Cancer Genetics最新文献

{"title":"68. ClinGen Cancer Variant Interpretation (CVI): Updates and recommendations on the ClinGen/CGC/VICC Oncogenicity SOP","authors":"Deborah Ritter ,&nbsp;Dmitriy Sonkin ,&nbsp;Malachi Griffith ,&nbsp;Obi Griffith ,&nbsp;Dean Pavlick ,&nbsp;Jason Saliba ,&nbsp;Morteza Seifi ,&nbsp;Gordana Raca ,&nbsp;Jason Rosenbaum ,&nbsp;Somak Roy ,&nbsp;Alex Wagner ,&nbsp;Shashikant Kulkarni ,&nbsp;Marilyn Li ,&nbsp;Sharon E. Plon","doi":"10.1016/j.cancergen.2024.08.070","DOIUrl":"10.1016/j.cancergen.2024.08.070","url":null,"abstract":"<div><div>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: <span><span>35101336</span><svg><path></path></svg></span>) 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.</div><div>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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S22"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323482","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}

{"title":"42. Piloting NTRK fusion-specific oncogenicity guidelines: Lessons learned","authors":"Jason Saliba ,&nbsp;Laura B. Corson ,&nbsp;Arpad Danos ,&nbsp;Shivani Golem ,&nbsp;Valentina Nardi ,&nbsp;Johanna Carroll ,&nbsp;Elan Hahn ,&nbsp;Theodore W. Laetsch ,&nbsp;Marilyn M. Li ,&nbsp;Obi L. Griffith ,&nbsp;Malachi Griffith ,&nbsp;Larissa V. Furtado ,&nbsp;Gordana Raca ,&nbsp;Alanna J. Church ,&nbsp;Angshumoy Roy","doi":"10.1016/j.cancergen.2024.08.044","DOIUrl":"10.1016/j.cancergen.2024.08.044","url":null,"abstract":"<div><div>Gene fusions involving neurotrophic receptor tyrosine kinase genes (<em>NTRK1, NTRK2</em>, &amp; <em>NTRK3</em>) 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 <em>NTRK</em> Fusions Somatic Cancer Variant Curation Expert Panel (SC-VCEP) is addressing these challenges and creating publicly available high-quality clinically significant <em>NTRK</em> fusion assertions in the CIViC (civicdb.org) knowledgebase to support patient care.</div><div>Our <em>NTRK</em> fusion-specific oncogenicity guidelines (approved April 2022) classify <em>NTRK</em> 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 <em>NTRK</em> 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 <em>NTRK</em>-positive tumors; 2) further clarifying <em>NTRK</em> fusion structure; 3) requiring fusions to be reported in the published literature, as databases sometimes lack vetting; 4) expanding the <em>NTRK</em>-associated tumor list. Future efforts will evaluate the clinical utility of these guidelines and improve our workflows and guidance.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S14"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323296","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}

{"title":"78. Next generation cytogenomics improves patient risk stratification in acute myeloid leukemia","authors":"Cecilia Yeung ,&nbsp;Maika Malig ,&nbsp;Emily Reister ,&nbsp;Mary Wood ,&nbsp;Alexander Muratov ,&nbsp;Ivan Liachko ,&nbsp;Stephen Eacker ,&nbsp;Olga Sala-Torra ,&nbsp;Jerald Radich ,&nbsp;Min Fang","doi":"10.1016/j.cancergen.2024.08.080","DOIUrl":"10.1016/j.cancergen.2024.08.080","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S25"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323333","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}

{"title":"14. Ethnic and molecular disparities in prostate adenocarcinoma incidence: Data from 19 cohort studies","authors":"Amy Brady ,&nbsp;Lisa C. Smith ,&nbsp;Scott C. Smith","doi":"10.1016/j.cancergen.2024.08.016","DOIUrl":"10.1016/j.cancergen.2024.08.016","url":null,"abstract":"<div><div>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 <em>PTEN</em> losses, and <em>FXA1</em> alterations are common irrespective of ethnicity. While <em>ERG</em> 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, <em>FOXA1, TP53</em>, and <em>SPOP</em> were among the most commonly altered genes in each ethnicity. Copy number alterations (CNAs) in 74 genes, including amplification of the antigen receptor gene (<em>AR</em>), 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 <em>ATRX, CDK12, FH, NF1</em>, and <em>RAD51D</em> that tended to co-mutate. Finally, 16 genes were found to be altered exclusively in a minority of the Asian population, including <em>BLM</em>, and <em>CHD2</em>. The described molecular differences may contribute to the ethnic disparities of PAC incidence.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S5"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323468","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}

{"title":"56. Variants of established clinical significance: Progress and challenges in the VECS SC-VCEP","authors":"Mariam Khanfar ,&nbsp;Jason Saliba ,&nbsp;Arpad Danos ,&nbsp;Nilan Patel ,&nbsp;Alexandra E. Kovach ,&nbsp;Cameron J. Grisdale ,&nbsp;Charles Mullighan ,&nbsp;Chimene Kesserwan ,&nbsp;Ian King ,&nbsp;Jason Merker ,&nbsp;Laveniya Satgunaseelan ,&nbsp;Rashmi Kanagal-Shamanna ,&nbsp;Ramaswamy Govindan ,&nbsp;Malachi Griffith ,&nbsp;Yassmine Akkari ,&nbsp;Obi Griffith","doi":"10.1016/j.cancergen.2024.08.058","DOIUrl":"10.1016/j.cancergen.2024.08.058","url":null,"abstract":"<div><div>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.</div><div>The VECS SC-VCEP will address a set of 15 genes: <em>BRAF, EGFR, ERBB2, ESR1, EZH2, FGFR3, FLT3, IDH1, IDH2, KIT, KRAS, MET, NRAS, PIK3CA,</em> and <em>RET</em>. 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.</div><div>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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S18"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323475","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}

{"title":"65. Creating a common language for categorical variants","authors":"Daniel Puthawala ,&nbsp;Wesley Goar ,&nbsp;Brendan Reardon ,&nbsp;Salem Bajjali ,&nbsp;Kori Kuzma ,&nbsp;James Stevenson ,&nbsp;Parijat Kundu ,&nbsp;Catherine Procknow ,&nbsp;Robert Dolin ,&nbsp;Beth Pitel ,&nbsp;Robert Freimuth ,&nbsp;Lawrence Babb ,&nbsp;Alex Wagner","doi":"10.1016/j.cancergen.2024.08.067","DOIUrl":"10.1016/j.cancergen.2024.08.067","url":null,"abstract":"<div><div>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.</div><div>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.</div><div>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.</div><div>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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S21"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323477","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}

{"title":"23. Detection of somatic tumor mutations in circulating plasma DNA of patients with sellar and skull base tumors","authors":"Mallory Tucker,&nbsp;Eric Lassiter,&nbsp;Shruthi Kondaboina","doi":"10.1016/j.cancergen.2024.08.025","DOIUrl":"10.1016/j.cancergen.2024.08.025","url":null,"abstract":"<div><div>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 <em>CSPG4</em> and <em>GOLGA6L9</em> 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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S8"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323387","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}

{"title":"25. Enhancing precision oncology: The value of open-source knowledgebase integration","authors":"Cameron Grisdale ,&nbsp;Erin Pleasance ,&nbsp;Connor Frey ,&nbsp;Caralyn Reisle ,&nbsp;Laura Williamson ,&nbsp;Jing Xu ,&nbsp;Veronika Csizmok ,&nbsp;John Dupuis ,&nbsp;Kathleen Wee ,&nbsp;Yaoqing Shen ,&nbsp;Zakhar Krekhno ,&nbsp;Melika Bonakdar ,&nbsp;Greg Taylor ,&nbsp;Asmita Jain ,&nbsp;Melissa McConechy ,&nbsp;Kilannin Krysiak ,&nbsp;Jason Saliba ,&nbsp;Arpad Danos ,&nbsp;Adam Coffman ,&nbsp;Susanna Kiwala ,&nbsp;Steven Jones","doi":"10.1016/j.cancergen.2024.08.027","DOIUrl":"10.1016/j.cancergen.2024.08.027","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S8"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323389","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}

{"title":"67. An undiagnosed chronic myeloid leukemia (CML) with p190 BCR::ABL1 transcript, an extra Philadelphia chromosome, and IKARO","authors":"Fabiola Quintero-Rivera,&nbsp;Sumayya Aslam,&nbsp;Lynn Yang,&nbsp;Johnson Tso,&nbsp;Melissa Lyon,&nbsp;Katherine Dang,&nbsp;Ying Zhang,&nbsp;Kiran Naqvi,&nbsp;Sherif Rezk","doi":"10.1016/j.cancergen.2024.08.069","DOIUrl":"10.1016/j.cancergen.2024.08.069","url":null,"abstract":"<div><div>Chronic myeloid leukemia (CML) with p190 <em>BCR::ABL1</em> transcript is rare but when present, it is usually associated with increased monocytes. <em>IKZF1</em>, 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 <em>BCR::ABL1</em> 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 <em>IKZF1</em> 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 <em>IKZF1</em> 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 <em>IKZF1/ BCR::ABL1</em> results led to a diagnosis of a preceding CML presenting in lymphoid blast crisis. Patient is undergoing initial</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Pages S21-S22"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323396","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}

{"title":"10. Standardizing fusion calls in a computable format with FUSOR for downstream clinical assessment","authors":"Jeremy A. Arbesfeld ,&nbsp;James S. Stevenson ,&nbsp;Kathryn Stahl ,&nbsp;Kori Kuzma ,&nbsp;Alex H. Wagner","doi":"10.1016/j.cancergen.2024.08.012","DOIUrl":"10.1016/j.cancergen.2024.08.012","url":null,"abstract":"<div><div>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.</div><div>We tested use of FUSOR on patient sample data through development of a Translator module (<span><span>http://tinyurl.com/FUSOR-Translator</span><svg><path></path></svg></span>) 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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S4"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323462","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}