Dataset Information

Targeted next generation sequencing in Chinese colorectal cancer patients guided anti-EGFR treatment and facilitated precision cancer medicine.

ABSTRACT:

Objective

Colorectal cancer (CRC) patients with both RAS and BRAF wild-type tumors determined by non-next generation sequencing (NGS) testing may still not respond due to the presence of additional mutated genes such as PIK3CA or PTEN. In this study, a broad, hybrid capture-based NGS assay was used to identify RAS, BRAF and additional targetable genetic alterations from Chinese CRC tissues.

Methods

Fifty-seven cases of CRC were enrolled, and all the patients signed the informed consent. In total, 7708 exons of 508 tumor-related genes and 78 introns of 19 frequently rearranged genes were assessed for base substitutions, INDELs, copy number alterations, and gene fusions.

Results

The study found that 50.9% (29/57) of the tumors harbored KRAS mutations, 3.5% (2/57) harbored NRAS mutations and 3.5% (2/57) harbored BRAF mutations. More specifically, 89.7% (26/29) of RAS mutations were located in codon 12. Except for RAS and RAF, anti-EGFR therapy response genetic mutations in PTEN (n=2) and PIK3CA (n=1) were found in 4.7% (3/64) of the samples. Actionable alterations were found in HER2 (n = 7), CCND2 (n = 2), NF1 (n = 1), and BRCA1 (n = 1).

Conclusions

Our results illustrated that 82.5% (47/57) of the samples harbored at least one actionable genetic alteration identified by NGS. HER2 amplifications or mutations, which were identified in 12.3% of the tissues, defined a unique molecular subtype of CRC. The study suggests that high-throughput NGS testing in CRC tissues is a comprehensive and efficient genomic profiling assay to guide personalized therapy.

SUBMITTER: Hou H

PROVIDER: S-EPMC5739621 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Publications

Targeted next generation sequencing in Chinese colorectal cancer patients guided anti-EGFR treatment and facilitated precision cancer medicine.

Hou Helei H Liu Dong D Zhang Chuantao C Jiang Yanxia Y Lu Guifang G Zhou Na N Yang Xiaonan X Zhang Xiaoping X Li Zhuokun Z Zhu Hongmei H Qian Zhaoyang Z Zhang Xiaochun X

Oncotarget 20170927 62

<h4>Objective</h4>Colorectal cancer (CRC) patients with both <i>RAS</i> and <i>BRAF</i> wild-type tumors determined by non-next generation sequencing (NGS) testing may still not respond due to the presence of additional mutated genes such as <i>PIK3CA</i> or <i>PTEN</i>. In this study, a broad, hybrid capture-based NGS assay was used to identify <i>RAS, BRAF</i> and additional targetable genetic alterations from Chinese CRC tissues.<h4>Methods</h4>Fifty-seven cases of CRC were enrolled, and all ...[more]

PMID: 29285234

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Project description:BackgroundTargeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 (CYP) 2D6 gene, or to identify the promoter (TA)7 TAA repeat polymorphism UDP glucuronosyltransferase (UGT) 1A1*28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response.MethodsA panel of capture probes was generated to assess 422 kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms.ResultsAdequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1*28. Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy.ConclusionsPGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a tumor with an extremely poor prognosis, predominantly as a result of chemotherapy resistance and numerous somatic mutations. Consequently, PDAC is a prime candidate for the use of sequencing to identify causative mutations, facilitating subsequent administration of targeted therapy. In a feasibility study, we retrospectively assessed the therapeutic recommendations of a novel, evidence-based software that analyzes next-generation sequencing (NGS) data using a large panel of pharmacogenomic biomarkers for efficacy and toxicity. Tissue from 14 patients with PDAC was sequenced using NGS with a 620 gene panel. FASTQ files were fed into treatmentmap. The results were compared with chemotherapy in the patients, including all side effects. No changes in therapy were made. Known driver mutations for PDAC were confirmed (e.g. KRAS, TP53). Software analysis revealed positive biomarkers for predicted effective and ineffective treatments in all patients. At least one biomarker associated with increased toxicity could be detected in all patients. Patients had been receiving one of the currently approved chemotherapy agents. In two patients, toxicity could have been correctly predicted by the software analysis. The results suggest that NGS, in combination with an evidence-based software, could be conducted within a 2-week period, thus being feasible for clinical routine. Therapy recommendations were principally off-label use. Based on the predominant KRAS mutations, other drugs were predicted to be ineffective. The pharmacogenomic biomarkers indicative of increased toxicity could be retrospectively linked to reported negative side effects in the respective patients. Finally, the occurrence of somatic and germline mutations in cancer syndrome-associated genes is noteworthy, despite a high frequency of these particular variants in the background population. These results suggest software-analysis of NGS data provides evidence-based information on effective, ineffective and toxic drugs, potentially forming the basis for precision cancer medicine in PDAC.

Dataset Information

Targeted next generation sequencing in Chinese colorectal cancer patients guided anti-EGFR treatment and facilitated precision cancer medicine.

Objective

Methods

Results

Conclusions

Publications

Targeted next generation sequencing in Chinese colorectal cancer patients guided anti-EGFR treatment and facilitated precision cancer medicine.

Similar Datasets

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