Genomic landscape of colorectal cancer in Japan: clinical implications of comprehensive genomic sequencing for precision medicine

Abstract

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.

Accurate Pan-Cancer Molecular Diagnosis of Microsatellite Instability by Single-Molecule Molecular Inversion Probe Capture and High-Throughput Sequencing

“…However, tumor mutational burden has an unpredictable relationship with MSI, and its prognostic significance for immunotherapy response remains of questionable clinical utility (36–39). The accurate prediction of tumor mutational burden also requires sequencing large numbers of genes, either whole exome sequence data or panels of at least 400 genes in size (40), which is both cost and material limiting for many tumors.…”

Formalin-fixed paraffin-embedded sample conditions for deep next generation sequencing

“…28 Moreover, the collection of a large number of samples enables analysis of tumor genome signature differences between various ethnicities. 14 However, the NGS approach has limitations. First of all, one of the major limitations of NGS is the cost.…”

“…In our study, DNA with a Q-ratio (129 bp/41 bp) > 0.1 was designated as being of high enough quality for NGS analysis based on our previous results. 14, 19 …”

“…13 The essence of precision medicine is to minimize the toxicity of cancer treatment while maximizing benefit by subgrouping patients according to genomic alterations that can be treated with specific molecular-targeted therapy. 14 Given its concept, precision medicine is expected to provide cost-effectiveness by improving treatment efficacy while avoiding ineffective treatments. 15 …”

Next generation sequencing‐based gene panel tests for the management of solid tumors

“…Large‐scale genomic studies, including The Cancer Genome Atlas (TCGA; http://cancergenome.nih.gov/) and the International Cancer Genome Consortium (ICGC; http://www.icgc.org/), have identified major driver‐gene mutations in various types of solid tumors, which have led to new therapeutic strategies for precision cancer medicine . The main platform for TCGA and ICGC projects was whole exome sequencing (WES) utilizing next generation sequencing (NGS), which has provided comprehensive gene alteration data in protein‐coding regions for all types of human cancer .…”