Dataset Information

Mutational load in carotid body tumor.

ABSTRACT: BACKGROUND:Carotid body tumor (CBT) is a rare neoplasm arising from paraganglion located near the bifurcation of the carotid artery. There is great intra-tumor heterogeneity, and CBT development could be associated with both germline and somatic allelic variants. Studies on the molecular genetics of CBT are limited, and the molecular mechanisms of its pathogenesis are not fully understood. This work is focused on the estimation of mutational load (ML) in CBT. METHODS:Using the NextSeq 500 platform, we performed exome sequencing of tumors with matched lymph node tissues and peripheral blood obtained from six patients with CBT. To obtain reliable results in tumors with low ML, we developed and successfully applied a complex approach for the analysis of sequencing data. ML was evaluated as the number of somatic variants per megabase (Mb) of the target regions covered by the Illumina TruSeq Exome Library Prep Kit. RESULTS:The ML in CBT varied in the range of 0.09-0.28/Mb. Additionally, we identified several pathogenic/likely pathogenic somatic and germline allelic variants across six patients studied (including TP53 variants). CONCLUSIONS:Using the developed approach, we estimated the ML in CBT, which is much lower than in common malignant tumors. Identified variants in known paraganglioma/pheochromocytoma-causative genes and novel genes could be associated with the pathogenesis of CBT. The obtained results expand our knowledge of the mutation process in CBT as well as the biology of tumor development.

SUBMITTER: Kudryavtseva AV

PROVIDER: S-EPMC6416835 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Mutational load in carotid body tumor.

Kudryavtseva Anna V AV Lukyanova Elena N EN Kalinin Dmitry V DV Zaretsky Andrew R AR Pokrovsky Anatoly V AV Golovyuk Alexander L AL Fedorova Maria S MS Pudova Elena A EA Kharitonov Sergey L SL Pavlov Vladislav S VS Kobelyatskaya Anastasiya A AA Melnikova Nataliya V NV Dmitriev Alexey A AA Polyakov Andrey P AP Alekseev Boris Y BY Kiseleva Marina V MV Kaprin Andrey D AD Krasnov George S GS Snezhkina Anastasiya V AV

BMC medical genomics 20190313 Suppl 2

<h4>Background</h4>Carotid body tumor (CBT) is a rare neoplasm arising from paraganglion located near the bifurcation of the carotid artery. There is great intra-tumor heterogeneity, and CBT development could be associated with both germline and somatic allelic variants. Studies on the molecular genetics of CBT are limited, and the molecular mechanisms of its pathogenesis are not fully understood. This work is focused on the estimation of mutational load (ML) in CBT.<h4>Methods</h4>Using the Nex ...[more]

PMID: 30871634

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Project description:BackgroundCarotid body tumors (CBTs) are rare entities for which surgical resection remains the gold standard. Given their hypervascularity, preoperative embolization is often used; however, controversy exists over whether a benefit is associated. Proponents of embolization argue that it minimizes blood loss and complications. Critics argue that cost and stroke outweigh benefits. This study aimed to investigate the impact of embolization on outcomes following CBT resection.MethodsPatients undergoing CBT resection were identified using the Healthcare Cost and Utilization Project State Inpatient Database for 5 states between 2006 and 2013. Patients were divided into 2 groups: carotid body tumor resection alone (CBTR) and carotid body tumor resection with preoperative arterial embolization (CBETR). Descriptive statistics were calculated using arithmetic means with standard deviations for continuous variables and proportions for categorical variables. Patients were propensity score matched on the basis of sex, age, race, insurance, and comorbidity prior to analysis. Risk-adjusted odds of mortality, stroke, nerve injury, blood loss, and length of stay (LOS) were calculated using mixed-effects regression models with fixed effects for age, race, sex, and comorbidities.ResultsA total of 547 patients were identified. Of these, 472 patients underwent CBTR and 75 underwent CBETR. Mean age was 54.7 ± 16 years. Mean number of days between embolization and resection was 0.65 ± 0.72 days (range 0-3). When compared with CBTR, there were no significant differences in mortality for CBETR (1.35% vs. 0%, P = 0.316), cranial nerve injury (2.7% vs. 0%, P = 0.48), and blood loss (2.7% vs. 6.8%, P = 0.245). Following risk adjustment, CBETR increased the odds of prolonged LOS (odds ratio 5.3, 95% confidence interval 2.1-13.3).ConclusionsCBT resection is a relatively rare procedure. The utility of preoperative tumor embolization has been questioned. This study demonstrates no benefit of preoperative tumor embolization.

Project description:Background:Tumor mutational burden (TMB) is an increasingly important biomarker for immune checkpoint inhibitors. Recent publications have described strong association between high TMB and objective response to mono- and combination immunotherapies in several cancer types. Existing methods to estimate TMB require large amount of input DNA, which may not always be available. Methods:In this study, we develop a method to estimate TMB using the Oncomine Tumor Mutation Load (TML) Assay with 20 ng of DNA, and we characterize the performance of this method on various formalin-fixed, paraffin-embedded (FFPE) research samples of several cancer types. We measure the analytical performance of TML workflow through comparison with control samples with known truth, and we compare performance with an orthogonal method which uses matched normal sample to remove germline variants. We perform whole exome sequencing (WES) on a batch of FFPE samples and compare the WES TMB values with TMB estimates by the TML assay. Results:In-silico analyses demonstrated the Oncomine TML panel has sufficient genomic coverage to estimate somatic mutations with a strong correlation (r2=0.986) to WES. Further, in silico prediction using WES data from three separate cohorts and comparing with a subset of the WES overlapping with the TML panel, confirmed the ability to stratify responders and non-responders to immune checkpoint inhibitors with high statistical significance. We found the rate of somatic mutations with the TML assay on cell lines and control samples were similar to the known truth. We verified the performance of germline filtering using only a tumor sample in comparison to a matched tumor-normal experimental design to remove germline variants. We compared TMB estimates by the TML assay with that from WES on a batch of FFPE research samples and found high correlation (r2=0.83). We found biologically interesting tumorigenesis signatures on FFPE research samples of colorectal cancer (CRC), lung, and melanoma origin. Further, we assessed TMB on a cohort of FFPE research samples including lung, colon, and melanoma tumors to discover the biologically relevant range of TMB values. Conclusions:These results show that the TML assay targeting a 1.7-Mb genomic footprint can accurately predict TMB values that are comparable to the WES. The TML assay workflow incorporates a simple workflow using the Ion GeneStudio S5 System. Further, the AmpliSeq chemistry allows the use of low input DNA to estimate mutational burden from FFPE samples. This TMB assay enables scalable, robust research into immuno-oncology biomarkers with scarce samples.

Dataset Information

Mutational load in carotid body tumor.

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Mutational load in carotid body tumor.

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