Dataset Information

A pilot study using next-generation sequencing in advanced cancers: feasibility and challenges.

ABSTRACT:

Purpose

New anticancer agents that target a single cell surface receptor, up-regulated or amplified gene product, or mutated gene, have met with some success in treating advanced cancers. However, patients' tumors still eventually progress on these therapies. If it were possible to identify a larger number of targetable vulnerabilities in an individual's tumor, multiple targets could be exploited with the use of specific therapeutic agents, thus possibly giving the patient viable therapeutic alternatives.

Experimental design

In this exploratory study, we used next-generation sequencing technologies (NGS) including whole genome sequencing (WGS), and where feasible, whole transcriptome sequencing (WTS) to identify genomic events and associated expression changes in advanced cancer patients.

Results

WGS on paired tumor and normal samples from nine advanced cancer patients and WTS on six of these patients' tumors was completed. One patient's treatment was based on targets and pathways identified by NGS and the patient had a short-lived PET/CT response with a significant reduction in his tumor-related pain. To design treatment plans based on information garnered from NGS, several challenges were encountered: NGS reporting delays, communication of results to out-of-state participants and their treating oncologists, and chain of custody handling for fresh biopsy samples for Clinical Laboratory Improvement Amendments (CLIA) target validation.

Conclusion

While the initial effort was a slower process than anticipated due to a variety of issues, we demonstrate the feasibility of using NGS in advanced cancer patients so that treatments for patients with progressing tumors may be improved.

SUBMITTER: Weiss GJ

PROVIDER: S-EPMC3813699 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

A pilot study using next-generation sequencing in advanced cancers: feasibility and challenges.

Weiss Glen J GJ Liang Winnie S WS Demeure Michael J MJ Kiefer Jeff A JA Hostetter Galen G Izatt Tyler T Sinari Shripad S Christoforides Alexis A Aldrich Jessica J Kurdoglu Ahmet A Phillips Lori L Benson Hollie H Reiman Rebecca R Baker Angela A Marsh Vickie V Von Hoff Daniel D DD Carpten John D JD Craig David W DW

PloS one 20131030 10

<h4>Purpose</h4>New anticancer agents that target a single cell surface receptor, up-regulated or amplified gene product, or mutated gene, have met with some success in treating advanced cancers. However, patients' tumors still eventually progress on these therapies. If it were possible to identify a larger number of targetable vulnerabilities in an individual's tumor, multiple targets could be exploited with the use of specific therapeutic agents, thus possibly giving the patient viable therape ...[more]

PMID: 24204627

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Project description:To date we have little knowledge of how accurate next-generation sequencing (NGS) technologies are in sequencing repetitive sequences beyond known limitations to accurately sequence homopolymers. Only a handful of previous reports have evaluated the potential of NGS for sequencing short tandem repeats (microsatellites) and no empirical study has compared and evaluated the performance of more than one NGS platform with the same dataset. Here we examined yeast microsatellite variants from both long-read (454-sequencing) and short-read (Illumina) NGS platforms and compared these to data derived through Sanger sequencing. In addition, we investigated any locus-specific biases and differences that might have resulted from variability in microsatellite repeat number, repeat motif or type of mutation. Out of 112 insertion/deletion variants identified among 45 microsatellite amplicons in our study, we found 87.5% agreement between the 454-platform and Sanger sequencing in frequency of variant detection after Benjamini-Hochberg correction for multiple tests. For a subset of 21 microsatellite amplicons derived from Illumina sequencing, the results of short-read platform were highly consistent with the other two platforms, with 100% agreement with 454-sequencing and 93.6% agreement with the Sanger method after Benjamini-Hochberg correction. We found that the microsatellite attributes copy number, repeat motif and type of mutation did not have a significant effect on differences seen between the sequencing platforms. We show that both long-read and short-read NGS platforms can be used to sequence short tandem repeats accurately, which makes it feasible to consider the use of these platforms in high-throughput genotyping. It appears the major requirement for achieving both high accuracy and rare variant detection in microsatellite genotyping is sufficient read depth coverage. This might be a challenge because each platform generates a consistent pattern of non-uniform sequence coverage, which, as our study suggests, may affect some types of tandem repeats more than others.

Project description:BACKGROUND:Appendiceal cancers (ACs) are rare. The genomic landscape of ACs has not been well studied. The aim of this study was to confirm the feasibility of next-generation sequencing (NGS) using circulating tumor DNA (ctDNA) in ACs and characterize common genomic alterations. MATERIALS AND METHODS:Molecular alterations in 372 plasma samples from 303 patients with AC using clinical-grade NGS of ctDNA (Guardant360) across multiple institutions were evaluated. Test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes. RESULTS:A total of 303 patients with AC were evaluated, of which 169 (56%) were female. Median age was 56.8 (25-83) years. ctDNA NGS testing was performed on 372 plasma samples; 48 patients had testing performed twice, 9 patients had testing performed three times, and 1 patient had testing performed four times. Genomic alterations were defined in 207 (n =?207/372, 55.6%) samples, and 288 alterations were identified excluding variants of uncertain significance and synonymous mutations. Alterations were identified in at least one sample from 184 patients; TP53-associated genes (n =?71, 38.6%), KRAS (n =?33, 17.9%), APC (n =?14, 7.6%), EGFR (n =?12, 6.5%), BRAF (n =?11, 5.9%), NF1 (n =?10, 5.4%), MYC (n =?9, 4.9%), GNAS (n =?8, 4.3%), MET (n =?6, 3.3%), PIK3CA (n =?5, 2.7%), and ATM (n =?5, 2.7%). Other low-frequency but clinically relevant genomic alterations were as follows: AR (n =?4, 2.2%), TERT (n =?4, 2.2%), ERBB2 (n =?4, 2.2%), SMAD4 (n =?3, 1.6%), CDK4 (n =?2, 1.1%), NRAS (n =?2, 1.1%), FGFR1 (n =?2, 1.1%), FGFR2 (n =?2, 1.1%), PTEN (n =?2, 1.1%), RB1 (n =?2, 1.1%), and CDK6, CDKN2A, BRCA1, BRCA2, JAK2, IDH2, MAPK, NTRK1, CDH1, ARID1A, and PDGFRA (n =?1, 0.5%). CONCLUSION:Evaluation of ctDNA is feasible among patients with AC. The frequency of genomic alterations is similar to that previously reported in tissue NGS. Liquid biopsies are not invasive and can provide personalized options for targeted therapies in patients with AC. IMPLICATIONS FOR PRACTICE:The complexity of appendiceal cancer and its unique genomic characteristics suggest that customized combination therapy may be required for many patients. Theoretically, as more oncogenic pathways are discovered and more targeted therapies are approved, customized treatment based on the patient's unique molecular profile will lead to personalized care and improve patient outcomes. Liquid biopsies are noninvasive, cost-effective, and promising methods that provide patients with access to personalized treatment.

Dataset Information

A pilot study using next-generation sequencing in advanced cancers: feasibility and challenges.

Purpose

Experimental design

Results

Conclusion

Publications

A pilot study using next-generation sequencing in advanced cancers: feasibility and challenges.

Similar Datasets

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