Next generation sequencing (NGS) has been an invaluable tool to put genomic sequencing into clinical practice. The incorporation of clinically relevant target sequences into NGS‐based gene panel tests has generated practical diagnostic tools that enable individualized cancer‐patient care. The clinical utility of gene panel testing includes investigation of the genetic basis for an individual's response to therapy, such as signaling pathways associated with a response to specific therapies, microsatellite instability and a hypermutated phenotype, and deficiency in the DNA double‐strand break repair pathway. In this review, we describe the concept of precision cancer medicine using target sequences in gene panel tests as well as the importance of the control of sample quality in routine NGS‐based genomic testing. We describe geographic and ethnic differences in cancer genomes, and discuss issues that need to be addressed in the future based on our experiences in Japan.
BackgroundComprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC).MethodsUsing next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC.ResultsThe 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double-strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy.ConclusionsUse of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0387-8) contains supplementary material, which is available to authorized users.
BackgroundIntertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed.MethodsA total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were obtained from surgical or biopsy specimens and were subjected to DNA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired with US Food and Drug Administration-approved targeted therapies, and the evaluation of Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status.ResultsComprehensive genomic sequencing detected at least one alteration of 435 cancer-related genes in 194 GCs (93.7%) and of 69 actionable genes in 141 GCs (68.1%). We classified the 207 GCs into four The Cancer Genome Atlas (TCGA) subtypes using the genomic profiling data; EBV (N = 9), MSI (N = 17), chromosomal instability (N = 119), and genomically stable subtype (N = 62). Actionable gene alterations were not specific and were widely observed throughout all TCGA subtypes. To discover a novel classification which more precisely selects candidates for targeted therapies, 207 GCs were classified using hypermutated phenotype and the mutation profile of 69 actionable genes. We identified a hypermutated group (N = 32), while the others (N = 175) were sub-divided into six clusters including five with actionable gene alterations: ERBB2 (N = 25), CDKN2A, and CDKN2B (N = 10), KRAS (N = 10), BRCA2 (N = 9), and ATM cluster (N = 12). The clinical utility of this classification was demonstrated by a case of unresectable GC with a remarkable response to anti-HER2 therapy in the ERBB2 cluster.ConclusionsThis actionable gene-based classification creates a framework for further studies for realizing precision medicine in GC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0484-3) contains supplementary material, which is available to authorized users.
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