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

Nagahashi M1, Wakai T2, Shimada Y1, Ichikawa H1, Kameyama H1, Kobayashi T1, Sakata J1, Yagi R1, Sato N3, Kitagawa Y4, Uetake H5, Yoshida K6, Oki E7, Kudo SE8, Izutsu H9, Kodama K9, Nakada M9, Tse J10, Russell M10, Heyer J10, Powers W10, Sun R10, Ring JE10, Takabe K11,12, Protopopov A10, Ling Y13, Okuda S14, Lyle S15,16.

Author information

Abstract

BACKGROUND:

Comprehensive 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).

METHODS:

Using 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.

RESULTS:

The 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.

CONCLUSIONS:

Use 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.