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  • 1
    Online Resource
    Online Resource
    Tumor mutational burden and driver mutations: Characterizing the genomic landscape of pediatric brain tumors
    Wiley ; 2020
    In:  Pediatric Blood & Cancer Vol. 67, No. 7 ( 2020-07)
    Details
    In: Pediatric Blood & Cancer, Wiley, Vol. 67, No. 7 ( 2020-07)
    Abstract: Tumor mutational burden (TMB) and driver mutations are potential biomarkers to guide targeted therapy selection. Malignant gliomas with high TMB in children may preferentially benefit from treatment with immune checkpoint inhibitors (ICPIs). Higher TMB may relate to lower incidence of driver mutations, but this relationship has not been studied in pediatric brain tumors. Procedure Comprehensive genomic profiling was performed on 723 pediatric (≤21 years) brain tumor samples using DNA extracted from formalin‐fixed paraffin‐embedded tissue. TMB was calculated as mutations per megabase and categorized as low (0‐6), intermediate (6‐20), or high ( 〉 20). Analysis included 80 clinically relevant driver mutations; genomic alterations known to confer a selective growth advantage. Results Of 723 brain tumors, TMB was low in 91.8%, intermediate in 6.1%, and high in 2.1%. In the high TMB cohort, 93% of tumors harbored a driver mutation; 70% and 63% in the intermediate and low TMB cohorts, respectively ( P   〈  0.05). However, when excluding tumor suppressor genes, high TMB tumors had a decreased incidence of driver mutations ( P   〈  0.001). BRAF alterations were not identified in high TMB tumors, but were enriched in low TMB tumors ( P   〈  0.01). Conversely, there was an association between high TMB tumors and TP53 mutations ( P   〈  10 −13 ). Of the 15 tumors with high TMB, 14 were high‐grade gliomas and 13 had alterations in TP53 . Three homozygous mismatch repair deletions identified were associated with a higher TMB ( P   〈  0.01). Conclusions Specific driver mutations appear to have a relationship with TMB. These represent populations in which ICPIs may be more or less effective.
    Type of Medium: Online Resource
    ISSN: 1545-5009 , 1545-5017
    URL: Issue
    URL: Article
    DOI: 10.1002/pbc.v67.7
    DOI: 10.1002/pbc.28338
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2130978-4
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  • 2
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    Online Resource
    POU2AF3 ‐rearranged sarcomas: A novel tumor defined by fusions of EWSR1 or FUS to a gene formerly designated COLCA2
    Wiley ; 2023
    In:  Genes, Chromosomes and Cancer Vol. 62, No. 8 ( 2023-08), p. 460-470
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    In: Genes, Chromosomes and Cancer, Wiley, Vol. 62, No. 8 ( 2023-08), p. 460-470
    Abstract: Gene fusions involving EWSR1 or FUS as the 5′ partner have been reported in a diverse array of sarcomas. Here, we characterize the histopathology and genomics of six tumors harboring a gene fusion between EWSR1 or FUS and POU2AF3 , an understudied, putative colorectal cancer predisposition gene. Striking morphologic features reminiscent of synovial sarcoma were observed including a biphasic appearance with variable fusiform to epithelioid cytomorphology and staghorn‐type vasculature. RNA sequencing demonstrated variable breakpoints in EWSR1 / FUS along with similar breakpoints in POU2AF3 that encompassed a 3′ portion of this gene. For cases in which additional information was available, the behavior of these neoplasms was aggressive with local spread and/or distant metastases. Although further studies are needed to confirm the functional significance of our findings, POU2AF3 fusions to EWSR1 or FUS may define a novel type of POU2AF3 ‐rearranged sarcomas with aggressive, malignant behavior.
    Type of Medium: Online Resource
    ISSN: 1045-2257 , 1098-2264
    URL: Issue
    URL: Article
    DOI: 10.1002/gcc.v62.8
    DOI: 10.1002/gcc.23136
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1018988-9
    detail.hit.zdb_id: 1492641-6
    SSG: 12
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  • 3
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    Online Resource
    Predictive Biomarkers for Immune Checkpoint Inhibitors in Metastatic Breast Cancer
    Wiley ; 2021
    In:  Cancer Medicine Vol. 10, No. 1 ( 2021-01), p. 53-61
    Details
    In: Cancer Medicine, Wiley, Vol. 10, No. 1 ( 2021-01), p. 53-61
    Abstract: We examined a large dataset of female metastatic breast cancers (MBCs) profiled with comprehensive genomic profiling (CGP) to identify the prevalence and distribution of immunotherapy responsiveness‐associated biomarkers. DNA was extracted from 3831 consecutive MBCs: 1237 (ER pos / HER2 neg ), 1953 ER neg / HER2 amp , and 641 triple‐negative breast cancer (TNBC). CGP was performed using the FoundationOne ® or FoundationOne ® CDx NGS assay. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined in a subset of cases. PD‐L1 expression in immunocytes in a subset of cases was determined by immunohistochemistry using the companion diagnostic VENTANA PD‐L1 SP142 Assay. The median age of the cohort was 54 years (range 20–89). Genomic alterations (GAs)/tumor were similar (range: 5.9–7.3). Markers of potential immune checkpoint inhibitor (ICPI) benefit included: CD274 (PD‐L1) amplification (1%–3%), BRAF GA (1%–4%), TMB of ≥10 mutations/Mb (8%–12%), MSI‐high (0.1%–0.4%), PBRM1 GA (1%), and positive PD‐L1 staining of immunocytes ranging from 13% in ER pos / HER2 neg and 33% in ER neg / HER2 amp to 47% in the TNBC group. Potential markers of ICPI resistance included inactivating STK11 GA (1%–2%) and MDM2 amplification (3%–6%). MTOR pathway targets were common with lowest frequency in TNBC. ERBB2 short variant mutations were most frequent ER pos / HER2 neg and absent in TNBC. BRCA1 / 2 GA were least frequent in ER neg / HER2 amp . The demonstrations of clinical benefit of immunotherapy in MBC support the need for development and utilization of biomarkers to guide the use of ICPIs for these patients. In addition to guiding therapy selection, CGP shows potential to identify GA linked to response and resistance to ICPI in MBC.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    URL: Article
    DOI: 10.1002/cam4.v10.1
    DOI: 10.1002/cam4.3550
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2659751-2
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  • 4
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    Online Resource
    Genomic landscape of non‐small‐cell lung cancer with methylthioadenosine phosphorylase ( MTAP ) deficiency
    Wiley ; 2023
    In:  Cancer Medicine Vol. 12, No. 2 ( 2023-01), p. 1157-1166
    Details
    In: Cancer Medicine, Wiley, Vol. 12, No. 2 ( 2023-01), p. 1157-1166
    Abstract: New treatment strategies for advanced non‐small‐cell lung carcinoma (NSCLC) include synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of genomic loss of methylthioadenosine phosphorylase ( MTAP) . Methods Twenty nine thousand three hundred seventy nine advanced NSCLC cases underwent hybrid‐capture based comprehensive genomic profiling between June 1, 2018 and May 31, 2020. PD‐L1 expression was determined by immunohistochemistry (Dako 22C3 PharmDx assay). Results 13.4% (3928/29,379) NSCLC cases exhibited MTAP loss distributed in adenocarcinoma (59%), squamous cell carcinoma (22%), NSCLC not otherwise specified (16%), and 1% each for large‐cell neuroendocrine, sarcomatoid, and adenosquamous carcinoma. Statistically significant differences in mitogenic driver alterations included more KRAS G12C mutations in MTAP ‐intact versus MTAP‐ lost (12% vs. 10%, p  = 0.0003) and fewer EGFR short variant mutations in MTAP ‐intact versus MTAP ‐lost NSCLC (10% vs. 13%, p   〈  0.0001). Statistically significant differences in currently untargetable genomic alterations included higher frequencies of TP53 (70% vs. 63%, p   〈  0.0001) and RB1 inactivation (10% vs. 2%, p   〈  0.0001) in MTAP ‐intact compared to MTAP ‐lost NSCLC. SMARCA4 inactivation (7% vs. 10%, p   〈  0.0001) was less frequent in MTAP ‐intact versus MTAP ‐lost NSCLC. Alterations in ERBB2 , MET , ALK, ROS1 , and NTRK1 did not significantly differ between the two groups. Predictors of immunotherapy efficacy were higher in MTAP ‐intact versus MTAP ‐lost NSCLC including tumor mutational burden (9.4 vs. 8.6 mut/Mb, p  = 0.001) and low (30% vs. 28%, p  = 0.01) and high PD‐L1 (32% vs. 30%, p  = 0.01) expression. Alterations in biomarkers potentially predictive of immune checkpoint inhibitor resistance ( STK11 , KEAP1 , and MDM2 ) were similar in the two groups. Conclusions MTAP loss occurs in 13% of NSCLC, supporting the development of targeted therapies to exploit PRMT5 hyper‐dependence. MTAP loss is accompanied by small differences in targeted and immunotherapy options which may impact future combination strategies.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    URL: Article
    DOI: 10.1002/cam4.v12.2
    DOI: 10.1002/cam4.4971
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2659751-2
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