board decision-making for neoantigen cancer vaccine design 76.新抗原癌症疫苗设计的免疫基因组肿瘤委员会决策自动化

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.078

Jennie Yao , Kartik Singhal , Susanna Kiwala , Peter Goedegebuure , Christopher Miller , Huiming Xia , My Hoang , Mariam Khanfar , Kelsy Cotto , Sherri Davies , Feiyu Du , Evelyn Schmidt , Gue Su Chang , Jasreet Hundal , Jeffrey Ward , William Inabinett , William Hoos , William Gillanders , Obi Griffith , Malachi Griffith

Advancements in immunogenomics and immuno-oncology have enabled the development of neoantigen vaccines, offering personalized cancer therapies by targeting cancer cell-specific somatic mutations. These mutations produce neoantigens that, when presented on tumor cells by MHC molecules, can elicit a robust and specific immune response. To date, there are 108 interventional studies listed on clinicaltrials.gov that explore the use of cancer vaccines. We have supported a number of these trials through the creation of bioinformatic pipelines, tools and procedures for the identification of patient-specific neoantigen candidates. Final prioritization of neoantigen candidates relies on manual review by an Immunogenomics Tumor Board (ITB) that meets weekly, increasing turnaround time and presenting a barrier to scaling.

Addressing this challenge, we introduce a machine learning-based approach to automate the selection of neoantigens peptides. We implemented a random forest model to train and test on existing ITB results from 21 patients and 1,324 peptides, including 297 peptides prioritized for personalized vaccine inclusion. This model aims to use features such as mutation position, driver gene status, tumor variant allele frequency, RNA expression, and other features to automatically predict whether a peptide will be accepted, rejected, or require further review for the vaccine. The model achieved an 88.89% sensitivity and 86.4% specificity, with an area under the curve of 0.933. By integrating this model into the vaccine development pipeline, we foresee a significant reduction in the time required to transition from patient sample collection to vaccine manufacturing, thereby enhancing the efficiency and scalability of personalized cancer vaccine production.

免疫基因组学和免疫肿瘤学的进步促进了新抗原疫苗的开发，通过靶向癌细胞特异性体细胞突变提供个性化癌症疗法。这些突变产生的新抗原通过 MHC 分子呈现在肿瘤细胞上时，可引起强大的特异性免疫反应。迄今为止，clinicaltrials.gov 上已列出 108 项探索癌症疫苗应用的干预性研究。我们通过创建生物信息学管道、工具和程序来识别患者特异性新抗原候选物，从而为其中一些试验提供了支持。新抗原候选物的最终优先排序依赖于免疫组学肿瘤委员会（ITB）的人工审核，该委员会每周召开一次会议，这增加了周转时间，也阻碍了规模的扩大。我们采用随机森林模型对来自 21 名患者和 1,324 个肽段的现有 ITB 结果进行训练和测试，其中包括优先纳入个性化疫苗的 297 个肽段。该模型旨在利用突变位置、驱动基因状态、肿瘤变异等位基因频率、RNA表达等特征，自动预测疫苗是否接受、拒绝或需要进一步审查多肽。该模型的灵敏度为 88.89%，特异度为 86.4%，曲线下面积为 0.933。通过将该模型集成到疫苗开发流水线中，我们预计从患者样本采集到疫苗生产所需的时间将大大缩短，从而提高个性化癌症疫苗生产的效率和可扩展性。

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引用次数: 0

44. UMI-based expanded NGS panel in precision molecular diagnosis of vascular anomalies: Early results 44.基于 UMI 的扩展 NGS 面板用于血管异常的精确分子诊断：早期结果

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.046

Avinash Dharmadhikari, Sara Kreimer, Jianling Ji, Ryan Schmidt, Miao Sun, Gordana Raca, Yachen Pan, Cindy Fong, Meagan Hughes, Jessica Lee, Minnelly Lu, Joseph Miller, Dean Anselmo, Jaclyn Biegel, Matthew Deardorff

Purpose

To describe early results from a highly sensitive genetic panel to evaluate patients with largely mosaic vascular anomalies

Methods

This is a single-center study utilizing a 218 gene panel with unique molecular identifier (UMI) adapters and an average 1000X target coverage. DNA was obtained from fresh, frozen or paraffin-embedded tissue, blood, buccal brushes, or cells pelleted from fluid.

Results

24 patients were evaluated in a vascular anomalies center and 6 patients were evaluated by dermatology, genetics, or oncology. 23/30 patients (76.7%) had identified causal variants. 25 variants were described: 11 PIK3CA, 4 TEK, 2 GNAQ, 2 KRAS, 1 KDR, 1 CELSR1, 1 PTEN, 1 SUFU, 1 MAP2K1, and 1 MTOR. These variants were classified as 21 pathogenic, 1 likely pathogenic, and 3 variants of uncertain significance (VUS). Of the 11 variants in PIK3CA, the kinase domain substitution at p.His1047 was the most frequently observed (36.3%). Mean variant allele frequency (VAF) was 18.7%, with a minimum VAF of 1.9%, therefore most variants were consistent with somatic mosaicism. Variants in CELSR1 and SUFU were identified at VAFs suggestive of a germline origin in patients who were not known to have germline variants. 6 patients had an alteration of clinical management based on the findings.

Conclusions

This genetic panel is highly effective in identifying somatic and germline clinically significant variants in patients with vascular anomalies. The prevalence of causative variants is higher than reported in previous studies. Future directions include validation of this panel in additional specimen types to extend utility.

目的描述高灵敏度基因检测面板的早期结果，以评估大部分镶嵌型血管畸形的患者。DNA 取自新鲜、冷冻或石蜡包埋组织、血液、口腔刷或从液体中提取的细胞。结果24 名患者在血管畸形中心接受了评估，6 名患者接受了皮肤科、遗传学或肿瘤科的评估。23/30（76.7%）名患者的病因变异已经确定。共描述了 25 个变体：11 个 PIK3CA、4 个 TEK、2 个 GNAQ、2 个 KRAS、1 个 KDR、1 个 CELSR1、1 个 PTEN、1 个 SUFU、1 个 MAP2K1 和 1 个 MTOR。这些变异被分为 21 个致病变异、1 个可能致病变异和 3 个意义不明的变异 (VUS)。在 PIK3CA 的 11 个变异中，p.His1047 的激酶域置换最常见（36.3%）。平均变异等位基因频率（VAF）为18.7%，最低VAF为1.9%，因此大多数变异与体细胞嵌合一致。在已知不存在种系变异的患者中，发现了CELSR1和SUFU的变异，其变异等位基因频率（VAF）提示为种系来源。6名患者的临床治疗根据研究结果进行了调整。结论该基因检测小组能有效识别血管异常患者中具有临床意义的体细胞和种系变异。致病变异的发生率高于以往的研究报告。未来的研究方向包括在更多标本类型中验证该面板，以扩大其效用。

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引用次数: 0

45. Examining potential candidate genes within deletions of 3p14.2 to 3p14.1 in two cases of autism and developmental delay 45.研究两例自闭症和发育迟缓患者 3p14.2 至 3p14.1 缺失部位的潜在候选基因

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.047

Rebecca Smith, Ashwini Yenamandra, Meng-Chang Hsiao, Monica Guardado, Jeanette Saffir, Scott Ward

Copy number deletions at chromosomal region 3p14 are rare constitutional occurrences and the genes within this region are mainly unclassified. The small number of publications describing patients with 3p14 deletions list phenotypes of multiple congenital anomalies, movement disorders, feeding difficulties, developmental delay, and autism. Despite these recurring patient phenotypes, no potential candidate genes within this region have been identified.

Here we describe two unrelated cases with overlapping 3p14.2 to 3p14.1 single-copy deletions. The first case is a 5-year-old male with childhood apraxia of speech, global developmental delay, autism spectrum disorder, and hyperkinesis. This patient's deletion is 3.1 Mb in size and contains 15 known genes and 8 OMIM genes. The second case is a 2-year-old female with prematurity, global developmental delay, failure to thrive, feeding difficulties, feeding tube dependency, short stature, microcephaly, PDA closure, autism spectrum disorder, and abnormalities on brain MRI. This patient's deletion is 3.5 Mb in size and contains 24 known genes and 10 OMIM genes.

Taken together, 7 OMIM genes are deleted in both patients: PTPRG, FEZF2, CADPS, SNTN, THOC7, ATXN7, SCAANT1. We will explore how deletion of these potential candidate genes may impact the patients' shared phenotypes of autism and global developmental delay. Additionally, we will examine the three genes (PSMD6, PRICKLE2, ADAMTS9) that are deleted only in the second patient, who displays a more severe phenotype. This assessment may identify candidate genes for follow-up functional studies and will contribute to the literature by describing patients with rare copy number losses in this region.

染色体 3p14 区域的拷贝数缺失是一种罕见的染色体病，该区域内的基因主要未分类。少量描述 3p14 缺失患者的文献列出了多种先天畸形、运动障碍、喂养困难、发育迟缓和自闭症等表型。尽管这些患者的表型反复出现，但尚未发现该区域的潜在候选基因。在此，我们描述了两例3p14.2至3p14.1单拷贝缺失重叠的无关病例。第一个病例是一名 5 岁的男性，患有儿童语言障碍、全面发育迟缓、自闭症谱系障碍和运动机能亢进症。该患者的缺失区大小为 3.1 Mb，包含 15 个已知基因和 8 个 OMIM 基因。第二个病例是一名 2 岁女性，患有早产、全面发育迟缓、发育不良、喂养困难、喂养管依赖、身材矮小、小头畸形、PDA 闭合、自闭症谱系障碍和脑核磁共振成像异常。该患者的基因缺失大小为 3.5 Mb，包含 24 个已知基因和 10 个 OMIM 基因：这两名患者共删除了 7 个 OMIM 基因：PTPRG、Fezf2、CADPS、SNTN、THOC7、ATXN7、SCAANT1。我们将探讨这些潜在候选基因的缺失会如何影响患者自闭症和全面发育迟缓的共同表型。此外，我们还将研究仅在第二名患者中被缺失的三个基因（PSMD6、PRICKLE2 和 ADAMTS9），该患者的表型更为严重。这项评估可能会确定后续功能研究的候选基因，并通过描述该区域罕见拷贝数缺失的患者，为文献做出贡献。

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引用次数: 0

47. Genomic characterization of the T-ALL cell line CCRF-CEM using optical genome mapping and nanopore sequencing 47.利用光学基因组图谱和纳米孔测序鉴定 T-ALL 细胞系 CCRF-CEM 的基因组特征

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.049

Hussain Alcassab, Chin-Ting Wu, Awdhesh Kalia, Manjunath Nimmakayalu, Xiaojun Liu

Human Cancer cell lines provide a valuable model for detecting genomic alterations and chromosomal aberrations to identify and validate new diagnostic or therapeutic targets. Here, we recharacterize the T-cell acute lymphocytic leukemia (T-ALL) cell line CCRF-CEM (ATCC #CCL-119) using karyotyping, FISH, aCGH, and emerging genomic technologies of optical genome mapping (OGM) and nanopore long-read sequencing (LRS). Consistent with the previous literature, karyotyping and FISH indicated a modal number of 47, with t(8;9)(p12;p24) and trisomy 20 in analyzed metaphases. ACGH confirmed trisomy 20 apparent in the karyotype but also showed both an unbalanced der(5)t(5;14)(q35.2;q32.2) translocation, independently confirmed by FISH, and a 226-kb deletion at 10q23.31 containing the tumor suppressor gene PTEN, concordant with existing literature. Saphyr-based OGM analysis confirmed the aCGH data; however, OGM analysis additionally identified monosomy X (copy number fraction 1.579), which could arise from a subclonal population as previously reported, and the breakpoint at 8p11.21 as the true region of the balanced translocation. Strikingly, OGM also identified a novel likely pathogenic cryptic 81.9-kb deletion at 1p33 overlapping the STIL gene (80X coverage). Deletions of STIL are known to occur in T-cell leukemias although this aberration has not been described in the CCRF-CEM cell line. We are currently in the process of analyzing LRS data to validate OGM findings and determine precise deletion breakpoints. Collectively, our data have identified a novel chromosomal aberration in the CCRF-CEM cell line providing a framework for further functional characterization.

人类癌症细胞系是检测基因组改变和染色体畸变的宝贵模型，可用于鉴定和验证新的诊断或治疗靶点。在这里，我们利用核型分析、FISH、aCGH以及光学基因组图谱（OGM）和纳米孔长读序测序（LRS）等新兴基因组学技术，对T细胞急性淋巴细胞白血病（T-ALL）细胞系CCRF-CEM（ATCC #CCL-119）进行了重新定性。与以前的文献一致，核型分析和 FISH 显示的模态数为 47，在分析的分裂相中有 t(8;9)(p12;p24)和 20 三体。ACGH 证实了核型中明显的 20 三体综合征，但也显示了不平衡的 der(5)t(5;14)(q35.2;q32.2) 易位（经 FISH 独立证实），以及 10q23.31 处 226 kb 的缺失（包含肿瘤抑制基因 PTEN），与现有文献一致。基于 Saphyr 的 OGM 分析证实了 aCGH 数据；然而，OGM 分析还发现了单体 X（拷贝数分数 1.579），这可能来自于之前报道的亚克隆群体，而 8p11.21 断点则是平衡易位的真正区域。引人注目的是，OGM 还在 1p33 处发现了一个新的可能致病的 81.9-kb 缺失，与 STIL 基因重叠（覆盖率为 80X）。众所周知，STIL 基因缺失会发生在 T 细胞白血病中，但在 CCRF-CEM 细胞系中尚未发现这种畸变。我们目前正在分析 LRS 数据，以验证 OGM 的发现并确定精确的缺失断点。总之，我们的数据在 CCRF-CEM 细胞系中发现了一种新的染色体畸变，为进一步的功能鉴定提供了一个框架。

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引用次数: 0

51. Utility of microarray in the diagnosis of hematologic neoplasms with normal FISH and karyotype 51.微阵列在诊断 FISH 和核型正常的血液肿瘤中的作用

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.053

Marwa Daghsni, Taimoor Sheikh, Lynn H. Sniezek, Michaelia M. Austin, Mahmoud Aarabi, Svetlana Yatsenko

Chromosome analysis and fluorescence in situ hybridization (FISH) testing are the standard techniques in diagnosis, classification, and risk assessment of hematologic neoplasms such as myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), and chronic lymphocytic leukemia (CLL). Notably, the result of conventional cytogenetic testing is normal or non-informative in at least 10% of B-ALL, 50% of MDS/AML, and 15% of CLL cases, preventing accurate characterization of cancer genomic profile. Chromosomal microarray analysis (CMA) is widely used for detection of cryptic chromosomal imbalances and copy-neutral loss of heterozygosity, which are beyond the resolution of conventional cytogenetic methodologies. This study has evaluated the CMA utility and diagnostic yield in patients with an established diagnosis of either B-ALL, MDS/AML, or CLL, and negative findings of G-banding karyotype and disease-relevant FISH panel testing. During a 5-year period, karyotype, FISH and CMA were performed on 3628 samples, including 2720 cases of MDS/AML, 240 B-ALL and 668 CLL cases. At diagnosis normal karyotype and FISH were reported for 1466/2720 (54%) of patients with MDS/AML, 23/240 (9.6%) of B-ALL, and 112/668 (16.8%) of CLL cases. Using CMA, submicroscopic copy number alterations of diagnostic and prognostic significance were identified in 14.6% of MDS/AML cases, 26.1% of B-ALL, and 6.3% of CLL patients. Additionally, CMA revealed clones with large chromosomal abnormalities that were not observed among metaphase cells. Implementation of CMA in diagnosis of hematologic malignancies can significantly improve the diagnostic yield and provide data for a patient-specific risk stratification, prognostication, and therapeutic decisions.

染色体分析和荧光原位杂交（FISH）检测是诊断、分类和评估骨髓增生异常综合征（MDS）、急性髓性白血病（AML）、B 细胞急性淋巴细胞白血病（B-ALL）和慢性淋巴细胞白血病（CLL）等血液肿瘤风险的标准技术。值得注意的是，至少有 10% 的 B-ALL、50% 的 MDS/AML 和 15% 的 CLL 病例的常规细胞遗传学检测结果是正常或无信息的，这阻碍了癌症基因组特征的准确描述。染色体微阵列分析（CMA）被广泛用于检测隐性染色体失衡和拷贝中性杂合性缺失，这超出了传统细胞遗传学方法的分辨率。本研究对已确诊为 B-ALL、MDS/AML 或 CLL，且 G 带核型和疾病相关 FISH 面板检测结果为阴性的患者的 CMA 实用性和诊断率进行了评估。在 5 年的时间里，共对 3628 份样本进行了核型、FISH 和 CMA 检测，其中包括 2720 例 MDS/AML、240 例 B-ALL 和 668 例 CLL。在诊断时，有 1466/2720 例 MDS/AML 患者（54%）、23/240 例 B-ALL 患者（9.6%）和 112/668 例 CLL 患者（16.8%）的核型和 FISH 报告正常。利用 CMA，在 14.6% 的 MDS/AML 病例、26.1% 的 B-ALL 和 6.3% 的 CLL 患者中发现了具有诊断和预后意义的亚显微拷贝数改变。此外，CMA 还发现了在分裂期细胞中未观察到的染色体大面积异常的克隆。在血液系统恶性肿瘤的诊断中使用 CMA 可显著提高诊断率，并为患者的特定风险分层、预后和治疗决策提供数据。

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引用次数: 0

60. AI-guided histopathology predicts brain metastasis in lung cancer patients 60.人工智能引导下的组织病理学预测肺癌患者的脑转移

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.062

Brianna Munnich , Haowen Zhou , Mark Watson , Cory Bernadt , Steven (Siyu) Lin , Jon Ritter , Chieh-Yu Lin , Ramaswamy Govindan , Siddarth Rawal , Changhuei Yang , Richard Cote

Brain metastases can occur in nearly half of patients with early and locally advanced (stage I-III) non-small cell lung cancer (NSCLC). There are no reliable histopathologic or molecular means to identify those who are likely to develop brain metastases. We sought to determine if deep learning (DL) could be applied to routine hematoxylin and eosin (H&E) stained primary tumor tissue sections from Stage I-III NSCLC patients to predict the development of brain metastasis. Diagnostic slides from 158 patients with Stage I to III NSCLC followed for at least 5 years for development of brain metastases (Met+, 65 patients) versus no progression (Met-, 93 patients) were subjected to whole slide imaging. Three separate iterations of DL were performed by first selecting 118 cases (45 Met+, 73 Met-) to train and validate the DL algorithm, while 40 separate cases (20 Met+, 20 Met-) were used as the test set. DL algorithm results were compared to a blinded review by four expert pathologists. The DL-based algorithm was able to distinguish eventual development of brain metastases with an accuracy of 87% (p<0.0001) compared to an average of 57.3% by the four pathologists, and appears to be particularly useful in predicting brain metastases in Stage I patients. DL-based algorithms using routine H&E-stained slides may identify patients likely to develop brain metastases from those that will remain disease free over extended (>5 year) follow-up and may thus be spared systemic therapy.

近一半的早期和局部晚期（I-III 期）非小细胞肺癌（NSCLC）患者会发生脑转移。目前还没有可靠的组织病理学或分子方法来识别那些可能发生脑转移的患者。我们试图确定深度学习（DL）能否应用于 I-III 期 NSCLC 患者的常规苏木精和伊红（H&E）染色原发肿瘤组织切片，以预测脑转移的发生。对 158 名随访至少 5 年的 I 至 III 期 NSCLC 患者的诊断切片进行了全切片成像，这些患者均出现脑转移（Met+，65 人）或无进展（Met-，93 人）。首先选择 118 个病例（45 个 Met+，73 个 Met-）来训练和验证 DL 算法，然后分别选择 40 个病例（20 个 Met+，20 个 Met-）作为测试集，对 DL 算法进行了三次迭代。将 DL 算法结果与四位病理专家的盲审结果进行比较。与四位病理学家平均 57.3% 的准确率相比，基于 DL 的算法能够以 87% 的准确率（p<0.0001）区分脑转移的最终发展，而且似乎对预测 I 期患者的脑转移特别有用。使用常规H&E染色切片的基于DL的算法可以从那些在长期（>5年）随访中保持无病的患者中识别出可能发生脑转移的患者，从而避免全身治疗。

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引用次数: 0

Whole genome joint analysis reveals ATM:C.1564_1565del variant segregating with Ataxia-Telangiectasia and breast cancer 全基因组联合分析发现，ATM:C.1564_1565del 变体与共济失调-特朗吉特氏病和乳腺癌存在分离关系。

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.07.002

Mario Ćuk , Busra Unal , Connor P. Hayes , McKenzie Walker , Anđela Bevanda , Viktorija Antolović , Arezou A. Ghazani

ATM gene is implicated in the development of breast cancer in the heterozygous state, and Ataxia-telangiectasia (A-T) in a homozygous or compound heterozygous state. Ataxia-telangiectasia (A-T) is a rare cerebellar ataxia syndrome presenting with progressive neurologic impairment, telangiectasia, and an increased risk of leukemia and lymphoma.

Although the role of ATM, separately, in association with A-T and breast cancer is well documented, there is a limited number of studies investigating ATM variants when segregating with both phenotypes in the same family. Here, using joint analysis and whole genome sequencing, we investigated ATM c.1564_1565del in a family with one homozygous member presenting with A-T (OMIM # 208900) and three heterozygous members, of whom one had breast cancer (OMIM #114480). To our knowledge, this is the first study of ATM c.1564_1565del segregation with both A-T and breast cancer phenotypes within the same kindred. This study highlights the need for a comprehensive genomic approach in the appropriate cancer risk management of heterozygote carriers of ATM in families with A-T.

ATM基因的杂合状态与乳腺癌的发病有关，而共济失调-毛细血管扩张症（A-T）的同型或复合杂合状态则与乳腺癌的发病有关。共济失调-毛细血管扩张症（A-T）是一种罕见的小脑共济失调综合征，表现为进行性神经功能损害、毛细血管扩张以及白血病和淋巴瘤风险增加。尽管 ATM 在 A-T 和乳腺癌中的作用已得到充分证实，但对同一家族中同时出现这两种表型的 ATM 变异进行研究的数量有限。在这里，我们利用联合分析和全基因组测序，调查了一个家族中的 ATM c.1564_1565del，该家族中有一名同基因成员患有 A-T（OMIM # 208900），还有三名杂合成员，其中一人患有乳腺癌（OMIM #114480）。据我们所知，这是首次对同一家族中同时出现 A-T 和乳腺癌表型的 ATM c.1564_1565del 基因分离进行研究。这项研究强调，在对A-T家族中的ATM杂合子携带者进行适当的癌症风险管理时，需要采用全面的基因组学方法。

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引用次数: 0