Dataset Information

Inflation of tumor mutation burden by tumor-only sequencing in under-represented groups.

ABSTRACT: With the recent FDA approval of tumor mutational burden-high (TMB-H) status as a biomarker for treatment with a PD-1 inhibitor regardless of tumor type, accurate assessment of patient-specific TMB is more critical now more than ever. Using paired tumor and germline exome sequencing data from 701 patients newly diagnosed with multiple myeloma, including 575 self-reported White patients and 126 self-reported Black patients, we observed that compared to the gold standard of filtering germline variants with patient-paired germline sequencing data, TMB estimates were significantly higher in both Black and White patients when using public databases for filtering non-somatic mutations; however, TMB was more significantly inflated in Black patients compared to White patients. TMB as a biomarker for patient selection to receive immune checkpoint inhibitors (ICIs) therapy without patient-paired germline sequencing may introduce racial bias due to the under-representation of minority groups in public databases.

SUBMITTER: Asmann YW

PROVIDER: S-EPMC7979755 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inflation of tumor mutation burden by tumor-only sequencing in under-represented groups.

Asmann Yan W YW Parikh Kaushal K Bergsagel P Leif PL Dong Haidong H Adjei Alex A AA Borad Mitesh J MJ Mansfield Aaron S AS

NPJ precision oncology 20210319 1

With the recent FDA approval of tumor mutational burden-high (TMB-H) status as a biomarker for treatment with a PD-1 inhibitor regardless of tumor type, accurate assessment of patient-specific TMB is more critical now more than ever. Using paired tumor and germline exome sequencing data from 701 patients newly diagnosed with multiple myeloma, including 575 self-reported White patients and 126 self-reported Black patients, we observed that compared to the gold standard of filtering germline varia ...[more]

PMID: 33742076

Similar Datasets

Project description:ObjectiveWe performed a scoping review of randomised clinical trials (RCTs) assessing pharmacological therapies for the initial management of lupus nephritis (LN), focusing on study design, included populations and outcome definitions, to assess the generalisability of their results and identify gaps in the evidence.MethodsRCTs evaluating pharmacological interventions for the initial therapy of LN published between 2000 and 2024 were evaluated. Extracted variables included study design, selection criteria, outcome definitions, populations recruited and clinical characteristics of participants. Each study arm was included as intervention and segregated into guideline-recommended regimens (cyclophosphamide (CYC), mycophenolic acid analogues (MPAAs), calcineurin inhibitors and belimumab) or other regimens. Data were analysed by descriptive statistics, and Fragility Index (FI) was estimated to assess robustness of studies.ResultsWe included 124 intervention arms within 61 RCT, involving 7058 participants. Seventy-nine arms (63.7%) corresponded to guideline-recommended therapies: 33 (26.6%) MPAA, 28 (22.6%) NIH-CYC and 7 (5.6%) triple-drug therapies. While 100% of triple-drug therapies RCT were multinational, only 7.1% of NIH-CYC and 0% of tacrolimus RCTs were conducted in more than one country. Only 9 (14.8%) had follow-up ≥24 months. Ten (16.4%) RCTs exclusively included participants with severe or refractory LN. Only 29 (47.5%) reported serious adverse events, and few described patient-reported outcomes. Black and other race participants were under-represented, as well as participants from Middle East, North Africa, and the sub-Saharan African region. Response was variably defined and assessed at different intervals. Robustness of RCTs evaluating double-drug guideline-recommended therapies were mostly low, with FI ranging from 1 to 3.ConclusionsConsidering new recommendations for the management of LN, we call for broader inclusion of under-represented populations and homogenisation of study design. This study provides the rationale for evaluating unexplored treatment comparisons and conducting research on newer interventions in clinical settings where evidence is currently lacking.

Project description:BackgroundTumor mutation burden (TMB) is a key characteristic used in a tumor-type agnostic context to inform the use of immune checkpoint inhibitors (ICI). Accurate and consistent measurement of TMB is crucial as it can significantly impact patient selection for therapy and clinical trials, with a threshold of 10 mutations/Mb commonly used as an inclusion criterion. Studies have shown that the most significant contributor to variability in mutation counts in whole genome sequence (WGS) data is differences in analysis methods, even more than differences in extraction or library construction methods. Therefore, tools for improving consistency in whole genome TMB estimation are of clinical importance.MethodsWe developed a distributable TMB analysis suite, TMBur, to address the need for genomic TMB estimate consistency in projects that span jurisdictions. TMBur is implemented in Nextflow and performs all analysis steps to generate TMB estimates directly from fastq files, incorporating somatic variant calling with Manta, Strelka2, and Mutect2, and microsatellite instability profiling with MSISensor. These tools are provided in a Singularity container downloaded by the workflow at runtime, allowing the entire workflow to be run identically on most computing platforms. To test the reproducibility of TMBur TMB estimates, we performed replicate runs on WGS data derived from the COLO829 and COLO829BL cell lines at multiple research centres. The clinical value of derived TMB estimates was then evaluated using a cohort of 90 patients with advanced, metastatic cancer that received ICIs following WGS analysis. Patients were split into groups based on a threshold of 10/Mb, and time to progression from initiation of ICIs was examined using Kaplan-Meier and cox-proportional hazards analyses.ResultsTMBur produced identical TMB estimates across replicates and at multiple analysis centres. The clinical utility of TMBur-derived TMB estimates were validated, with a genomic TMB ≥ 10/Mb demonstrating improved time to progression, even after correcting for differences in tumor type (HR = 0.39, p = 0.012).ConclusionsTMBur, a shareable workflow, generates consistent whole genome derived TMB estimates predictive of response to ICIs across multiple analysis centres. Reproducible TMB estimates from this approach can improve collaboration and ensure equitable treatment and clinical trial access spanning jurisdictions.

Project description:BackgroundHigh tumor mutational burden (TMB) is one of the widely researched predictive biomarkers of immune checkpoint inhibitors and has been shown to be closely related with response to immunotherapy in multiple cancer types. However, for patients who have failed conventional therapy and are about to undergo immunotherapy, there is no consensus recommendation on the timing of tumor sampling for TMB analysis, and the effects of different therapies on TMB have not been clarified. This retrospective observational study aimed to investigate the heterogeneity of TMB and genomic mutation under the treatment pressure.Patients and methodsWe retrospectively collected the available genomic and therapeutic information from 8051 samples across 15 tumor types (>50 samples/tumor) found in 30 published studies and investigated the distribution and heterogeneity of TMB under treatment across diverse cohorts.ResultsThis integrated analysis has shown anticancer treatments increased TMB. Significant effects of treatment on TMB were more frequently observed in tumor types with lower treatment-naïve TMB, including breast, prostate, and pediatric cancers. For different cancer therapies, chemotherapy was prone to be correlated with an increased TMB in most cancer types. Meanwhile, the fraction of the TMB-high category of breast, prostate, and bladder cancers and glioma increased significantly after chemotherapy. Several actionable genes including ERS1 and NF1 in breast cancer, as well as some prognostic markers including TERT in bladder cancer and IDH1 in glioma, were significantly changed in post-chemotherapy tumors compared to treatment-naïve tumors.ConclusionOur study reveals the heterogeneity of TMB under treatment across diverse cancer types and provides evidences that chemotherapy was associated with increases in TMB as well as the fraction of TMB-high category, suggesting that resampling tumor tissues for calculating post-chemotherapy TMB could be a better option for predicting the response to immunotherapy, especially for tumors with initially low TMB.

Project description:BackgroundCirculating tumor DNA (ctDNA) carries information on tumor burden. However, the mutation spectrum is different among tumors. This study was designed to examine the utility of ctDNA for monitoring tumor burden based on an individual mutation profile.MethodologyDNA was extracted from a total of 176 samples, including pre- and post-operational plasma, primary tumors, and peripheral blood mononuclear cells (PBMC), from 44 individuals with colorectal tumor who underwent curative resection of colorectal tumors, as well as nine healthy individuals. Using a panel of 50 cancer-associated genes, tumor-unique mutations were identified by comparing the single nucleotide variants (SNVs) from tumors and PBMCs with an Ion PGM sequencer. A group of the tumor-unique mutations from individual tumors were designated as individual marker mutations (MMs) to trace tumor burden by ctDNA using droplet digital PCR (ddPCR). From these experiments, three major objectives were assessed: (a) Tumor-unique mutations; (b) mutation spectrum of a tumor; and (c) changes in allele frequency of the MMs in ctDNA after curative resection of the tumor.ResultsA total of 128 gene point mutations were identified in 27 colorectal tumors. Twenty-six genes were mutated in at least 1 sample, while 14 genes were found to be mutated in only 1 sample, respectively. An average of 2.7 genes were mutated per tumor. Subsequently, 24 MMs were selected from SNVs for tumor burden monitoring. Among the MMs found by ddPCR with > 0.1% variant allele frequency in plasma DNA, 100% (8 out of 8) exhibited a decrease in post-operation ctDNA, whereas none of the 16 MMs found by ddPCR with < 0.1% variant allele frequency in plasma DNA showed a decrease.ConclusionsThis panel of 50 cancer-associated genes appeared to be sufficient to identify individual, tumor-unique, mutated ctDNA markers in cancer patients. The MMs showed the clinical utility in monitoring curatively-treated colorectal tumor burden if the allele frequency of MMs in plasma DNA is above 0.1%.

Dataset Information

Inflation of tumor mutation burden by tumor-only sequencing in under-represented groups.

Publications

Inflation of tumor mutation burden by tumor-only sequencing in under-represented groups.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets