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  • 1
    Online Resource
    Online Resource
    Novel SOX10 indel mutations drive schwannomas through impaired transactivation of myelination gene programs
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology ( 2023-07-12)
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), ( 2023-07-12)
    Abstract: Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas. Methods We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10. Results We identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs. Conclusions We thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad121
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2094060-9
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  • 2
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    Online Resource
    Real-World Comprehensive Genomic Profiling Success Rates in Tissue and Liquid Prostate Carcinoma Specimens
    Oxford University Press (OUP) ; 2022
    In:  The Oncologist Vol. 27, No. 12 ( 2022-12-09), p. e970-e972
    Details
    In: The Oncologist, Oxford University Press (OUP), Vol. 27, No. 12 ( 2022-12-09), p. e970-e972
    Abstract: Challenges with sequencing tissue samples from patients with prostate cancer have been reported in clinical trials. To assess the success rate of comprehensive genomic profiling (CGP) for prostate cancer patients, we analyzed a real-world cohort who underwent sequencing of their prostate tissue sample as well as a subset of patients with a reflex liquid biopsy. Overall, a significant majority (82%) of tissue prostate carcinoma samples yielded reportable CGP results. Of those samples that were unsuccessful, most (75%) were inadequate samples that did not meet pre-established criteria to advance into sequencing. For cases where liquid CGP was performed if tissue CGP was unsuccessful, mutations that were likely attributable to prostate carcinoma were observed in most cases and all cases were successful in generating a report. These results suggest that, for CGP testing, prostate cancer tissue is a reasonable matrix type and that liquid samples can be effectively used as an alternative to tissue.
    Type of Medium: Online Resource
    ISSN: 1083-7159 , 1549-490X
    URL: Article
    DOI: 10.1093/oncolo/oyac181
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 3
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    Online Resource
    Clinicopathologic and Genomic Landscape of Non-Small Cell Lung Cancer Brain Metastases
    Oxford University Press (OUP) ; 2022
    In:  The Oncologist Vol. 27, No. 10 ( 2022-10-01), p. 839-848
    Details
    In: The Oncologist, Oxford University Press (OUP), Vol. 27, No. 10 ( 2022-10-01), p. 839-848
    Abstract: In patients with non-small cell lung cancer (NSCLC), 10%-40% will eventually develop brain metastases. We present the clinicopathologic, genomic, and biomarker landscape of a large cohort of NSCLC brain metastases (NSCLC-BM) samples. Materials and Methods We retrospectively analyzed 3035 NSCLC-BM tested with comprehensive genomic profiling (CGP) during routine clinical care. In addition, we compared the NSCLC-BM to a separate cohort of 7277 primary NSCLC (pNSCLC) specimens. Finally, we present data on 67 paired patients with NSCLC-BM and pNSCLC. Results Comprehensive genomic profiling analysis of the 3035 NSCLC-BMs found that the most frequent genomic alterations (GAs) were in the TP53, KRAS, CDKN2A, STK11, CDKN2B, EGFR, NKX2-1, RB1, MYC, and KEAP1 genes. In the NSCLC-BM cohort, there were significantly higher rates of several targetable GAs compared with pNSCLC, including ALK fusions, KRAS G12C mutations, and MET amplifications; and decreased frequency of MET exon14 skipping mutations (all P & lt; .05). In the subset of NSCLC-BM (n = 1063) where concurrent PD-L1 immunohistochemistry (IHC) was performed, 54.7% of the patients with NSCLC-BM were eligible for pembrolizumab based on PD-L1 IHC (TPS ≥ 1), and 56.9% were eligible for pembrolizumab based on TMB-High status. In addition, in a series 67 paired pNSCLC and NSCLC-BM samples, 85.1% (57/67) had at least one additional GA discovered in the NSCLC-BM sample when compared with the pNSCLC sample. Conclusions Herein, we defined the clinicopathologic, genomic, and biomarker landscape of a large cohort of patients with NSCLC-BM which can help inform study design of future clinical studies for patients with NSCLC with BM. In certain clinical situations, metastatic NSCLC brain tissue or cerebral spinal fluid specimens may be needed to fully optimize personalized treatment.
    Type of Medium: Online Resource
    ISSN: 1083-7159 , 1549-490X
    URL: Article
    DOI: 10.1093/oncolo/oyac094
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 4
    Online Resource
    Online Resource
    Circulating Cell-Free DNA Yield and Circulating-Tumor DNA Quantity from Liquid Biopsies of 12 139 Cancer Patients
    Oxford University Press (OUP) ; 2021
    In:  Clinical Chemistry Vol. 67, No. 11 ( 2021-11-01), p. 1554-1566
    Details
    In: Clinical Chemistry, Oxford University Press (OUP), Vol. 67, No. 11 ( 2021-11-01), p. 1554-1566
    Abstract: The amounts of circulating cell-free DNA (cfDNA) and circulating-tumor DNA (ctDNA) present in peripheral blood liquid biopsies can vary due to preanalytic/analytic variables. In this study, we examined the impact of patient age, sex, stage, and tumor type on cfDNA yield, ctDNA fraction, and estimated ctDNA quantity from a large cohort of clinical liquid biopsy samples. Methods We performed a retrospective analysis of 12 139 consecutive samples received for liquid biopsy (FoundationOne® Liquid) clinical testing. Results Significant differences in both cfDNA yield and estimated ctDNA quantity were observed based on the underlying tumor type that initiated the liquid biopsy analysis and the stage of the patient (P  & lt; 0.001). In addition, significant differences in ctDNA quantity were present based in both the patient age and sex (P  & lt; 0.001). Importantly, we saw a significantly higher success rate of issuing a clinically useful report in patients with higher levels of cfDNA yield and ctDNA quantity (P  & lt; 0.001). Conclusions In this study, we show that ctDNA quantity varied significantly based on patient age, sex, stage, and tumor type, which could offer an explanation as to why certain liquid biopsy specimens are more likely to fail sequencing or provide clinically meaningful results. In addition, this could affect future clinical decisions on the blood sample volumes required to allow successful liquid biopsy testing.
    Type of Medium: Online Resource
    ISSN: 0009-9147 , 1530-8561
    URL: Article
    DOI: 10.1093/clinchem/hvab176
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 5
    Online Resource
    Online Resource
    Variable Landscape of PD-L1 Expression in Breast Carcinoma as Detected by the DAKO 22C3 Immunohistochemistry Assay
    Oxford University Press (OUP) ; 2023
    In:  The Oncologist Vol. 28, No. 4 ( 2023-04-06), p. 319-326
    Details
    In: The Oncologist, Oxford University Press (OUP), Vol. 28, No. 4 ( 2023-04-06), p. 319-326
    Abstract: In 2020, pembrolizumab was approved as a therapy for triple-negative breast cancer (TNBC) with the companion diagnostic DAKO 22C3 programmed death ligand-1 (PD-L1) immunohistochemistry assay. The study aimed to determine the landscape of PD-L1 expression as detected by the DAKO 22C3 PD-L1 assay in breast cancer subtypes and compare the clinicopathologic and genomic characteristics of PD-L1 positive and negative TNBC. Methods PD-L1 expression using the DAKO 22C3 antibody was scored using a combined positive score (CPS) and positive status was defined as CPS ≥10. Comprehensive genomic profiling was performed using the FoundationOne CDx assay. Results Of the 396 BC patients stained with DAKO 22C3, the majority were HR+/HER2− and TNBC (42% and 36%, respectively). Median PD-L1 expression and frequency of CPS ≥10 was highest in TNBC cases (median: 7.5, 50% CPS ≥10) and lowest in the HR+/HER2− group (median: 1.0, 15.5% CPS ≥10) (P  & lt; .0001). A comparison of PD-L1 positive and PD-L1 negative TNBC demonstrated no significant differences in clinicopathologic or genomic characteristics. TNBC tissue samples from the breast did have an observed enrichment for PD-L1 positivity compared to TNBC tissue samples from a metastatic site (57% vs. 44%), but this was not statistically significant (P = .1766). In the HR+/HER2− group, genomic alterations in TP53, CREBBP, and CCNE1 were more prevalent and genomic loss of heterozygosity was higher in the PD-L1(+) group compared to the PD-L1(−) group. Conclusions The subtypes of breast cancer have distinct patterns of PD-L1 expression, supporting that further research of immunotherapies may include specific evaluation of optimum cutoffs for non-TNBC patients. In TNBC, PD-L1 positivity is not associated with other clinicopathologic or genomic features and should be integrated into future studies of immunotherapy efficacy.
    Type of Medium: Online Resource
    ISSN: 1083-7159 , 1549-490X
    URL: Article
    DOI: 10.1093/oncolo/oyad025
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 6
    Online Resource
    Online Resource
    Variable Genomic Landscapes of Advanced Melanomas with Heavy Pigmentation
    Oxford University Press (OUP) ; 2022
    In:  The Oncologist Vol. 27, No. 8 ( 2022-08-05), p. 655-662
    Details
    In: The Oncologist, Oxford University Press (OUP), Vol. 27, No. 8 ( 2022-08-05), p. 655-662
    Abstract: In the current study, we examined the real-world prevalence of highly pigmented advanced melanomas (HPMel) and the clinicopathologic, genomic, and ICPI biomarker signatures of this class of tumors. Materials and Methods Our case archive of clinical melanoma samples for which the ordering physician requested testing for both PD-L1 immunohistochemistry (IHC) and comprehensive genomic profiling (CGP) was screened for HPMel cases, as well as for non-pigmented or lightly pigmented advanced melanoma cases (LPMel). Results Of the 1268 consecutive melanoma biopsies in our archive that had been submitted for PD-L1 IHC, 13.0% (165/1268) were HPMel and 87.0% (1103/1268) were LPMel. In the HPMel cohort, we saw a significantly lower tumor mutational burden (TMB, median 8.8 mutations/Mb) than in the LPMel group (11.4 mut/Mb), although there was substantial overlap. In examining characteristic secondary genomic alterations (GA), we found that the frequencies of GA in TERTp, CDKN2A, TP53, and PTEN were significantly lower in the HPMel cases than in LPMel. A higher rate of GA in CTNNB1, APC, PRKAR1A, and KIT was identified in the HPMel cohort compared with LPMel. Conclusions In this study, we quantified the failure rates of melanoma samples for PD-L1 testing due to high melanin pigmentation and showed that CGP can be used in these patients to identify biomarkers that can guide treatment decisions for HPMel patients. Using this practical clinical definition for tumor pigmentation, our results indicate that HPMel are frequent at 13% of melanoma samples, and in general appear molecularly less developed, with a lower TMB and less frequent secondary GA of melanoma progression.
    Type of Medium: Online Resource
    ISSN: 1083-7159 , 1549-490X
    URL: Article
    DOI: 10.1093/oncolo/oyac090
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    Online Resource
    Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition
    Oxford University Press (OUP) ; 2023
    In:  The Oncologist Vol. 28, No. 1 ( 2023-01-18), p. e26-e35
    Details
    In: The Oncologist, Oxford University Press (OUP), Vol. 28, No. 1 ( 2023-01-18), p. e26-e35
    Abstract: B-cell primary central nervous system (CNS) lymphoma (PCL) is diffuse large B-cell lymphoma (DLBCL) confined to the CNS. Less than 50% of patients with PCL achieve complete remission with current therapies. We describe the findings from comprehensive genomic profiling (CGP) of a cohort of 69 patients with PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL to highlight their differences and characterize the PCL cohort. In addition, we highlight the differences in frequency of germinal center B-cell like (GCB) and non-GCB subtypes and molecular subtypes, particularly MCD and EZH subtypes, between PCL and DLBCL. Materials and Methods Sixty-nine cases of B-cell PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL were evaluated by CGP of 405 genes via DNAseq and 265 genes via RNAseq for fusions (FoundationOne Heme). Tumor mutational burden (TMB) was calculated from 1.23 Mb of sequenced DNA. Results Genomic alterations with significant differences between PCL and DLBCL included MYD88, ETV6, PIM1, PRDM1, CXCR4, TP53, and CREBBP, while only MYD88 was significantly different between SCL and DLBCL. PCL cases were significantly enriched for the MCD molecular subtypes, which have an excellent response to BTKi. We report a patient with a durable complete response to BTKi consistent with their genomic profile. EBV status, CD274 amplification, and TMB status suggest that 38% of PCL patients may benefit from ICPI; however further study is warranted. Conclusion CGP of PCLs reveals biomarkers, genomic alterations, and molecular classifications predictive of BTKi efficacy and potential ICPI efficacy. Given the limitations of standard of care for PCL, CGP is critical to identify potential therapeutic approaches for patients in this rare form of lymphoma.
    Type of Medium: Online Resource
    ISSN: 1083-7159 , 1549-490X
    URL: Article
    DOI: 10.1093/oncolo/oyac190
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 8
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    Online Resource
    A Retrospective Genomic Landscape of 661 Young Adult Glioblastomas Diagnosed Using 2016 WHO Guidelines for Central Nervous System Tumors
    Oxford University Press (OUP) ; 2023
    In:  The Oncologist ( 2023-08-24)
    Details
    In: The Oncologist, Oxford University Press (OUP), ( 2023-08-24)
    Abstract: The authors present a cohort of 661 young adult glioblastomas diagnosed using 2016 WHO World Health Organization Classification of Tumors of the Central Nervous System, utilizing comprehensive genomic profiling (CGP) to explore their genomic landscape and assess their relationship to currently defined disease entities. This analysis explored variants with evidence of pathogenic function, common copy number variants (CNVs), and several novel fusion events not described in literature. Tumor mutational burden (TMB) mutational signatures, anatomic location, and tumor recurrence are further explored. Using data collected from CGP, unsupervised machine-learning techniques were leveraged to identify 10 genomic classes in previously assigned young adult glioblastomas. The authors relate these molecular classes to current World Health Organization guidelines and reference current literature to give therapeutic and prognostic descriptions where possible.
    Type of Medium: Online Resource
    ISSN: 1083-7159 , 1549-490X
    URL: Article
    DOI: 10.1093/oncolo/oyad224
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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