Dataset Information

Integrative pipeline for profiling DNA copy number and inferring tumor phylogeny.

ABSTRACT:

Summary

Copy number variation is an important and abundant source of variation in the human genome, which has been associated with a number of diseases, especially cancer. Massively parallel next-generation sequencing allows copy number profiling with fine resolution. Such efforts, however, have met with mixed successes, with setbacks arising partly from the lack of reliable analytical methods to meet the diverse and unique challenges arising from the myriad experimental designs and study goals in genetic studies. In cancer genomics, detection of somatic copy number changes and profiling of allele-specific copy number (ASCN) are complicated by experimental biases and artifacts as well as normal cell contamination and cancer subclone admixture. Furthermore, careful statistical modeling is warranted to reconstruct tumor phylogeny by both somatic ASCN changes and single nucleotide variants. Here we describe a flexible computational pipeline, MARATHON, which integrates multiple related statistical software for copy number profiling and downstream analyses in disease genetic studies.

Availability and implementation

MARATHON is publicly available at https://github.com/yuchaojiang/MARATHON.

Supplementary information

Supplementary data are available at Bioinformatics online.

SUBMITTER: Urrutia E

PROVIDER: S-EPMC6248831 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Publications

Integrative pipeline for profiling DNA copy number and inferring tumor phylogeny.

Urrutia Eugene E Chen Hao H Zhou Zilu Z Zhang Nancy R NR Jiang Yuchao Y

Bioinformatics (Oxford, England) 20180601 12

<h4>Summary</h4>Copy number variation is an important and abundant source of variation in the human genome, which has been associated with a number of diseases, especially cancer. Massively parallel next-generation sequencing allows copy number profiling with fine resolution. Such efforts, however, have met with mixed successes, with setbacks arising partly from the lack of reliable analytical methods to meet the diverse and unique challenges arising from the myriad experimental designs and stud ...[more]

PMID: 29415173

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Project description:MYCN amplification (MNA), segmental chromosomal aberrations (SCA) and ALK activating mutations are biomarkers for risk-group stratification and for targeted therapeutics for neuroblastoma, both of which are currently assessed on tissue biopsy. Increase in demand for tumor genetic testing for neuroblastoma diagnosis is posing a challenge to current practice, as the small size of the core needle biopsies obtained are required for multiple molecular tests. We evaluated the utility of detecting these biomarkers in the circulation. Various pre-analytical conditions tested to optimize circulating-tumor DNA (ctDNA) copy number changes evaluations. Plasma samples from 10 patients diagnosed with neuroblastoma assessed for SCA and MNA using single nucleotide polymorphism (SNP) array approach currently used for neuroblastoma diagnosis, with MNA status assessed independently using digital-droplet PCR (ddPCR). Three patients (one in common with the previous 10) tested for ALK activating mutations p.F1174L and p.F1245I using ddPCR. Copy number detection is highly affected by physical perturbations of the blood sample (mimicking suboptimal sample shipment), which could be overcome using specialized preservative collection tubes. Pre-analytical DNA repair procedures on ctDNA before SNP chromosome microarray processing improved the lower limit of detection for SCA and MNA, defined as 20% and 10%, respectively. We detected SCA in 10/10 (100%) patients using SNP array, 7 of which also presented MNA. Circulating-free DNA (cfDNA) and matched tumor DNA profiles were generally identical. MNA was detected using ddPCR in 7/7 (100%) of MNA and 0/12 (0%) non-MNA cases. MNA and ALK mutation dynamic change was assessed in longitudinal samples from 4 and 3 patients (one patient with both), respectively, accurately reflected response to treatment in 6/6 (100%) and disease recurrence in 5/6 (83%) of cases. Samples taken prior to targeted treatment with the ALK inhibitor Lorlatinib and 6-8 weeks on treatment showed reduction/increase in ALK variants according to response to treatment. These results demonstrate the feasibility of ctDNA profiling for molecular risk-stratification, and treatment monitoring in a clinically relevant time frame and the potential to reduce fresh tissue requirements currently embedded in the management of neuroblastoma.

Dataset Information

Integrative pipeline for profiling DNA copy number and inferring tumor phylogeny.

Summary

Availability and implementation

Supplementary information

Publications

Integrative pipeline for profiling DNA copy number and inferring tumor phylogeny.

Similar Datasets

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