Cancer Genetics最新文献

{"title":"34. Identifying challenges in variant normalization","authors":"Anastasia Bratulin ,&nbsp;Wesley A. Goar ,&nbsp;Kori Kuzma ,&nbsp;Lawrence Babb ,&nbsp;Kyle Ferriter ,&nbsp;Terry O'Neill ,&nbsp;Austin A. Antoniou ,&nbsp;Jeremy A. Arbesfeld ,&nbsp;Daniel Puthawala ,&nbsp;James S. Stevenson ,&nbsp;Jiachen Liu ,&nbsp;Xuelu Liu ,&nbsp;Brian Walsh ,&nbsp;William C. Ray ,&nbsp;Savanna Funk ,&nbsp;Bimal P. Chaudhari ,&nbsp;Heidi L. Rehm","doi":"10.1016/j.cancergen.2024.08.036","DOIUrl":"10.1016/j.cancergen.2024.08.036","url":null,"abstract":"<div><div>Genomic medicine relies on collecting information from multiple sources to make optimal therapeutic and diagnostic decisions for the patient. However, integration of this information, at the time of variant interpretation, is a major bottleneck. Challenges including inconsistent formats (e.g. HGVS and SPDI), and variant contexts (genome and proteome), increase the time and effort required to formulate and communicate a complete variant interpretation. To more clearly understand inter-resource differences in variant representation, variants from the Clinical Interpretations of Variants in Cancer (CIViC), Molecular Oncology Almanac (MOAlmanac), and ClinVar were evaluated using a normalization protocol. Of the variants in the knowledgebases, ∼53% of the CIViC, ∼42% of the MOAlmanac, and ∼99% of ClinVar variants were successfully normalized. We categorically assessed remaining variants for which normalization methods are still needed, and analyzed these for clinical impact. Gene fusion (e.g. 'ALK G1202R') and region-defined variant categories (e.g. '3′ UTR Mutations') respectively constitute 16% and 10% of all the variants that were not normalized, and were found to hold the greatest potential clinical impact. Additionally, fusion variants are responsible for ∼25% of all of the evidence items associated with not normalized variants from CIViC and MOAlmanac, illustrating the weight that fusion variants carry in the overall group. The Variation Normalizer is an open-source toolkit and is available for use with independent data sets to facilitate precise matching of evidence from knowledgebases to genomic variant data.</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":"142323288","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":"43. Challenges of classifying variants associated with disorders of somatic mosaicism and guideline creation","authors":"Alexa Dickson,&nbsp;Kevin Bowling,&nbsp;Fernando Zazueta,&nbsp;Yang Cao","doi":"10.1016/j.cancergen.2024.08.045","DOIUrl":"10.1016/j.cancergen.2024.08.045","url":null,"abstract":"<div><div>Disorders of somatic mosaicism (DoSM) constitute rare genetic disorders characterized by post-zygotic events leading to segmental distribution of disease. The early presentation of associated phenotypes often mimics germline diseases, complicating molecular diagnosis. Additionally, current guidelines from the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) focus specifically on germline and cancer variants, complicating the interpretation of DoSM-associated somatic variation. The ClinGen Brain Malformation Expert Panel guidelines have created valuable updates to account for brain-specific disorders of somatic mosaicism, but their applicability to the diverse DoSM presentations is limited. At Washington University School of Medicine, we have identified shortcomings in applying ACMG/AMP germline guidelines to DoSM variants, prompting the development of DoSM-specific variant interpretation guidelines. Leveraging our laboratory's extensive experience in somatic variation interpretation, we have developed DoSM guidelines that are applicable across genes and clinical contexts pertinent to non-cancerous somatic testing. These guidelines address the critical need for accurate somatic variant interpretation in DoSM, where treatment advances hinge on understanding the overlap between somatic variants in DoSM and tumors. This comprehensive framework addresses the gap in existing guidelines, offering an iinvaluable resource for clinical laboratories engaged in non-cancerous somatic testing and advancing precision medicine for patients with DoSM. We will present the developed guidelines, discuss challenges specific to DoSM and criteria development, and interesting cases studies where DoSM-specific guidelines were critical to accurate diagnosis.</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":"142323297","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":"62. Characterization of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with KMT2A amplification","authors":"John O'Shea,&nbsp;Jian Zhao,&nbsp;Erica Andersen,&nbsp;Bo Hong","doi":"10.1016/j.cancergen.2024.08.064","DOIUrl":"10.1016/j.cancergen.2024.08.064","url":null,"abstract":"<div><div><em>KMT2A</em> amplification is a rare high risk cytogenetic abnormality in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), which has been associated with complex karyotype, resistance to chemotherapy and higher frequency in elderly patients. Comprehensive elucidation of cytogenetic signatures in AML/MDS with <em>KMT2A</em> amplification, the subsequent clinical impact, as well as accompanying gene mutation profile would be beneficial for stratified patient care.</div><div>Herein, we present karyotyping/fluorescence in situ hybridization (FISH) data on 42 AML/MDS patients with <em>KMT2A</em> amplification, along with next generation sequencing (NGS) results and prognostic information in a subset of patients. The median age at diagnosis was 70 years. The male to female ratio was 1.8 (27:15). The median survival was 45 days. <em>KMT2A</em> amplification was identified by FISH. Chromosome analysis showed complex karyotype in all cases analyzed (n=38). The structural mechanisms associated with <em>KMT2A</em> amplification included homogeneously staining region (n=27), double minutes (n=6) and ring chromosome 11 (n=8). Deletions of 5q (64%) and 17p (62%) were the most common concurrent cytogenetic findings. Additional major concurrent cytogenetic abnormalities included loss of 7q (31%) and gain of chromosome 8 (29%). NGS results were available for 14 cases and <em>TP53</em> mutation was the most common alteration (n=12). Other mutations were detected in <em>TET2</em> (n=2), <em>NSD1</em> (n=2), <em>SAMD9L</em> (n=2), <em>DNMT3A</em> (n=1), <em>U2AF2</em> (n=1), <em>FLT3</em> (TKD, n=1), <em>NOTCH1</em> (n=1) and <em>SMC3</em> (n=1).</div><div>AML/MDS with <em>KMT2A</em> amplification is associated with poor outcome and specific concurrent cytogenetic and molecular abnormalities. Documenting additional data is valuable for improving the treatment landscape in these myeloid neoplasms.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S20"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323478","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":"39. Modifying cancer variant interpretation guidelines for the curation of histone H3 variants: The 'next step' of the Cl","authors":"Laveniya Satgunaseelan ,&nbsp;Somak Roy ,&nbsp;Shivani Golem ,&nbsp;Jianling Ji ,&nbsp;Yassmine Akkari ,&nbsp;Elizabeth Spiteri ,&nbsp;Arpad Danos ,&nbsp;Wan-Hsin Lin ,&nbsp;Cameron Grisdale ,&nbsp;Obi Griffith ,&nbsp;Malachi Griffith ,&nbsp;Jason Saliba ,&nbsp;David Meredith","doi":"10.1016/j.cancergen.2024.08.041","DOIUrl":"10.1016/j.cancergen.2024.08.041","url":null,"abstract":"<div><div>Histone H3 variants pose numerous challenges for curation due to varied nomenclature for their isoforms and encoding genes. These are further compounded by the tumor-specific settings in which histone H3 variants occur. Therefore, the Histone H3 SC-VCEP aimed to adapt and modify the ClinGen/CGC/VICC Oncogenicity SOP and AMP/ASCO/CAP guidelines for the interpretation of H3 variants specific to diffuse midline glioma, H3 K27-altered and diffuse hemispheric glioma, H3 G34-mutant.</div><div>The main proposed specifications to the ClinGen/CGC/VICC Oncogenicity SOP include: (1) the incorporation of trimethylation loss at the K27 residue and functional studies at G34 into evidence code OS2 and (2) stipulation of location at a 'conserved residue affecting epigenetic modification (e.g. histone H3 K27, G34, or K36)' for evidence code OM1.</div><div>The main proposed modifications to the ClinGen/CGC/VICC Oncogenicity SOP include: (1) an 'OS1_moderate' criterion (2 points), allowing for the same amino acid change as a previously established oncogenic variant in a homologous H3 gene; (2) an 'OS2_supportive' criterion (1 point), incorporating supportive evidence of frequent co-occurring variants (e.g. TP53, PDGFRA, ACVR1) or other supportive evidence of histone H3 mutation (e.g. gene expression analysis); and (3) an alternate OP2 criterion (1 point) applied when clinicopathologic features align with a corresponding histone mutant glioma in the WHO Classification. This novel modification introduces clinicopathological correlation into the assessment of oncogenicity. Evidence specifications have also been made to the AMP/ASCO/CAP guidelines.</div><div>Evaluation of our proposed changes to the guidelines is underway in a defined set of pilot variants.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Pages S12-S13"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323293","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":"41. Step 2 updates for the oncogenic assessment of FLT3 variants by the ClinGen FLT3 somatic cancer variant curation expert","authors":"Nathan Kopp ,&nbsp;Mani Coumarane ,&nbsp;Rong He ,&nbsp;Yuwen Li ,&nbsp;Somayyeh Fahiminiya ,&nbsp;Nikita Mehta ,&nbsp;Shivani Golem ,&nbsp;Xiaonan Zhao ,&nbsp;Yiming Zhong ,&nbsp;Haluk Kavus ,&nbsp;Xiangqiang Shao ,&nbsp;Rashmi Kanagal-Shamanna ,&nbsp;Jason Saliba ,&nbsp;Obi Griffith ,&nbsp;Malachi Griffith ,&nbsp;Xinjie Xu ,&nbsp;Kilannin Krysiak ,&nbsp;Arpad Danos","doi":"10.1016/j.cancergen.2024.08.043","DOIUrl":"10.1016/j.cancergen.2024.08.043","url":null,"abstract":"<div><div>Variant interpretation guidelines aid genetic professionals in assessing the strength of evidence for the variant pathogenicity and clinical significance. Currently, there are no standard guidelines for evaluation of <em>FLT3</em> variants, leading to variability in interpretation of <em>FLT3</em> tyrosine kinase and non-tyrosine kinase variants. The FLT3 Somatic Cancer Variant Curation Expert Panel (SC-VCEP), within the ClinGen Somatic Cancer CDWG, is actively developing the variant oncogenicity interpretation rules for the <em>FLT3</em> gene using ClinGen/CGC/VICC (PMID: <span><span>35101336</span><svg><path></path></svg></span>) to facilitate accurate classification of <em>FLT3</em> variants.</div><div>We will provide an update on the <em>FLT3</em>-specific modifications to evidence criteria OP1/SBP1 and OP4/SBS1. To address OP1/SBP1 we assessed multiple <em>in silico</em> prediction tools and their performance on FLT3-specific variants. Based on the analysis, we selected ClinPred and REVEL as optimal prediction tools for further evaluation during the pilot phase. We also modify the population allele frequency criteria for OP4/SBS1 using the spectrum of allele frequency of <em>FLT3</em> variants. Recognizing the need for applicability to internal tandem duplication (ITD) variants, the strength of OM2 has been increased to OM2_strong for this variant type. With these updates, all rules have been evaluated and modifications/specifications proposed for OVS1, OS2/SBS2, OS3/OM3/OP3, OM1, OM2, OP1/SBP1, OP2, SBVS1, and OP4/SBS1. Once approved, the validity of the rules will be assessed on a set of pilot variants.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S13"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323295","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":"52. A ClinGen Somatic curation effort focused on EGFR variants","authors":"Arpad Danos ,&nbsp;Jason Saliba ,&nbsp;Laura Corson ,&nbsp;Daniel Jay Brat ,&nbsp;Destiney Allen ,&nbsp;Gokce Toruner ,&nbsp;Haleh Farzanmehr ,&nbsp;Haluk Kavus ,&nbsp;Ian King ,&nbsp;Ariana Gonzalez ,&nbsp;Lauren Akesson ,&nbsp;Liz Spiteri ,&nbsp;Mamta Rao ,&nbsp;Rimas Lukas ,&nbsp;Shivani Golem ,&nbsp;Obi Griffith ,&nbsp;Malachi Griffith ,&nbsp;Madina Sukhanova ,&nbsp;Laveniya Satgunaseelan","doi":"10.1016/j.cancergen.2024.08.054","DOIUrl":"10.1016/j.cancergen.2024.08.054","url":null,"abstract":"<div><div>As next generation sequencing becomes a routine part of clinical diagnostic and follow up workup for tumor assessment, consensus on cancer variant interpretation and expanded knowledgebase curation is needed. <em>EGFR</em> (Epidermal Growth Factor Receptor) is a well recognized oncogene and <em>EGFR</em> SNVs, CNVs, indels, and fusions have important predictive, diagnostic, and prognostic roles in a variety of cancer types. A definitive collection of tumor-specific <em>EGFR</em> somatic variants and their responses to FDA-approved EGFR inhibitors has not yet been assembled and <em>EGFR</em>-specific guidelines for defining variant oncogenicity have not been proposed. Due to their growing clinical relevance, the ClinGen Somatic Clinical Domain Working Group Solid Tumor Taskforce (STTf) performed a pilot curation effort on 15 <em>EGFR</em> fusions, and a number of curation challenges were noted. For instance, <em>EGFR</em> fusions can be primary events in cancer or part of complex molecular alterations (e.g., involving amplification). The group will compile a list of EGFR fusions and collect data on characteristics such as genomic breakpoints, tumor-type associations, functional evidence, and sensitivity to inhibitors. We are forming an <em>EGFR</em> Somatic Cancer Variant Curation Expert Panel (<em>EGFR</em> SC-VCEP) to develop oncogenicity classification recommendations specific to <em>EGFR</em> fusions with future expansion to other <em>EGFR</em> sequence changes. The Step 1 ClinGen SC-VCEP application is in-progress for this effort. The results of this expert-led curation and the resulting guidelines will be publicly available through multiple avenues including the CIViC knowledgebase and ClinVar.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S17"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142322860","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":"71. Validation of automated cell counter instruments for downstream cytogenetic testing","authors":"Derek Smith,&nbsp;Wenhua Zhou,&nbsp;Eric Fredrickson,&nbsp;Erica Andersen,&nbsp;Jian Zhao","doi":"10.1016/j.cancergen.2024.08.073","DOIUrl":"10.1016/j.cancergen.2024.08.073","url":null,"abstract":"<div><div>Counting while blood cells (WBCs) from blood and bone marrow samples before culturing aids in standardizing workflows, yields, and quality of downstream testing in the cytogenetics laboratory. However, traditional cell counting methods are limited in speed and accuracy, prompting the search for a high-throughput, reliable replacement method. Here, we describe the results from validations of two automated fluorescent cell counting instruments (Cellaca MX and DeNovix CellDrop FL) for use in a high-throughput cytogenetics laboratory setting. These instruments utilize imaging cytometry principles and Acridine Orange/Propidium Iodide (AOPI) stains for assessing cellularity and viability assessment and do not require lysing of non-nucleated cells. Both instruments underwent validation incorporating a range of performance criteria including accuracy, precision, reagent stability, cellularity range, and cytogenetic culture (mitotic index) performance. The Cellaca MX was initially validated against a traditional Coulter counter, followed by the validation of the CellDrop FL compared to the Cellaca MX. Validation samples representing the clinical diagnostic encounter and with sufficient cellularity to set up concurrent cultures were counted using the clinical and test methods. A minimum of 10 samples were used for accuracy and internal volume/cellularity thresholds were evaluated. Concurrent cultures were evaluated for mitotic index following dropping and staining to assess quality. Ranges of cellularity used for inoculums were established to culture at 1M cells/mL. Both instruments have shown reliable operation across the full clinical range of sample cellularity. Our work shows automated fluorescent cell counting instruments employing AOPI stains can provide accurate and reproducible results in a high throughput setting.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S23"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323481","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":"15. Clinical impact of in-house molecular testing for underserved cancer patients in southern Alabama","authors":"Thuy Phung,&nbsp;John Larrimore,&nbsp;Kathy Navia,&nbsp;Kelley Doug Hebert","doi":"10.1016/j.cancergen.2024.08.017","DOIUrl":"10.1016/j.cancergen.2024.08.017","url":null,"abstract":"<div><div>Molecular profiling is critical in identifying genomic mutations for targeted cancer therapy. This study assesses the outcome of in-house molecular testing at a healthcare organization that cares for underserved population in southern Alabama.</div><div>We assessed the clinical impact of in-house single-gene mutation assays for <em>BRAF</em> V600 for metastatic melanoma, microsatellite instability (MSI) for colorectal carcinoma, and quantitative <em>BCR::ABL1</em> p210 for chronic myelogenous leukemia. We determined test result turnaround time (TAT), and QNS and specimen rejection rate.</div><div>For <em>BRAF</em> V600 assay, there were 63 cases with 43 (68%) <em>BRAF</em> wild type, 20 (32%) <em>BRAF</em> mutant, 0 (0%) QNS and specimen rejection, and &lt;24 hours TAT. For MSI assay, there were 100 cases with 91 (91%) MSI-Stable, 9 (9%) MSI-High, 0 (0%) QNS and specimen rejection, and &lt;24 hours TAT. For quantitative p210 assay, there were 185 cases with 126 (68%) p210 detected, 59 (32%) p210 not detected, 10 (5.4%) cases were rejected due to pre-analytical errors, and &lt;24 hours TAT. For <em>BRAF</em> and MSI assays, QNS and specimen rejection rate was 0% for in-house testing vs. 12.5% for send-out. For quantitative <em>BCR::ABL1</em> p210 assay, the rate was 5.4% for in-house testing vs. 20% for send-out. The TAT for all in-house assays was &lt;24 hours vs. &gt;7 days for send-outs.</div><div>In-house molecular testing has significant positive clinical impact. Faster TAT, cost effectiveness and better management of testing are major advantages of local testing that would enable broader access to precision therapy for underserved cancer patients.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Pages S5-S6"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323469","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":"57. Developing oncogenicity guidelines for BCR::ABL1-like B-lymphoblastic leukemia/lymphoma through expert consensus","authors":"Kilannin Krysiak ,&nbsp;Jason Saliba ,&nbsp;Chimène Kesserwan ,&nbsp;Yassmine Akkari ,&nbsp;Mark D. Ewalt ,&nbsp;Ilaria Iacobucci ,&nbsp;Paulo Campregher ,&nbsp;Paul G. Ekert ,&nbsp;Deepa Bhojwani ,&nbsp;Laura B. Corson ,&nbsp;Nikita Mehta ,&nbsp;Shivani Golem ,&nbsp;Rashmi Kanagal-Shamanna ,&nbsp;Alexandra E. Kovach ,&nbsp;Kristy Lee ,&nbsp;Arpad Danos ,&nbsp;Hannah Helber ,&nbsp;Sandeep Gurbuxani ,&nbsp;Christine J. Harrison ,&nbsp;Nitin Jain ,&nbsp;Charles Mullighan","doi":"10.1016/j.cancergen.2024.08.059","DOIUrl":"10.1016/j.cancergen.2024.08.059","url":null,"abstract":"<div><div>B-lymphoblastic leukemia/lymphoma (B-ALL) includes multiple distinct genetic subtypes. <em>BCR::ABL1-</em>like B-ALL is associated with high-risk disease with alterations impacting cytokine receptors and kinases that drive a gene expression profile which mimics <em>BCR::ABL1</em>-positive B-ALL. Given the significant genetic heterogeneity and various methodologies used to identify gene fusions, clinical diagnosis and decision-making for patients with this B-ALL subtype remain challenging.</div><div>Existing professional guidelines for <em>BCR::ABL1</em>-like B-ALL are not sufficiently detailed for consistent variant interpretation and routine practice between labs, which may impact both treatment decisions and clinical trial enrollment. To promote consensus, ClinGen has assembled a <em>BCR::ABL1</em>-like B-ALL Somatic Cancer Variant Curation Expert Panel (SC-VCEP) for variant interpretation related to this high-risk disease based on guidelines from the Somatic Cancer Clinical Domain Working Group.</div><div>Initially using <em>ABL1</em> fusions not involving BCR, we have drafted oncogenicity guidelines for fusions in this subtype of B-ALL. Adapting the NTRK SC-VCEP fusion guidelines we are evaluating fusion structure, cancer association, and functional evidence to support variant classification. To establish the scope of our pilot fusions for oncogenicity guidelines and AMP/ASCO/CAP categorization, we have expanded our evaluation to include other ABL-class genes (e.g., <em>ABL2, CSF1R</em>). These guidelines will be publicly available with finalized interpretations relevant to B-ALL. Ultimately, these efforts aim to provide community consensus related to the diagnostic, prognostic, and therapeutic implications of genetic changes in B-ALL.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Pages S18-S19"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323474","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":"20. FIP1L1::KIT fusion in a case of peripheral T-cell lymphoproliferative neoplasm responsive to tyrosine kinase inhibitor","authors":"Kristin Deeb,&nbsp;Linsheng Zhang,&nbsp;Tatiana Tvrdik,&nbsp;Deniz Peker Barclift,&nbsp;Saja Asakrah,&nbsp;Shiyong Li","doi":"10.1016/j.cancergen.2024.08.022","DOIUrl":"10.1016/j.cancergen.2024.08.022","url":null,"abstract":"<div><div>Myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangements commonly involve <em>FIP1L1::PDGFRA</em>. Eosinophilia is not an invariable feature. Neoplastic myeloid/lymphoid populations may be present at the same or different sites, with T-cell neoplasms being the conventional lymphoid component.</div><div>The case involves a 43-year-old male with chronic intractable disseminated skin rashes. Blood flow cytometry showed an aberrant T-cell population with no surface CD3 expression. Atypical T-cell infiltrates were present in the bone marrow, skin, and inguinal lymph node biopsy, and clonal <em>TRG</em> rearrangements were detected in blood, skin, and lymph node. However, there were no specific features to definitively classify the abnormal T-cell infiltrates. Bone marrow was fibrotic and hypercellular with only focal eosinophilia. Next-generation sequencing of blood and lymph node detected no significant mutations, and bone marrow cells demonstrated a normal karyotype. Fluorescence in situ hybridization demonstrated loss of both the <em>CHIC2</em> and <em>PDGFRA</em> signals, with retention of the <em>FIP1L1</em> signal. Whole-genome microarray analysis revealed an ∼1.3 Mb loss in the 4q12 region with breakpoints within the <em>FIP1L1</em> and <em>KIT</em> genes. A novel <em>FIP1L1::KIT</em> fusion was confirmed by RNA-sequencing demonstrating in-frame retention of the <em>KIT</em> tyrosine kinase domain. The patient had a poor response to chemotherapy but superb response to the tyrosine kinase inhibitor, dasatinib.</div><div><em>FIP1L1::KIT</em> fusion has not been described in systemic peripheral T-cell neoplasms without significant abnormality in myeloid lineage. This case indicates that <em>KIT</em> fusions are targetable genetic lesions and supports the inclusion of <em>KIT</em> fusions in the myeloid/lymphoid neoplasms with defining gene rearrangement.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"286 ","pages":"Page S7"},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323385","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}