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Targeted exome sequencing for the identification of common mutational signatures and potential driver mutations for brain metastases and prognosis.

ABSTRACT: Brain metastases (BMs) are malignancies in the central nervous system with poor prognosis. Genetic landscapes of the primary tumor sites have been extensively profiled; however, mutations associated with BMs are poorly understood. In the present study, target exome sequencing of 560 cancer-associated genes in samples from 52 patients with brain metastasis from various primary sites was performed. Recurrent mutations for BMs from distinct origins were identified. There were both genetic homogeneity and heterogeneity between BMs and primary lung tumor tissues. The mutation rate of the major cancer driver gene, TP53, was consistently high in both the primary lung cancer sites and BMs, while some genetic alterations, associated with DNA damage response deficiency, were specifically enriched in BMs. The mutational signatures enriched in BMs could serve as actionable targets for treatment. The mutation in the primary site of the potential brain metastasis driver gene, nuclear mitotic apparatus protein 1 (NUMA1), affected the progression-free survival time of patients with lung cancer, and patients with the NUMA1 mutation in BMs had a good prognosis. This suggested that the occurrence and clinical outcome of brain metastases could be independent of each other.

SUBMITTER: Zhang D

PROVIDER: S-EPMC7816386 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Targeted exome sequencing for the identification of common mutational signatures and potential driver mutations for brain metastases and prognosis.

Zhang Dainan D Wang Xi X Ma Shunchang S Li Peiliang P Xue Fei F Mao Beibei B Guan Xiudong X Zhou Wenjianlong W Peng Jiayi J Su Kun K Zhang Chuanbao C Jia Wang W

Oncology letters 20210106 3

Brain metastases (BMs) are malignancies in the central nervous system with poor prognosis. Genetic landscapes of the primary tumor sites have been extensively profiled; however, mutations associated with BMs are poorly understood. In the present study, target exome sequencing of 560 cancer-associated genes in samples from 52 patients with brain metastasis from various primary sites was performed. Recurrent mutations for BMs from distinct origins were identified. There were both genetic homogenei ...[more]

PMID: 33574918

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Project description:BackgroundWith the expanded availability of next generation sequencing (NGS)-based clinical genetic tests, clinicians seeking to test patients with Mendelian diseases must weigh the superior coverage of targeted gene panels with the greater number of genes included in whole exome sequencing (WES) when considering their first-tier testing approach. Here, we use an in silico analysis to predict the analytic sensitivity of WES using pathogenic variants identified on targeted NGS panels as a reference.MethodsCorresponding nucleotide positions for 1533 different alterations classified as pathogenic or likely pathogenic identified on targeted NGS multi-gene panel tests in our laboratory were interrogated in data from 100 randomly-selected clinical WES samples to quantify the sequence coverage at each position. Pathogenic variants represented 91 genes implicated in hereditary cancer, X-linked intellectual disability, primary ciliary dyskinesia, Marfan syndrome/aortic aneurysms, cardiomyopathies and arrhythmias.ResultsWhen assessing coverage among 100 individual WES samples for each pathogenic variant (153,300 individual assessments), 99.7% (n = 152,798) would likely have been detected on WES. All pathogenic variants had at least some coverage on exome sequencing, with a total of 97.3% (n = 1491) detectable across all 100 individuals. For the remaining 42 pathogenic variants, the number of WES samples with adequate coverage ranged from 35 to 99. Factors such as location in GC-rich, repetitive, or homologous regions likely explain why some of these alterations were not detected across all samples. To validate study findings, a similar analysis was performed against coverage data from 60,706 exomes available through the Exome Aggregation Consortium (ExAC). Results from this validation confirmed that 98.6% (91,743,296/93,062,298) of pathogenic variants demonstrated adequate depth for detection.ConclusionsResults from this in silico analysis suggest that exome sequencing may achieve a diagnostic yield similar to panel-based testing for Mendelian diseases.

Project description:PurposeExome- and whole-genome sequencing of muscle-invasive bladder cancer has revealed important insights into the molecular landscape; however, there are few studies of non-muscle-invasive bladder cancer with detailed risk factor information.Experimental designWe examined the relationship between smoking and other bladder cancer risk factors and somatic mutations and mutational signatures in bladder tumors. Targeted sequencing of frequently mutated genes in bladder cancer was conducted in 322 formalin-fixed paraffin-embedded bladder tumors from a population-based case-control study. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI), evaluating mutations and risk factors. We used SignatureEstimation to extract four known single base substitution mutational signatures and Poisson regression to calculate risk ratios (RR) and 95% CIs, evaluating signatures and risk factors.ResultsNon-silent KDM6A mutations were more common in females than males (OR = 1.83; 95% CI, 1.05-3.19). There was striking heterogeneity in the relationship between smoking status and established single base substitution signatures: current smoking status was associated with greater ERCC2-Signature mutations compared with former (P = 0.024) and never smoking (RR = 1.40; 95% CI, 1.09-1.80; P = 0.008), former smoking was associated with greater APOBEC-Signature13 mutations (P = 0.05), and never smoking was associated with greater APOBEC-Signature2 mutations (RR = 1.54; 95% CI, 1.17-2.01; P = 0.002). There was evidence that smoking duration (the component most strongly associated with bladder cancer risk) was associated with ERCC2-Signature mutations and APOBEC-Signature13 mutations among current (P trend = 0.005) and former smokers (P = 0.0004), respectively.ConclusionsThese data quantify the contribution of bladder cancer risk factors to mutational burden and suggest different signature enrichments among never, former, and current smokers.

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Targeted exome sequencing for the identification of common mutational signatures and potential driver mutations for brain metastases and prognosis.

Publications

Targeted exome sequencing for the identification of common mutational signatures and potential driver mutations for brain metastases and prognosis.

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