Integrated genomic profiling expands clinical options for patients with cancer

Beaubier, Nike; Bontrager, Martin; Huether, Robert; Igartua, Catherine; Lau, Denise; Tell, Robert; Bobe, Alexandria M.; Bush, Stephen J.; Chang, Alan L.; Hoskinson, Derick; Khan, Aly A.; Kudalkar, Emily; Leibowitz, Benjamin D.; Lozac’hmeur, Ariane; Michuda, Jackson; Parsons, Jerod; Perera, Jason; Salahudeen, Ameen A.; Shah, Kaanan P.; Taxter, Timothy J.; Zhu, Wei; White, Kevin P.

doi:10.1038/s41587-019-0259-z

Cited by 118 publications

(143 citation statements)

References 60 publications

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“…The assessment of molecular profiling combined with clinical data had identified personalized therapies and clinical trials for a large proportion of patients with cancer [6]. As a new promising treatment, studies on genetic aspects related to immunotherapy were urgently required.…”

Section: Discussionmentioning

confidence: 99%

“…However, due to the complexity of immunotherapy and tumour heterogeneity, this method is only effective for some patients. To match patients suffering from cancers to new promising treatments or clinical trials, genomic analysis of tumor samples could be performed [6]. Thus, it is important to determine the characteristics of the tumour immune microenvironment and to identify patients eligible for immunotherapy to improve the effects of immunotherapy [7].…”

Section: Introductionmentioning

confidence: 99%

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Prognostic values of immune scores and immune microenvironment-related genes for hepatocellular carcinoma

Wang

et al. 2020

Aging

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It is crucial to grasp the characteristics of tumour immune microenvironment to improve effects of immunotherapy. In this study, the immune and stromal scores of 371 cases were calculated for quantitative analysis of immune and stromal cell infiltration in the tumour microenvironment of hepatocellular carcinoma (HCC). The weighted gene co-expression network analysis and protein-protein interaction network were analysed to identify immune microenvironment-related genes. The results showed that patients with high immune scores had a higher 4-year recurrence-free rate. TP53, CTNNB1, and AXIN1 mutations significantly varied with immune scores. In immune score-related modules analysis, Kyoto encyclopaedia of genes and genomes pathways and gene ontology terms were closely related to immune processes, tumorigenesis, and metastasis. Twelve new immune microenvironment-related genes were identified and had significantly positive correlations with seven immune checkpoint genes. In prognostic analysis, eleven immune microenvironmentrelated genes exhibited high expression, nine of which were validated in the GSE62232 dataset and were significantly associated with a good prognosis. Our findings suggest that calculating immune score and stromal score could help to determine tumour purity and immune cell infiltration in the tumour microenvironment. Nine immune microenvironment-related genes identified in this study had potential as prognostic markers for HCC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prognostic values of immune scores and immune microenvironment-related genes for hepatocellular carcinoma

Wang

et al. 2020

Aging

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“…The control for the algorithm included a set of 50 unmatched normal samples that allowed the calculation of position quality scores and determination of a mean exon read depth for copy number analysis. 4,7 JAMA Network Open | Oncology Downloaded From: https://jamanetwork.com/ on 07/14/2020…”

Section: Tumor Mutation Burden Calculation and Variant Groupingmentioning

confidence: 99%

Tumor Mutational Burden From Tumor-Only Sequencing Compared With Germline Subtraction From Paired Tumor and Normal Specimens

et al. 2020

Self Cite

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IMPORTANCE Tumor mutation burden (TMB) is an emerging factor associated with survival with immunotherapy. When tumor-normal pairs are available, TMB is determined by calculating the difference between somatic and germline sequences. In the case of commonly used tumor-only sequencing, additional steps are needed to estimate the somatic alterations. Computational tools have been developed to determine germline contribution based on sample copy state, purity estimates, and occurrence of the variant in population databases; however, there is potential for sampling bias in population data sets. OBJECTIVE To investigate whether tumor-only filtering approaches overestimate TMB. DESIGN, SETTING, AND PARTICIPANTS This was a retrospective cohort study of 50 tumor samples from 10 different tumor types. A 595-gene panel test was used to assess TMB by adding all missense, indels, and frameshift variants with an allelic fraction of at least 5% and coverage of at least 100× within each tumor. Tumor-only TMB was evaluated against the criterion standard of matched germline-subtracted TMB at 3 levels. Level 1 removed all the tumor-only variants with allelic fraction of at least 1% in the Exome Aggregation Consortium database (with the Cancer Genome Atlas cohort removed). Level 2 removed all variants observed in population databases, simulating a naive approach of removing germline variation. Level 3 used an internal tumor-only pipeline for calculating TMB. These specimens were processed with a commercially available panel, and results were analyzed at the Mayo Clinic. Data were analyzed between December 1, 2018, and May 28, 2019. MAIN OUTCOMES AND MEASURES Tumor mutation burden per megabase (Mb) as determined by 3 levels of filtering and germline subtraction. RESULTS There were significantly higher estimates of TMB with level 1 (median [range] mutations per Mb, 28.8 [17.5-67.1]), level 2 (median [range] mutations per Mb, 20.8 [10.4-30.8]), and level 3 (median [range] mutations per Mb, 3.8 [0.8-12.1]) tumor-only filtering approaches than those determined by germline subtraction (median [range] mutations per Mb, 1.7 [0.4-9.2]). There were no strong associations between TMB estimates and tumor-germline TMB for level 1 filtering

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“…Illumina sequencing of patient tumor samples DNA and RNA sequencing was performed on clinical tumor specimens and saliva samples (from the same patients as the tumor specimens) for 6 of the 8 patients using the Tempus xT assay [26]. Briefly, nucleic acid was extracted from tumor tissue sections with tumor cellularity greater than 20% using a Chemagic360 instrument and a source-specific magnetic bead protocol.…”

Section: Single Nucleotide Variant Callingmentioning

confidence: 99%

A novel Cas9-targeted long-read assay for simultaneous detection of IDH1/2 mutations and clinically relevant MGMT methylation in fresh biopsies of diffuse glioma

Wongsurawat

Jenjaroenpun

Loose

et al. 2020

acta neuropathol commun

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Molecular biomarkers provide both diagnostic and prognostic results for patients with diffuse glioma, the most common primary brain tumor in adults. Here, we used a long-read nanopore-based sequencing technique to simultaneously assess IDH mutation status and MGMT methylation level in 4 human cell lines and 8 fresh human brain tumor biopsies. Currently, these biomarkers are assayed separately, and results can take days to weeks. We demonstrated the use of nanopore Cas9-targeted sequencing (nCATS) to identify IDH1 and IDH2 mutations within 36 h and compared this approach against currently used clinical methods. nCATS was also able to simultaneously provide high-resolution evaluation of MGMT methylation levels not only at the promoter region, as with currently used methods, but also at CpGs across the proximal promoter region, the entirety of exon 1, and a portion of intron 1. We compared the methylation levels of all CpGs to MGMT expression in all cell lines and tumors and observed a positive correlation between intron 1 methylation and MGMT expression. Finally, we identified single nucleotide variants in 3 target loci. This pilot study demonstrates the feasibility of using nCATS as a clinical tool for cancer precision medicine.

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Integrated genomic profiling expands clinical options for patients with cancer

Cited by 118 publications

References 60 publications

Prognostic values of immune scores and immune microenvironment-related genes for hepatocellular carcinoma

Prognostic values of immune scores and immune microenvironment-related genes for hepatocellular carcinoma

Tumor Mutational Burden From Tumor-Only Sequencing Compared With Germline Subtraction From Paired Tumor and Normal Specimens

A novel Cas9-targeted long-read assay for simultaneous detection of IDH1/2 mutations and clinically relevant MGMT methylation in fresh biopsies of diffuse glioma

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