Inflation of tumor mutation burden by tumor-only sequencing in under-represented groups.
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ABSTRACT:
SUBMITTER: Asmann YW
PROVIDER: S-EPMC7979755 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Genotype-based dosing recommendations are provided in the US FDA-approved warfarin labeling. However, data that informed these recommendations were from predominately Caucasian populations. Studies show that variants contributing to warfarin dose requirements in Caucasians provide similar contributions to dose requirements in US Hispanics, but significantly lesser contributions in African-Americans. Further data demonstrate that variants occurring commonly in individuals of African ancestry, but rarely in other racial groups, significantly influence dose requirements in African-Americans. These data suggest that it is important to consider variants specific for African-Americans when implementing genotype-guided warfarin dosing in this population.
| S-EPMC3463230 | biostudies-literature
Project description:Many important decisions in societies such as school admissions, hiring or elections are based on the selection of top-ranking individuals from a larger pool of candidates. This process is often subject to biases, which typically manifest as an under-representation of certain groups among the selected or accepted individuals. The most common approach to this issue is debiasing, for example, via the introduction of quotas that ensure a proportional representation of groups with respect to a certain, often binary attribute. This, however, has the potential to induce changes in representation with respect to other attributes. For the case of two correlated binary attributes, we show that quota-based debiasing based on a single attribute can worsen the representation of the most under-represented intersectional groups and decrease the overall fairness of selection. Our results demonstrate the importance of including all relevant attributes in debiasing procedures and that more efforts need to be put into eliminating the root causes of inequalities as purely numerical solutions such as quota-based debiasing might lead to unintended consequences.
| S-EPMC8456145 | biostudies-literature
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.
| S-EPMC11292426 | biostudies-literature
Project description:Renal cell carcinoma (RCC) is one of most common cancers with gradually increasing incidence and high mortality. Chromogenic RCC (chRCC) is the third most common histological subtype of RCC, accounting for approximately 5-7% of RCC. In our study, the transcriptome expression profile data (n=89) of chRCC, corresponding clinical data (n=113) and the somatic mutation data (n=66) were obtained from the TCGA database. We first analyzed the mutation data of chRCC patients and divided chRCC patients into high and low tumor mutation burden (TMB) groups based on the median TMB. We found that high TMB was significantly associated with worse prognosis and could promote tumor metastasis and development. Moreover, four different immune-related genes (BIRC5, PDGFRL, INHBE, IL20RB) were also identified. We found that BIRC5 was significantly overexpressed in the high TMB group and correlated with worse prognosis. The results of univariate and multivariate COX analyses demonstrated that BIRC5 (hazard ratio (HR) = 2.094) may serve as a prognostic indicator for patients with chRCC with high TMB. In addition, we identified the possible functional pathways of BIRC5 through gene set enrichment analysis (GSEA) enrichment. A positive correlation was obtained between BIRC5 and the abundance of CD4+ T cells. The results of our study revealed their correlation between the immune-related genes and clinicopathologic features as well as potential functional pathways as well as immune infiltrating cells, which may provide more data about the development of chRCC immunotherapy.
| S-EPMC7378265 | biostudies-literature
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%.
| S-EPMC4699643 | biostudies-literature
Project description:Tumor mutation burden (TMB) is a well-known efficacy predictor for checkpoint inhibitor immunotherapies. Currently, TMB assessment relies on DNA sequencing data. Gene expression profiling by RNA sequencing (RNAseq) is another type of analysis that can inform clinical decision-making and including TMB estimation may strongly benefit this approach, especially for the formalin-fixed, paraffin-embedded (FFPE) tissue samples. Here, we for the first time compared TMB levels deduced from whole exome sequencing (WES) and RNAseq profiles of the same FFPE biosamples in single-sample mode. We took TCGA project data with mean sequencing depth 23 million gene-mapped reads (MGMRs) and found 0.46 (Pearson)-0.59 (Spearman) correlation with standard mutation calling pipelines. This was converted into low (<10) and high (>10) TMB per megabase classifier with area under the curve (AUC) 0.757, and application of machine learning increased AUC till 0.854. We then compared 73 experimental pairs of WES and RNAseq profiles with lower (mean 11 MGMRs) and higher (mean 68 MGMRs) RNA sequencing depths. For higher depth, we observed ~1 AUC for the high/low TMB classifier and 0.85 (Pearson)-0.95 (Spearman) correlation with standard mutation calling pipelines. For the lower depth, the AUC was below the high-quality threshold of 0.7. Thus, we conclude that using RNA sequencing of tumor materials from FFPE blocks with enough coverage can afford for high-quality discrimination of tumors with high and low TMB levels in a single-sample mode.
| S-EPMC8506044 | biostudies-literature
Project description:The causes underlying racial disparities in cancer are multifactorial. In addition to socioeconomic issues, biological factors may contribute to these inequities, especially in disease incidence and patient survival. To date, there have been few studies that relate the disparities in these aspects to genetic aberrations. In this work, we studied the impacts of race on the patient survival and tumor mutation burden using the data released by the Cancer Genome Atlas (TCGA). The potential relationship between mutation burden and disease incidence is further inferred by an integrative analysis of TCGA data and the data from the Surveillance, Epidemiology, and End Results (SEER) Program. The results show that disparities are present (p < 0.05) in patient survival of five cancers, such as head and neck squamous cell carcinoma. The numbers of tumor driver mutations are differentiated (p < 0.05) over the racial groups in five cancers, such as lung adenocarcinoma. By treating a specific cancer type and a racial group as an "experimental unit", driver mutation numbers demonstrate a significant (r = 0.46, p < 0.002) positive correlation with cancer incidence rates, especially when the five cancers with mutational disparities are exclusively focused (r = 0.88, p < 0.00002). These results enrich our understanding of racial disparities in cancer and carcinogenic process.
| S-EPMC5651797 | biostudies-literature
Project description:Background:With the increasing use of immune checkpoint inhibitors, tumor mutation burden (TMB) assessment is now routinely included in reports generated from targeted sequencing with large gene panels; however, not all patients require comprehensive profiling with large panels. Our study aims to explore the feasibility of using a small 56-gene panel as a screening method for TMB prediction. Methods:TMB from 406 non-small cell lung cancer (NSCLC) patients was estimated using a large 520-gene panel simulated with the prospective TMB status for the small panel. This information was then used to determine the optimal cut-off. An independent cohort of 30 NSCLC patients was sequenced with both panels to confirm the cut-off value. Results:By comparing sensitivity, specificity, and positive predictive value (PPV), the cut-off was set up as 10 mutations/megabase, yielding 81.4% specificity, 83.6% sensitivity, and 62.4% PPV. Further validation with an independent cohort sequenced with both panels using the same cut-off achieved 95.7% sensitivity, 71.4% specificity and 91.7% PPV. The decreasing trend of sensitivity with the increasing trend of both specificity and PPV with a concomitant increase in the cut-off for the small panel suggests that TMB is overestimated but highly unlikely to yield false-positive results. Hence, patients with low TMB (<10) can be reliably stratified from patients with high TMB (?10). Conclusions:The small panel, more cost-effective, can be used as a screening method to screen for patients with low TMB, while patients with TMB ?10 are recommended for further validation with a larger panel.
| S-EPMC7082297 | biostudies-literature
Project description:BackgroundTumor mutation burden is an emerging biomarker for immunotherapy. Although several clinical trials for immunotherapy in lymphoma have been carried out, the mutation burden of various lymphomas is not well known yet. Thus, the objective of this study was to compare tumor mutation burden of various non-Hodgkin lymphomas using panel based massively parallel sequencing.MethodsWe conducted 405 gene panel based massively parallel sequencing of 300 non-Hodgkin lymphomas and investigate the number of SNV/Indel in each lymphoma.ResultsThe number of SNV/Indel was higher in mature B-cell lymphoma than in mature T- and NK-cell lymphoma. (P < 0.001) The number of SNV/Indel in primary mediastinal large B-cell lymphoma and primary diffuse large B-cell lymphoma of the central nervous system was the highest, which was significantly higher than that in diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS).(P = 0.030 and P = 0.008, respectively) The SNV/Indel number in EBV-positive DLBCL NOS was significantly lower than that in DLBCL NOS. (P = 0.048) Peripheral T-cell lymphoma, NOS showed no significant difference in the number of SNV/Indel from extranodal NK/T-cell lymphoma, nasal type (P = 0.942) or angioimmunoblastic T-cell lymphoma (P = 0.739). The number of SNV/Indel in anaplastic large cell lymphoma, ALK-positive was significantly lower than that in anaplastic large cell lymphoma, ALK-negative (P = 0.049). It was the lowest among all the lymphomas considered.ConclusionVarious lymphomas have different mutation burdens. Thus, tumor mutation burden can be used as a promising biomarker for immunotherapy in lymphomas.
| S-EPMC8404326 | biostudies-literature
Project description:Bladder cancer is one of the most commonly diagnosed tumors and is results from the accumulation of somatic mutations in the DNA. Tumor mutation burden (TMB) has been associated with cancer immunotherapeutic response. In this study, we attempted to explore the correlation between TMB and cancer prognosis. Identify the different expressed genes and immune cell infiltration signatures between low and high TMB group. Mutation data, gene expression profiles and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Patients were divided into high and low TMB groups, allowing differentially expressed genes (DEGs) to be identified. Functional enrichment and protein-protein interaction (PPI) network analysis were used to identify the functions of the DEGs. And immune cell infiltration signatures were evaluated by CIBERSORT algorithm. These results shown that high TMB was significantly associated with prognosis. We obtained a list of TMB related genes which may influence the infiltrations of immune cells. We also found a higher proportion of CD8 T cells, CD4 T cells and NK cells in the high TMB group. Our data suggest that higher TMB tends to promote the infiltrations of T cells and NK cells and patients with higher TMB may achieve a more favorable prognosis in bladder cancer.
| S-EPMC6945555 | biostudies-literature