Cancer Genetics最新文献_第2页

Germline variant profiling of CHEK2 sequencing variants in breast cancer patients 乳腺癌患者中 CHEK2 测序变异的种系变异特征分析

IF 1.4 4区医学

Cancer Genetics Pub Date : 2024-08-23 DOI: 10.1016/j.cancergen.2024.08.081

{"title":"Germline variant profiling of CHEK2 sequencing variants in breast cancer patients","authors":"","doi":"10.1016/j.cancergen.2024.08.081","DOIUrl":"10.1016/j.cancergen.2024.08.081","url":null,"abstract":"<div><p>The cell cycle checkpoint kinase 2 (<em>CHEK2</em>) is a tumor suppressor gene coding for a protein kinase with a role in the cell cycle and DNA repair pathways. Variants within <em>CHEK2</em> are associated with an increased risk of developing breast, colorectal, prostate and several other types of cancer. Comprehensive genetic risk assessment leads to early detection of hereditary cancer and provides an opportunity for better survival. Multigene panel screening can identify the presence of pathogenic variants in hereditary cancer predisposition genes (HCPG), including <em>CHEK2</em>. Multigene panels, however, also result in large quantities of genetic data some of which cannot be interpreted and are classified as variants of uncertain significance (VUS). A VUS provides no information for use in medical management and leads to ambiguity in genetic counseling. In the absence of variant segregation data, in vitro functional analyses can be used to clarify variant annotations, aiding in accurate clinical management of patient risk and treatment plans. In this study, we performed whole exome sequencing (WES) to investigate the prevalence of germline variants in 210 breast cancer (BC) patients and conspicuously among the many variants in HCPGs that we found, we identified 16 individuals with non-synonymous or frameshift <em>CHEK2</em> variants, sometimes along with additional variants within other BC susceptibility genes. Using this data, we investigated the prevalence of these <em>CHEK2</em> variants in African American (AA) and Caucasian (CA) populations identifying the presence of two novel frameshift variants, c.1350delA (p.Val451Serfs*18) and c.1528delC (p.Gln510Argfs*3) and a novel missense variant, c262C>T (p.Pro88Ser). Along with the current clinical classifications, we assembled available experimental data and computational predictions of function for these <em>CHEK2</em> variants, as well as explored the role these variants may play in polygenic risk assessment.</p></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087053","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}

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Brain abscesses, neutropenia, and B-ALL: Multiple testing modalities required to confirm PDCD10 and ETV6 dual diagnoses 脑脓肿、中性粒细胞减少症和 B-ALL：确认 PDCD10 和 ETV6 双重诊断需要多种检测方式

IF 1.4 4区医学

Cancer Genetics Pub Date : 2024-08-15 DOI: 10.1016/j.cancergen.2024.08.001

引用次数: 0

Focal cortical dysplasia type IIIb associated with a KRAS-mutant ganglioglioma 伴有 KRAS 突变神经节胶质瘤的局灶性皮质发育不良 IIIb 型

IF 1.4 4区医学

Cancer Genetics Pub Date : 2024-08-03 DOI: 10.1016/j.cancergen.2024.07.004

引用次数: 0

17. Intrachromosomal amplification of chromosome 21 as the sole chromosomal aberration in a primary AML patient 17.一名原发性急性髓细胞性白血病患者的 21 号染色体染色体内扩增是唯一的染色体畸变

IF 1.4 4区医学

Cancer Genetics Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.019

{"title":"17. Intrachromosomal amplification of chromosome 21 as the sole chromosomal aberration in a primary AML patient","authors":"","doi":"10.1016/j.cancergen.2024.08.019","DOIUrl":"10.1016/j.cancergen.2024.08.019","url":null,"abstract":"<div><div>Intrachromosomal amplification of chromosome 21 (iAMP21), is a rare but recurrent acquired clonal chromosome aberration observed in acute myeloid leukemia (AML), usually associated with chemoresistance and poor prognosis. The vast majority of AML patients with iAMP21 also present with a complex karyotype and <em>TP53</em> mutations, which are known markers for poor prognosis and interfere with understanding the clinical impact of iAMP21 in AML. We present a primary AML patient who had a bone marrow karyotype study showing additional material of unknown origin on 21q as the sole abnormality. The AML and high risk MDS FISH panel studies did not identify any abnormalities, including a normal signal pattern for <em>RUNX1</em>. Additional FISH studies for chromosome 21 detected five copies of the 21q22.13q22.2-specific signals on the derivative chromosome 21, suggestive of iAMP21. Chromosomal microarray analysis confirmed amplification of 21q, which included <em>ERG</em> and <em>ETS2</em> genes but not <em>RUNX1</em>. The hematologic malignancy NGS panel revealed <em>KIT</em> and <em>U2AF1</em> mutations. This 58-year-old male patient presented with pancytopenia and a hypercellular marrow with increased myeloblasts. This patient's disease was refractory to induction and salvage chemotherapy. While the clinical course showed similar chemoresistance as observed in other 21q-amplified AML, there is no concurrent <em>TP53</em> aberration or complex karyotype observed in this case. This case demonstrates that iAMP21 may be an early driver for AML tumorigenesis, and these results implicate <em>ERG</em> and/or <em>ETS2</em> instead of <em>RUNX1</em> as the critical gene(s) of iAMP21 in AML. Further characterization of iAMP21 in AML and may provide opportunities for alternative therapies.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

8. Reduced subclone diversity in clonal cytopenia of undetermined significance compared to myelodysplastic syndrome 8.与骨髓增生异常综合征相比，意义未定的克隆性细胞减少症的亚克隆多样性降低

IF 1.4 4区医学

Cancer Genetics Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.010

{"title":"8. Reduced subclone diversity in clonal cytopenia of undetermined significance compared to myelodysplastic syndrome","authors":"","doi":"10.1016/j.cancergen.2024.08.010","DOIUrl":"10.1016/j.cancergen.2024.08.010","url":null,"abstract":"<div><div>Clonal cytopenias of undetermined significance (CCUS) is a precursor state to myelodysplastic syndrome (MDS), a blood cancer, and is distinguished solely on the absence of morphologic dysplasia, which has diagnostic variability. Determining differences in clonal architecture (total number and size of clones) may provide an objective assessment of disease status. We hypothesized that CCUS patients will have reduced molecular disease burden with fewer subclones compared to MDS patients suggesting that MDS is at higher risk of progressing to secondary acute myeloid leukemia (sAML). We performed whole genome sequencing with higher exome coverage (eWGS) on bone marrow (n=58) or peripheral blood (n=4) and paired normal DNA from baseline banked samples from patients with CCUS (n=13), MDS (n=29), and sAML (n=20) to define clonal architecture. While the median number of total validated somatic mutations per sample was not different between CCUS, MDS, and sAML, the median variant allele frequency of the dominant clone was lower in CCUS (21.3%) compared to MDS (39.2%, p<0.05) and sAML (45.2%, p<0.001). Additionally, the proportion of patients without subclones was higher for CCUS (5/13 [38.5%]) compared to MDS and sAML (4/29 [13.8%] and 0/20 [0%], respectively, p ≤ 0.0006), suggesting that CCUS samples have reduced subclonal diversity compared to MDS. The data suggest that leveraging clonal architecture and subclonal diversity in the evaluation of patients with low blood counts could provide an objective measure to characterize and monitor disease burden in CCUS and MDS, and potentially assess risk of sAML progression, rather than relying on dysplasia alone.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

2. Diagnostic next generation sequencing to detect MYD88 L265P in lymphoplasmacytic lymphoma compared to ddPCR 2.诊断性新一代测序检测淋巴浆细胞性淋巴瘤中的 MYD88 L265P 与 ddPCR 的比较

IF 1.4 4区医学

Cancer Genetics Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.004

{"title":"2. Diagnostic next generation sequencing to detect MYD88 L265P in lymphoplasmacytic lymphoma compared to ddPCR","authors":"","doi":"10.1016/j.cancergen.2024.08.004","DOIUrl":"10.1016/j.cancergen.2024.08.004","url":null,"abstract":"<div><div>Lymphoplasmacytic lymphoma (LPL) is a B-cell lymphoproliferative disorder characterized by bone marrow infiltration of lymphoplasmacytic cells. Studies have identified <em>MYD88</em> L265P mutation as a diagnostic marker to distinguish LPL from other small B-cell lymphomas (e.g. marginal zone lymphoma, chronic lymphocytic leukemia). However, detection rates for this mutation have varied depending on the analytic methodology, with data suggesting that routine Next Generation Sequencing (NGS) does not demonstrate the required sensitivity to reliably detect <em>MYD88</em> L265P. NGS has become a work-horse of the modern genetic laboratory by basketing multiple single-gene assays into one multiplexed assay. In several routine cases, visual observation using IGV demonstrated <em>MYD88</em> L265P variants in cases of suspected LPL with low tumor content. To study this, we performed droplet digital PCR (ddPCR) and our routine NGS for <em>MYD88</em> L265P in a cohort of 35 cases of lymphoid neoplasms (25 LPL, 6 CLL, 4 negative bone marrow cases). Our standard NGS method achieved an average depth of ∼535 reads across this region. We utilized manual review and BAMtools to assess <em>MYD88</em> L265P in NGS cases. Limit of detection for ddPCR was determined to be 0.3% variant allele frequency (VAF) with 10ng DNA input. <em>MYD88</em> L265P VAF detection by NGS and ddPCR was comparable down to 0.5% VAF (R<sup>2</sup>=0.968). Setting an appropriate threshold for detection based on ddPCR results resulted in zero NGS false positives. This study demonstrates that NGS can be a sensitive and reliable method for detection of <em>MYD88</em> L265P with adequate coverage and specific assessment parameters.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142322862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

75. Copy number variation heterogeneity as the measure for biological consistency in hierarchical cancer classifications 75.将拷贝数变异异质性作为癌症分层分类中生物一致性的衡量标准

IF 1.4 4区医学

Cancer Genetics Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.077

{"title":"75. Copy number variation heterogeneity as the measure for biological consistency in hierarchical cancer classifications","authors":"","doi":"10.1016/j.cancergen.2024.08.077","DOIUrl":"10.1016/j.cancergen.2024.08.077","url":null,"abstract":"<div><div>Cancers are heterogeneous diseases with unifying features of abnormal and consuming cell growth, where the deregulation of normal cellular functions is initiated by the accumulation of genomic mutations in cells of - potentially - any organ. At diagnosis malignant tumors present with patterns of somatic genome variants on diverse levels of heterogeneity. Among the different types of genomic alterations, copy number variants (CNV) represent a distinct, near-ubiquitous class of structural variants. Cancer classifications such as the National Cancer Institute Thesaurus (NCIt) provide large sets of hierarchical cancer classification vocabularies and promote data interoperability and ontology-driven computational analysis.</div><div>However, high heterogeneity in cellular phenotypes and dynamic plasticity of tumor microenvironments make tumor categorization a demanding and complicated task with the need to balance between categorical classifications and individual, 'personalized' feature definitions. To find out how categorical classifications reflect biological facts, we conducted a meta-analysis of inter-sample genomic heterogeneity at different levels of the classification hierarchies based on genome-spanning CNV profiles from 97,142 individual samples across 512 hierarchical cancer entities in the progenetix database. The use of a large data set of individual cancer samples allows for a greater exploration of genomic tumor heterogeneity between and inside given diagnostic concepts. With this study, we applied hierarchical clustering to quantify the heterogeneity among cancer entities through a refined measure of hamming dissimilarity based on CNV events. The results point out common/specific CNV patterns and potential subtypes of cancer entities, which will help in the improvement of patient stratification and current cancer classification.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

9. Best practices for testing and reporting of FISH studies in multiple myeloma: Recommendations from the CGC working group 9.多发性骨髓瘤 FISH 研究检测和报告的最佳实践：CGC 工作组的建议

IF 1.4 4区医学

Cancer Genetics Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.011

{"title":"9. Best practices for testing and reporting of FISH studies in multiple myeloma: Recommendations from the CGC working group","authors":"","doi":"10.1016/j.cancergen.2024.08.011","DOIUrl":"10.1016/j.cancergen.2024.08.011","url":null,"abstract":"<div><h3>Purpose</h3><div>Multiple myeloma (MM) remains an incurable plasma cell malignancy with recurrent primary and secondary cytogenetic abnormalities having prognostic and therapeutic implications. Fluorescence in situ hybridization (FISH) is the gold-standard assay to detect these genetic abnormalities. However, FISH testing for MM is heterogeneous among clinical laboratories, with differences in plasma cell isolation, FISH panel design, and reporting practices.</div></div><div><h3>Methods</h3><div>The CGC Plasma Cell Neoplasm workgroup conducted a survey targeting the international MM clinician community on utilization of FISH and result reporting/interpretation.</div></div><div><h3>Results</h3><div>There were 102 survey responses representing 14 countries. Most (74%) MM clinicians utilize their own in-house FISH testing service with 81% reporting plasma cell enrichment was performed by their lab. 90% of respondents desired FISH at diagnosis, 72% during disease progression and 40% for treatment/response assessment. The most-requested FISH probes included: TP53 (99%), t(4;14) (92%), 1q gain/amplification (91%), t(14;16) (90%), t(11;14) (85%), t(14;20) (76%), 1p deletion (67%), while FISH for ploidy status, deletion 13q/-13, t(6;14), MYC rearrangement, and other rare IG rearrangements were ranked lower in importance (10-50%). About 40% of respondents were dissatisfied with clarity, summary, and interpretation of FISH reports. When challenged to interpret a FISH report, only 2% of responders interpreted results correctly and the majority were either unsure or misinterpreted the report.</div></div><div><h3>Conclusion</h3><div>Our study showed that significant improvements are needed by clinical lab directors in MM FISH report clarity to benefit both the clinician and patient. We propose standardization of best MM FISH practices and reporting.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

16. An evaluation of clinical significance of the TP53 polyadenylation signal-disrupting variant rs78378222-G 16.评估 TP53 多腺苷酸化信号干扰变体 rs78378222-G 的临床意义

IF 1.4 4区医学

Cancer Genetics Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.018

{"title":"16. An evaluation of clinical significance of the TP53 polyadenylation signal-disrupting variant rs78378222-G","authors":"","doi":"10.1016/j.cancergen.2024.08.018","DOIUrl":"10.1016/j.cancergen.2024.08.018","url":null,"abstract":"<div><div><em>TP53</em> germline pathogenic variants (Li-Fraumeni syndrome) and somatic mutations are important in tumorigenesis and tumor classifications. However, the clinical significance of the <em>TP53</em> polyadenylation signal-disrupting variant rs78378222-G remains unclear. To address this, we employed a dual approach.</div><div>First, we used All of Us Research Program data to evaluate its disease association with phenome-wide association studies (PheWAS). In the trans-ancestry PheWAS (n = 245,378, 3383 were heterozygous and <20 were homozygous), the G-allele was significantly associated with uterine leiomyoma (OR = 1.75 [1.42-2.16]). In Blacks (n = 56,911, allele frequency [AF] = 0.00171), it was significantly associated with anal and rectal polyps (11.97 [4.46-32.07]), and nominally associated with hyperparathyroidism, head and neck cancer, and primary cardiomyopathies. In Whites (n = 133,572, AF = 0.0112), it was significantly associated with benign neoplasm of the uterus (1.61 [1.27-2.03]) and in Hispanics (n = 45,032, AF = 0.00276), with uterine leiomyoma (3.82 [2.11-6.84]).</div><div>Next, we imputed rs78378222 with microarray data from the Cancer Genomic Atlas (TCGA, overall carrier rate 1.9%). Adult glioma (GBMLGG) had the highest carrier rate for the G-allele (4.6% in IDH-wildtype and 3.2% in IDH-mutant). There was no evidence of differential prognosis or rates of <em>TP53</em> mutation/17p loss among carriers within the evaluated tumor types that had enough carriers for analysis.</div><div>Our preliminary analyses demonstrate that <em>TP53</em> rs78378222-G allele was consistently associated with higher risk of neoplasms and tissue overgrowth in multiple ancestry groups. However, its role in cancer classification and prognostication may be limited, necessitating further validation with more data.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

34. Identifying challenges in variant normalization 34.确定变体规范化的挑战

IF 1.4 4区医学

Cancer Genetics Pub Date : 2024-08-01 DOI: 10.1016/j.cancergen.2024.08.036

{"title":"34. Identifying challenges in variant normalization","authors":"","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":null,"pages":null},"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}

引用次数: 0