Evaluation of a Hybrid Capture–Based Pan-Cancer Panel for Analysis of Treatment Stratifying Oncogenic Aberrations and Processes

Kroeze, Leonie I.; Voer, Richarda M. de; Kamping, Eveline J.; Rhein, Daniel von; Jansen, Erik A. M.; Hermsen, Mandy J. W.; Barberis, Massimo; Botling, Johan; Garrido-Martín, Eva M.; Haller, Florian; Lacroix, Ludovic; Maes, Brigitte; Merkelbach‐Bruse, Sabine; Pestinger, Valerie; Pfarr, Nicole; Stenzinger, Albrecht; Heuvel, Michel M. van den; Grünberg, Katrien; Ligtenberg, Marjolijn J. L.

doi:10.1016/j.jmoldx.2020.02.009

Cited by 46 publications

(46 citation statements)

References 52 publications

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“…Mutational signature analysis was performed as described previously. 2 The MPC described in the current paper is represented as UPN40 in Kroeze et al 2 In Figure 5 of the Kroeze et al study, the high contribution of signature 10a and 10b is demonstrated. 2…”

Section: Tumor Mutational Burden Analysismentioning

confidence: 80%

“… 24 Moreover, a major contribution of mutational signature 10a and 10b, associated with POLE mutations, indicates that somatic monoallelic mutation in the exonuclease domain of POLE is a main mutational process driving the tumorigenesis and responsible for high TMB in this MPC. 19 Germline mutations in POLE and POLD1 polymerases predispose to rare polymerase proofreading-associated polyposis, imposing increased risk to develop polyposis, early-onset colorectal cancer (CRC), and endometrial carcinomas (ECs). 22 Recently, a large family harboring a novel germline POLE variant was described to have multiple cancers including 3 early-onset PC cases, potentially indicating that PC belongs to the tumor spectrum of polymerase proofreading-associated polyposis.…”

Section: Discussionmentioning

confidence: 99%

“…Further analysis revealed a mutational signature (signature 10, COSMIC), known to be associated with POLE mutations (for details, see Fig. 5 in Kroeze et al 19 ; current MPC is represented as UPN40). For details on TMB analysis, see Supplemental Methods, http://links.lww.com/MPA/A792 .…”

Section: Case Reportmentioning

confidence: 99%

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Medullary Pancreatic Carcinoma Due to Somatic POLE Mutation

et al. 2020

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NM_000546.5 >94% of the coding regions Markers for MSI analysis BAT25, BAT26, NR21, NR24 and NR27 Genomic DNA was isolated from deparaffinized formalin-fixed paraffin-embedded tumor and normal tissue using standard procedures. Library preparation and sequencing using a single-molecule molecular inversion probe (smMIP)-based NextSeq 500 approach were performed as described previously, 1 with the listed gene panel. Using a separate smMIP panel, 99% of the coding region of SMAD4 (SMAD4 RefSeq NM_005359.5) was analyzed. *For detection of point mutations and amplification. † For amplification detection. MSI, microsatellite instability.

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Section: Tumor Mutational Burden Analysismentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Medullary Pancreatic Carcinoma Due to Somatic POLE Mutation

et al. 2020

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“…DNA and RNA library preparations were performed separately using the hybrid capture-based TruSight Oncology (TSO) 500 DNA and RNA Library Preparation Kits, respectively (Illumina, San Diego, CA) according to the manufacturer's protocol essentially as described before. 15 The TSO500 DNA assay targets 523 cancer-related genes for assessment of single- and multiple-nucleotide variants, gene amplifications, tumor mutational burden (TMB), and microsatellite instability (MSI), whereas the RNA kit targets 55 genes for fusion gene analyses (Data Supplement). The use of unique molecular identifiers allows sensitive analysis of unique DNA molecules sequenced at every position.…”

Section: Methodsmentioning

confidence: 99%

Unraveling Neuroendocrine Gallbladder Cancer: Comprehensive Clinicopathologic and Molecular Characterization

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Kroeze

Reuver

et al. 2021

JCO Precision Oncology

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PURPOSE Neuroendocrine carcinomas and mixed neuroendocrine non-neuroendocrine neoplasms of the gallbladder (NE GBC) are rare and highly aggressive entities. The cell of origin of NE GBC has been a matter of controversy. Here, we performed a comparative histopathologic and molecular analysis of NE GBC cases and, if present, associated precancerous lesions. PATIENTS AND METHODS We selected cases diagnosed between 2000 and 2019 in the Netherlands. Precursors and carcinomas were immunohistochemically compared and analyzed for mutations, gene amplifications, microsatellite instability, and tumor mutational burden using an next-generation sequencing panel containing 523 cancer-related genes. In addition, presence of fusion genes was analyzed using a panel of 55 genes. RESULTS Sixty percent of neuroendocrine cases (6/10) presented with a precursor lesion, either intracholecystic papillary neoplasm (n = 3) or biliary intraepithelial neoplasia (n = 3). Immunohistochemically, neuroendocrine components were different from the epithelial precursor lesions. Molecular profiling, however, revealed TP53 mutations shared between different components in five of six cases, indicating a clonal relation. Furthermore, 40% of cases (4/10) harbored at least one potentially actionable alteration. This included (likely) pathogenic mutations in RAD54L, ATM, and BRCA2; amplifications of ERBB2 and MDM2; and a gene fusion involving FGFR3-TACC3. All cases were microsatellite-stable and had a tumor mutational burden of < 10 mutations/Mb. CONCLUSION Our data provide insight into the development of NE GBC and suggest a common origin of precancerous epithelial lesions and invasive neuroendocrine components, favoring the hypothesis of lineage transformation. Moreover, nearly half of the NE GBCs carried at least one potentially actionable molecular alteration, highlighting the importance of molecular testing in this highly lethal cancer.

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“…Biomarkers such as tumor mutational burden (TMB) and microsatellite instability are useful for stratification of patients for targeted immuno-oncology therapies, which require extensive genomic profiling for sensitive detection of clinically relevant variants. Detection of single and multiple nucleotide variants ‒ CNVs, microsatellite instability, and TMB ‒ has been evaluated using a commercially available next generation sequencing (NGS) panel containing 523 cancer-related genes and can be applied for detection of multiple DNA-based biomarkers relevant for treatment selection [6].…”

Section: Role Of Biomarkers In Personalized Immuno-oncologymentioning

confidence: 99%

Personalized Immuno-Oncology

Jain¹

2020

Med Princ Pract

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Cancer immunotherapy, which aims to control the immune system to eradicate cancer cells and prevent their spread, needs to be personalized because anticancer immune responses can be inhibited in several ways that vary from patient to patient. Cancer immunotherapy includes pharmaceuticals such as immune checkpoint inhibitors and monoclonal antibodies (MAbs) as well as cell therapy, immunogene therapy, and vaccines. Combination of programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) drugs with other immunotherapy drugs, for example, antibody-drug conjugates, as well as combination of PD-1/PD-L1 drugs with other therapies, for example, chemotherapy and radiation therapy, are being explored. Biomarkers are important for predicting the response to immunotherapy. Molecular diagnostics and sequencing are important technologies for guiding treatment in immuno-oncology. Genomic profiling of tumor mutational burden may enhance the predictive utility of PD-L1 expression and facilitate personalized combination immunotherapy. Optimization of personalized immuno-oncology requires integration of several technologies and selection of those best suited for an individual patient. Advances in immuno-oncology are also attributed to technologies for targeted delivery of anticancer therapeutics such as antigen-capturing nanoparticles for precision targeting and selective delivery. A breakthrough in cell therapy of cancer is a chimeric antigen receptors-T cell, which combines the antigen-binding site of a MAb with the signal activating machinery of a T cell, freeing antigen recognition from major histocompatibility complex restriction. Gene-editing tools such as clustered regularly interspaced short palindromic repeats have a promising application for removing alloreactivity and decreasing immunogenicity of third-party T cells. In conclusion, personalized immuno-oncology is one of the most promising approaches to management of cancer.

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Evaluation of a Hybrid Capture–Based Pan-Cancer Panel for Analysis of Treatment Stratifying Oncogenic Aberrations and Processes

Cited by 46 publications

References 52 publications

Medullary Pancreatic Carcinoma Due to Somatic POLE Mutation

Medullary Pancreatic Carcinoma Due to Somatic POLE Mutation

Unraveling Neuroendocrine Gallbladder Cancer: Comprehensive Clinicopathologic and Molecular Characterization

Personalized Immuno-Oncology

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