Cancer Genetics最新文献_第8页

68. ClinGen Cancer Variant Interpretation (CVI): Updates and recommendations on the ClinGen/CGC/VICC Oncogenicity SOP 68.ClinGen 癌症变异解释 (CVI)：ClinGen/CGC/VICC致癌性标准操作程序的更新和建议

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.070

Deborah Ritter , Dmitriy Sonkin , Malachi Griffith , Obi Griffith , Dean Pavlick , Jason Saliba , Morteza Seifi , Gordana Raca , Jason Rosenbaum , Somak Roy , Alex Wagner , Shashikant Kulkarni , Marilyn Li , Sharon E. Plon

The Clinical Genome Resource (ClinGen) Somatic Cancer Variant Interpretation Committee (CVI) provides oversight and recommendations in the expert panel process for ClinGen Somatic Cancer Variant Curation Expert Panels (SC-VCEPs). SC-VCEP use of the Oncogenicity SOP (PMID: 35101336) provides critical clarity where modifications (SOP changes), recommendations (CVI guidance), or specifications (SC-VCEP gene/cancer-specific use) are needed. We summarize SC-VCEP Oncogenicity SOP use informing guideline development. For example, Histone H3 SC-VCEP highlighted the need to incorporate classic phenotypes by creating a supporting evidence code (OP5). The CVI requested testing phenotype specificity within OP2, leading to developing recommendations on OP2 extended use. Conversely, if SC-VCEPs specify thresholds or alternative databases for cancer hotspots, these specifications are within the SC-VCEP scope and are not general CVI recommendations or modifications to the Oncogenicity SOP.

Additional work includes CVI developing guidance for using in-silico predictors (OP1). We are investigating two commonly used predictors - REVEL and FATHMM - that operate by distinct random forest ensemble prediction algorithms and the Hidden Markov model, respectively. On a small variant set from the Oncogenicity SOP manuscript, manually curated 'true' oncogenic GOF and LOF variants displayed modest but significant differences in REVEL scores and larger differences in FATHMM, with potential discriminatory applications. We will report on scaling this comparison as well as general-use considerations. In addition, we share updates and seek community feedback on incorporating detailed functional data (OS2) in the Oncogenicity SOP as well as considering structured text for the curation of resistance variants.

临床基因组资源（ClinGen）体癌变异解释委员会（ClinGen Somatic Cancer Variant Interpretation Committee，CVI）在专家小组程序中为 ClinGen 体癌变异鉴定专家小组（SC-VCEP）提供监督和建议。SC-VCEP 对致癌 SOP（PMID: 35101336）的使用为需要修改（SOP 更改）、建议（CVI 指导）或规范（SC-VCEP 基因/癌症特异性使用）的地方提供了重要的清晰度。我们总结了 SC-VCEP 肿瘤基因 SOP 的使用情况，为指南的制定提供参考。例如，组蛋白 H3 SC-VCEP 强调需要通过创建辅助证据代码 (OP5) 来纳入经典表型。CVI 要求在 OP2 中检测表型特异性，从而制定了 OP2 扩展使用建议。反之，如果 SC-VCEP 为癌症热点指定了阈值或替代数据库，则这些说明属于 SC-VCEP 的范围，不属于 CVI 的一般建议或对肿瘤致病性 SOP 的修改。我们正在研究两种常用的预测因子--REVEL 和 FATHMM，它们分别采用不同的随机森林集合预测算法和隐马尔可夫模型。在 "致癌 SOP "手稿中的一个小型变异集上，人工策划的 "真正 "致癌 GOF 和 LOF 变异在 REVEL 分数上显示出适度但显著的差异，而在 FATHMM 中则显示出更大的差异，具有潜在的鉴别应用价值。我们将报告这一比较的扩展情况以及一般使用方面的考虑。此外，我们还将分享在致癌 SOP 中纳入详细功能数据 (OS2) 的最新进展，并征求社区的反馈意见，同时考虑将结构化文本用于抗性变异的整理。

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引用次数: 0

42. Piloting NTRK fusion-specific oncogenicity guidelines: Lessons learned 42.试行 NTRK 融合特异性致癌指南：经验教训

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.044

Jason Saliba , Laura B. Corson , Arpad Danos , Shivani Golem , Valentina Nardi , Johanna Carroll , Elan Hahn , Theodore W. Laetsch , Marilyn M. Li , Obi L. Griffith , Malachi Griffith , Larissa V. Furtado , Gordana Raca , Alanna J. Church , Angshumoy Roy

Gene fusions involving neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, & NTRK3) are well-established oncogenic drivers and important diagnostic and therapeutic markers in cancers. Interpreting their clinical significance is a high priority given FDA approval of TRK inhibitors (e.g, larotrectinib and entrectinib), but remains challenging due to rapid fusion discovery, diversity of fusion partners and tumor types, and lack of fusion-specific classification rules. The ClinGen NTRK Fusions Somatic Cancer Variant Curation Expert Panel (SC-VCEP) is addressing these challenges and creating publicly available high-quality clinically significant NTRK fusion assertions in the CIViC (civicdb.org) knowledgebase to support patient care.

Our NTRK fusion-specific oncogenicity guidelines (approved April 2022) classify NTRK fusions as Oncogenic, Likely Oncogenic, Unknown Significance (VUS), or Benign based on Fusion Structure (orientation/breakpoints/reading frame), Cancer Association (number of unique cases), Clinical Validity (targeted inhibitor response), and Functional Status (pathway activation or expression). Pilot guideline application to a range of common to rare NTRK fusions found in cancers resulted in 11 Oncogenic Assertions (6 Oncogenic, 1 Likely Oncogenic, 4 VUS), 5 Diagnostic Assertions, and 10 Predictive Assertions supporting sensitivity to larotrectinib or entrectinib. This pilot introduced several modifications including: 1) reducing case number required to reach cancer association or clinical validity due to the rarity of reported NTRK-positive tumors; 2) further clarifying NTRK fusion structure; 3) requiring fusions to be reported in the published literature, as databases sometimes lack vetting; 4) expanding the NTRK-associated tumor list. Future efforts will evaluate the clinical utility of these guidelines and improve our workflows and guidance.

涉及神经营养受体酪氨酸激酶基因（NTRK1、NTRK2、& NTRK3）的基因融合是公认的致癌驱动因素，也是癌症的重要诊断和治疗标志物。鉴于美国食品药品管理局（FDA）批准了 TRK 抑制剂（如 larotrectinib 和 entrectinib），解释其临床意义成为当务之急，但由于融合发现速度快、融合伙伴和肿瘤类型多样以及缺乏融合特异性分类规则，解释其临床意义仍具有挑战性。ClinGen NTRK融合体细胞癌变异保藏专家小组（SC-VCEP）正在应对这些挑战，并在CIViC (civicdb.org)知识库中创建公开可用的高质量临床重要NTRK融合论断，以支持患者护理。我们的NTRK融合特异性致癌指南（2022年4月获批）根据融合结构（方向/断点/读取框）、癌症关联（独特病例数）、临床有效性（靶向抑制剂反应）和功能状态（通路激活或表达）将NTRK融合分为致癌、可能致癌、意义不明（VUS）或良性。对癌症中发现的一系列常见到罕见的 NTRK 融合体应用试点指南，得出了 11 项致癌论断（6 项致癌、1 项可能致癌、4 项 VUS）、5 项诊断论断和 10 项预测论断，支持对拉罗替尼或恩替替尼的敏感性。该试点引入了几项修改，包括1）由于报告的 NTRK 阳性肿瘤很少见，因此减少了达到癌症关联性或临床有效性所需的病例数；2）进一步明确了 NTRK 融合结构；3）由于数据库有时缺乏审查，因此要求融合必须在发表的文献中报告；4）扩大了 NTRK 相关肿瘤列表。未来的工作将评估这些指南的临床实用性，并改进我们的工作流程和指南。

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引用次数: 0

78. Next generation cytogenomics improves patient risk stratification in acute myeloid leukemia 78.新一代细胞基因组学改进了急性髓性白血病患者的风险分层

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.080

Cecilia Yeung , Maika Malig , Emily Reister , Mary Wood , Alexander Muratov , Ivan Liachko , Stephen Eacker , Olga Sala-Torra , Jerald Radich , Min Fang

The European Leukemia Network (ELN) has established criteria for patient risk stratification based on cytogenetic abnormalities in observed in acute myeloid leukemia (AML). Risk stratification based on cytogenetic analysis is commonly used to guide therapy selection and overall patient care. Proximity ligation sequencing (PLS) is a next generation cytogenomic method that uses short-read NGS to capture ultra-long-range genomic contiguity and detect chromosome abnormalities including those in the ELN risk stratification. To test the utility of PLS in evaluating cytogenetic risk in AML, we performed a retrospective study of AML cases gathered from clinical archives. In all, libraries from 95 samples were prepared using the OncoTerra PLS library preparation kit and sequenced on one of three platforms: Illumina, Element, or Singular short-read sequencing platforms. Libraries sequenced across all three platforms passed QC metrics for library performance. Patient risk based on variants identified by the OncoTerra PLS analytic platform and the reported standard-of-care cytogenetics were assessed following the ELN 2022 guidelines. The predictive power of OncoTerra and standard-of-care cytogenetics were evaluated based on the overall survival of patients segregated into favorable, intermediate, and adverse risk categories. Statistical comparison of Kaplan-Meier analysis between OncoTerra and standard-of-care cytogenetics demonstrated that PLS significantly improved the segregation of patient outcomes across risk groups. These findings show that PLS has the potential significantly improve cytogenetic risk stratification within the context of established ELN risk variants for AML using short-read sequencing platforms.

欧洲白血病网络（ELN）根据观察到的急性髓性白血病（AML）细胞遗传学异常，制定了患者风险分层标准。基于细胞遗传学分析的风险分层通常用于指导治疗选择和整体患者护理。近接测序（PLS）是一种下一代细胞基因组学方法，它使用短线程 NGS 捕获超长程基因组连续性并检测染色体异常，包括 ELN 风险分层中的染色体异常。为了测试 PLS 在评估急性髓细胞性白血病细胞遗传学风险方面的实用性，我们对临床档案中收集的急性髓细胞性白血病病例进行了回顾性研究。我们使用 OncoTerra PLS 文库制备试剂盒制备了 95 份样本的文库，并在三种平台之一上进行了测序：Illumina、Element或Singular短线程测序平台。在所有三个平台上测序的文库都通过了文库性能 QC 指标。根据 OncoTerra PLS 分析平台确定的变异和报告的标准护理细胞遗传学，按照 ELN 2022 指南评估了患者风险。OncoTerra 和标准护理细胞遗传学的预测能力根据患者的总生存期进行评估，患者被分为有利、中等和不利风险类别。通过对 OncoTerra 和标准护理细胞遗传学的 Kaplan-Meier 分析进行统计比较，结果表明 PLS 显著改善了不同风险类别患者的预后。这些研究结果表明，在使用短线程测序平台对急性髓细胞性白血病进行ELN风险变异的情况下，PLS有可能显著改善细胞遗传学风险分层。

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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

14. Ethnic and molecular disparities in prostate adenocarcinoma incidence: Data from 19 cohort studies 14.前列腺癌发病率的种族和分子差异：来自 19 项队列研究的数据

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.016

Amy Brady , Lisa C. Smith , Scott C. Smith

Prostate cancer is the most commonly occurring cancer in males overall, but ethnicity is a strong predictor of incidence. African and non-Hispanic Caucasian ethnicities possess the highest incidences, while those of Asian, East-Asian, and Indigenous peoples have the lowest. Comparisons between the genomic alterations of Asian, African, and non-Hispanic Caucasian (nHC) ethnicities have indicated that PTEN losses, and FXA1 alterations are common irrespective of ethnicity. While ERG deletions are less common in Asian populations, compared to African and nHC ethnicities. The ethnic contribution to prostate adenocarcinoma (PAC) was further evaluated using the cBioPortal Genomics data tool from Memorial Sloan Kettering (MSK). An evaluation of Asian (East Asian/Asian; N=131), African (N=165), and nHC (N=3,642) from 19 cohort studies, totaling 3,938 individuals, was undertaken. Overall survival outcomes were highest for nHC, individuals followed by African individuals. Comparative hazard ratios were highest for Asian individuals at 1.6. Expectedly, FOXA1, TP53, and SPOP were among the most commonly altered genes in each ethnicity. Copy number alterations (CNAs) in 74 genes, including amplification of the antigen receptor gene (AR), were significantly enriched in Asian PAC (p=4.6 × 10-3). CNAs in 14 driver genes were enriched in Asians and tended to be co-altered. Mutations in 66 genes were enriched in Asians, including in mutations in ATRX, CDK12, FH, NF1, and RAD51D that tended to co-mutate. Finally, 16 genes were found to be altered exclusively in a minority of the Asian population, including BLM, and CHD2. The described molecular differences may contribute to the ethnic disparities of PAC incidence.

前列腺癌是男性最常见的癌症，但种族是预测发病率的一个重要因素。非洲裔和非西班牙裔高加索人的发病率最高，而亚裔、东亚裔和土著人的发病率最低。对亚裔、非裔和非西班牙裔高加索人（nHC）的基因组改变进行比较后发现，PTEN缺失和FXA1改变与种族无关。与非洲裔和非西班牙裔白种人相比，ERG缺失在亚裔人群中并不常见。我们使用纪念斯隆-凯特琳癌症中心（MSK）的 cBioPortal 基因组学数据工具进一步评估了前列腺腺癌（PAC）的种族贡献。对19项队列研究中的亚洲人（东亚人/亚洲人；N=131）、非洲人（N=165）和nHC（N=3642）共3938人进行了评估。非裔健康人的总体存活率最高，其次是非洲人。亚洲人的比较危险比最高，为 1.6。在每个种族中，FOXA1、TP53 和 SPOP 是最常见的改变基因。74 个基因的拷贝数改变（CNA），包括抗原受体基因（AR）的扩增，在亚裔 PAC 中明显富集（p=4.6 × 10-3）。14 个驱动基因中的 CNAs 在亚洲人中富集，并有共同改变的趋势。66 个基因的突变在亚裔中富集，包括 ATRX、CDK12、FH、NF1 和 RAD51D 的突变，这些基因往往发生共同突变。最后，有 16 个基因只在少数亚洲人中发生改变，包括 BLM 和 CHD2。上述分子差异可能是造成 PAC 发病率种族差异的原因之一。

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引用次数: 0

56. Variants of established clinical significance: Progress and challenges in the VECS SC-VCEP 56.具有确定临床意义的变异：VECS SC-VCEP 的进展与挑战

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.058

Mariam Khanfar , Jason Saliba , Arpad Danos , Nilan Patel , Alexandra E. Kovach , Cameron J. Grisdale , Charles Mullighan , Chimene Kesserwan , Ian King , Jason Merker , Laveniya Satgunaseelan , Rashmi Kanagal-Shamanna , Ramaswamy Govindan , Malachi Griffith , Yassmine Akkari , Obi Griffith

The ClinGen Somatic Clinical Domain Working Group is working to develop and implement standards and guidelines for the curation of clinically significant cancer variants for new and emerging actionable genes. Characterizing variants with established clinical significance, especially predictive biomarkers and genomic variants with FDA-approved companion diagnostics classified under the AMP/ASCO/CAP Tier 1A category is of particular interest. However, interpreting such variants can present challenges due to insufficient detail in both the literature and FDA documentation, inadequate characterization of their function, direct correlation with disease, and associated therapeutic response. To address these challenges, the Variant of Established Clinical Significance (VECS) SC-VCEP was established to curate and maintain a comprehensive database of clinically significant somatic variants.

The VECS SC-VCEP will address a set of 15 genes: BRAF, EGFR, ERBB2, ESR1, EZH2, FGFR3, FLT3, IDH1, IDH2, KIT, KRAS, MET, NRAS, PIK3CA, and RET. Alterations in these genes are known drivers in various types of cancer and consist of SNVs, small indels, and exon loss. The VECS is piloting the ClinGen/VICC/CGC oncogenicity SOP and AMP/ASCO/CAP guidelines, focusing on 17 variants from 9 genes. The set of variants includes both well-studied and poorly characterized variants, variants that confer both resistance and sensitivity to FDA-approved drugs, and includes one representative gene from known pathways.

The VECS will determine the applicability of existing SOP codes and identify instances where additional criteria might be necessary for accurate code assignment. This initiative will ultimately provide publicly-available and high-quality oncogenic and predictive assertions to be utilized by clinicians and researchers.

ClinGen 体细胞临床领域工作组正致力于制定和实施有关标准和指南，以便对具有临床意义的新出现的可操作基因癌症变异进行整理。对已确定具有临床意义的变异，特别是预测性生物标记物和已获得 FDA 批准的辅助诊断（归入 AMP/ASCO/CAP Tier 1A 类别）的基因组变异进行特征描述尤其令人感兴趣。然而，由于文献和 FDA 文件不够详细，对其功能、与疾病的直接相关性和相关治疗反应的描述也不充分，解释这类变异可能会面临挑战。为了应对这些挑战，我们建立了具有确定临床意义的变异（VECS）SC-VCEP，以策划和维护一个具有临床意义的体细胞变异综合数据库：VECS SC-VCEP 将处理一组 15 个基因：BRAF、EGFR、ERBB2、ESR1、EZH2、FGFR3、FLT3、IDH1、IDH2、KIT、KRAS、MET、NRAS、PIK3CA 和 RET。这些基因的改变是各种类型癌症的已知驱动因素，包括 SNV、小嵌合和外显子缺失。VECS 正在试行 ClinGen/VICC/CGC 致癌 SOP 和 AMP/ASCO/CAP 指南，重点关注 9 个基因中的 17 个变异。VECS 将确定现有 SOP 编码的适用性，并找出准确分配编码可能需要额外标准的情况。该计划最终将为临床医生和研究人员提供可公开获取的高质量致癌和预测论断。

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引用次数: 0

65. Creating a common language for categorical variants 65.为分类变量创建共同语言

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.067

Daniel Puthawala , Wesley Goar , Brendan Reardon , Salem Bajjali , Kori Kuzma , James Stevenson , Parijat Kundu , Catherine Procknow , Robert Dolin , Beth Pitel , Robert Freimuth , Lawrence Babb , Alex Wagner

Categorical variants serve an indispensable role in genomic knowledgebases to represent discrete classes of genomic variation. Despite their role linking classes to genomic evidence, their usefulness is undermined by confusion about and inconsistent use of categorical variant labels and class membership criteria.

Multiple labels may exist for the same class of variants, such as a {gene} deletion interchangeably labeled as a {gene} loss. In other cases, a single label is applied to multiple distinct classes of variants, as when {gene} loss could denote either a copy number loss or a loss-of-function. These cases underscore the challenge of our current state where categorical variants are fraught with ambiguity.

The Global Alliance for Genomics and Health (GA4GH) Categorical Variation Working Group is developing the Categorical Variation Representation Specification (Cat-VRS) to alleviate these issues. The Cat-VRS describes categorical variants by the concrete properties common to the class of assayed variants they represent. Applying the Cat-VRS to the example above, a sequence variant showing a lack of the gene indicates deletion of that gene and is therefore a copy number loss. This is distinct from a loss of gene product with no corresponding sequence deletion that unambiguously characterizes a loss-of-function variant.

As an unambiguous and computable representation standard, Cat-VRS will improve knowledgebase search and curation, and support the development of automated tools for knowledgebase harmonization and clinical variant analysis. This specification aims to supersede VRSATILE as a representation standard for categorical variation.

分类变异在基因组知识库中扮演着不可或缺的角色，它代表着离散的基因组变异类别。尽管分类变异具有将类别与基因组证据联系起来的作用，但由于对分类变异标签和类别成员资格标准的混淆和使用不一致，它们的作用被削弱了。同一类别的变异可能存在多个标签，如{基因}缺失可交替标记为{基因}缺失。在其他情况下，一个标签适用于多个不同类别的变异，如{基因}缺失既可表示拷贝数缺失，也可表示功能缺失。全球基因组学与健康联盟（GA4GH）分类变异工作组正在开发分类变异表示规范（Cat-VRS），以缓解这些问题。Cat-VRS 通过分类变异所代表的检测变异类别的共同具体属性来描述分类变异。将 Cat-VRS 应用于上面的例子，显示基因缺失的序列变异表示该基因缺失，因此是拷贝数缺失。作为一种明确且可计算的表示标准，Cat-VRS 将改进知识库的搜索和整理，并支持知识库协调和临床变异分析自动化工具的开发。该规范旨在取代 VRSATILE，成为分类变异的表示标准。

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引用次数: 0

23. Detection of somatic tumor mutations in circulating plasma DNA of patients with sellar and skull base tumors 23.检测蝶鞍和颅底肿瘤患者循环血浆 DNA 中的体细胞肿瘤突变

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.025

Mallory Tucker, Eric Lassiter, Shruthi Kondaboina

The use of cell-free DNA (cfDNA) as a liquid biopsy is a promising clinical tool that allows for earlier detection of cancer, advanced therapeutic monitoring, and can even predict treatment outcomes. Its feasibility has been shown in lung, breast and prostate cancers, but there is a lack of investigation in rare CNS tumors which present unique challenges in treatment and surgical accessibility. Preoperative profiling of these tumors could help guide personalized treatment options. We performed Whole Exome Sequencing (WES) on matched plasma cell-free DNA and tumor DNA of 15 patients with CNS tumors resected at the University of Washington Medical Center. This cohort includes pituitary neuroendocrine tumors (pitNETs) which are the most common intracranial neoplasms, as well as rare tumors- craniopharyngiomas and recurrent and high-grade meningiomas. Somatic variant calling revealed an average of 368 mutations in the tumors alone, while cfDNA from the plasma harbored an average of 298,839 somatic mutations. We compared the genomic profiles of cfDNA and the respective tumor sample. A total of 11 exonic non-synonymous variants (7 SNVs, 4 INDELs) in 9 different genes were detected in matched cfDNA and tumor. Mutations on the CSPG4 and GOLGA6L9 genes were validated in 13 samples of a larger cohort of PitNET genomic DNA (n=66) and may serve as potential markers for pitNETs and their subtypes. Here we show that somatic shared somatic mutations in cfDNA and matching tumor tissue can be successfully identified through WES, demonstrating that liquid biopsy might be a feasible approach for PitNETs.

使用无细胞 DNA（cfDNA）作为液体活检是一种很有前景的临床工具，它可以更早地检测癌症、进行先进的治疗监测，甚至可以预测治疗结果。其可行性已在肺癌、乳腺癌和前列腺癌中得到证实，但对罕见的中枢神经系统肿瘤还缺乏研究，这些肿瘤在治疗和手术可及性方面存在独特的挑战。对这些肿瘤进行术前分析有助于指导个性化治疗方案。我们对在华盛顿大学医学中心切除的 15 名中枢神经系统肿瘤患者的匹配血浆无细胞 DNA 和肿瘤 DNA 进行了全外显子组测序（WES）。这些患者包括垂体神经内分泌肿瘤（pitNETs）（这是最常见的颅内肿瘤）以及罕见肿瘤--颅咽管瘤和复发性高级别脑膜瘤。体细胞变异调用显示，仅肿瘤就平均存在368个突变，而血浆中的cfDNA平均存在298,839个体细胞突变。我们比较了 cfDNA 和相应肿瘤样本的基因组图谱。在匹配的cfDNA和肿瘤中，共检测到9个不同基因的11个外显子非同义变异（7个SNV，4个INDEL）。CSPG4和GOLGA6L9基因上的变异在一个更大的PitNET基因组DNA样本群（n=66）的13个样本中得到了验证，可作为pitNET及其亚型的潜在标记物。我们在此表明，通过 WES 可以成功鉴定 cfDNA 和匹配肿瘤组织中的共享体细胞突变，这表明液体活检可能是治疗 PitNET 的一种可行方法。

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引用次数: 0

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