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Fusion Kinases Identified by Genomic Analyses of Sporadic Microsatellite Instability −High Colorectal Cancers

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Fusion Kinases Identified by Genomic Analyses of Sporadic Microsatellite Instability −High Colorectal Cancers Published OnlineFirst October 2, 2018; DOI: 10.1158/1078-0432.CCR-18-1574 Research Article Clinical Cancer Research Fusion Kinases Identified by Genomic Analyses of Sporadic Microsatellite Instability–High Colorectal Cancers Kazuhito Sato1,2, Masahito Kawazu3, Yoko Yamamoto1, Toshihide Ueno2, Shinya Kojima2, Genta Nagae4, Hiroyuki Abe5, Manabu Soda2, Takafumi Oga2, Shinji Kohsaka3, Eirin Sai3, Yoshihiro Yamashita2, Hisae Iinuma6, Masashi Fukayama5, Hiroyuki Aburatani4, Toshiaki Watanabe7,†, and Hiroyuki Mano2,8 Abstract Purpose: Colorectal cancers with microsatellite instability– LS-associated) or somatic, Lynch-like mutations in mismatch high (MSI-H) status, due to mismatch repair deficiency, are repair genes. MM tumors had more insertions and deletions associated with poor patient outcomes after relapse. We aimed and more recurrent mutations in BRAF and RNF43 than to identify novel therapeutic targets for them. LS-associated or Lynch-like MSI-H tumors. Eleven fusion Experimental Design: We performed MSI analyses of over kinases were exclusively detected in MM MSI-H colorectal 2,800 surgically resected colorectal tumors obtained from cancers lacking oncogenic KRAS/BRAF missense mutations consecutive patients treated in Japan from 1998 through June and were associated with worse post-relapse prognosis. We 2016. Whole-exome sequencing, transcriptome sequencing, developed a simple method to identify MM tumors and and methylation analyses were performed on 149 of 162 applied it to a validation cohort of 28 MSI-H colorectal tumors showing MSI in BAT25 and BAT26 loci. We analyzed cancers, identifying 16 MM tumors and 2 fusion kinases. patient survival times using Bonferroni-adjusted log-rank Conclusions: We discovered that fusion kinases are tests. frequently observed among sporadic MM MSI-H colorectal Results: Sporadic MSI-H colorectal cancers with promoter cancers. The new method to identify MM tumors enables us methylation of MLH1 (called MM) had a clinicopathological to straightforwardly group MSI-H patients into candidates profile that was distinct from that of colorectal cancers of LS or fusion kinase carriers. Clin Cancer Res; 1–12. Ó2018 of patients with germline mutations (Lynch syndrome, AACR. Introduction are frequently altered (1–3). Most patients with MSI-H colorectal cancers have poor prognosis after relapse according to consensus Approximately 10% of all colorectal cancers exhibit a micro- molecular subtyping (4, 5), supporting the concept that MSI-H satellite instability–high (MSI-H) status, in which the number of cancers are resistant to 5-fluorouracil (6). The considerable num- mono-, di-, or tri-nucleotide repeats in microsatellite sequences ber of mutations resulting from DNA mismatch repair (MMR) deficiency has hampered the identification of driver oncogenes that play essential pathogenic roles in MSI-H colorectal cancers. 1Department of Surgical Oncology, Graduate School of Medicine, The University MSI-H colorectal cancers have been conventionally divided of Tokyo, Tokyo, Japan. 2Department of Cellular Signaling, Graduate School of into hereditary or sporadic. To identify cases potentially involving 3 Medicine, The University of Tokyo, Tokyo, Japan. Department of Medical Lynch syndrome (LS), we have to rely on patients' clinical infor- Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. mation, such as family history or age. It is well known that MSI-H 4Genome Science Division, Research Center for Advanced Science and Tech- nologies, The University of Tokyo, Tokyo, Japan. 5Department of Pathology, colorectal cancers are tightly linked to the CpG island methylator Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. phenotype (CIMP; refs. 7, 8), which is characterized by the cancer- 6Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan. specific methylation of a definite set of CpG islands. Rational 7Department of Surgical Oncology and Vascular Surgery, Graduate School of patient stratification based on the precise recognition of the 8 Medicine, The University of Tokyo, Tokyo, Japan. National Cancer Center etiology is essential for the appropriate management of patients Research Institute, Tokyo, Japan. with MSI-H colorectal cancers. Note: Supplementary data for this article are available at Clinical Cancer To address these issues, we conducted an integrated molecular Research Online (http://clincancerres.aacrjournals.org/). characterization of 149 MSI-H colorectal tumors. †Deceased. Corresponding Author: Masahito Kawazu, Graduate School of Medicine, The Material and Methods University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, Phone: 81- Ethics 3-3547-5201: E-mail: [email protected] Patients with colorectal cancer gave written informed consent doi: 10.1158/1078-0432.CCR-18-1574 prior to their participation in the study. This project was approved Ó2018 American Association for Cancer Research. by the institutional ethics committees of The University of Tokyo www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst October 2, 2018; DOI: 10.1158/1078-0432.CCR-18-1574 Sato et al. genome-wide DNA methylation profiles of 93 tumors with an Translational Relevance Infinium Human MethylationEPIC BeadChip (Illumina) and Microsatellite instability–high (MSI-H) colorectal cancers performed whole-transcriptome sequencing (RNA-seq) from have been conventionally divided into hereditary (Lynch syn- 111 MSI-H with HiSeq2500 (Illumina). drome, LS) and sporadic categories. This report provides a fi rational basis for further classi cation of sporadic MSI-H colo- DNA methylation analyses rectal cancers into those with somatic mutations in mismatch Genome-wide DNA methylation analysis. Infinium Human repair genes (Lynch-like, LL) and those with promoter meth- MethylationEPIC BeadChip (Illumina) was used in accordance fi ylation of MLH1 (MM). There were signi cant differences with the manufacturer's protocol. Beta values were normalized between the LS/LL and MM groups in clinicopathological using BMIQ function in the R package wateRmelon (http:// properties including tumor localization, number of inser- www.bioconductor.org/packages/release/bioc/html/wateRmel tions/deletions, and recurrent mutations of KRAS/APC and on.html). For downstream analysis, we selected probes that fi BRAF/RNF43. Such a classi cation would enable precise man- were designed on promoter-associated sites of autosomes. agement of patients with MSI-H colorectal cancer. Fusion Then, we performed consensus clustering with 3,073 probes kinases were detected only in MM MSI-H colorectal cancers (probes with variance rankedinthetop1%)usingtheR lacking oncogenic KRAS or BRAF mutations and were associ- package ConsensusClusterPlus (http://www.bioconductor. ated with worse prognosis after relapse. A new, convenient org/packages/release/bioc/html/ConsensusClusterPlus.html). method for detecting MM tumors makes it possible to straight- forwardlyidentifyLScandidatesorMSI-Htumorslikelytocarry Bisulfite sequencing of MLH1 promoter. Genomic DNA was fusion kinases that are therapeutic targets of kinase inhibitors. subjected to bisulfite conversion using an EpiTect Bisulfite Kit (Qiagen). Converted DNA fragments were amplified by PCR using a Kapa HiFi Uracilþ Kit (Kapa Biosystems) with the primer sets indicated in Supplementary Table S1. Amplified PCR pro- (The Human Genome, Gene Analysis Research Ethics Committee; ducts were subjected to sequencing using the MiSeq system G10063 and G3546) and Teikyo University (#14–197), and the (Illumina) to determine the proportion of methylated alleles at study was conducted in accordance with the Declaration of each cytosine residue. Helsinki. MLH1 promoter methylation assay with methylation-sensitive Sample collection restriction enzyme. MLH1 promoter methylation was assessed by Surgically resected colorectal tumors (n ¼2,800) were PCR after digestion of genomic DNA with methylation-sensitive obtained from consecutive patients treated at The University of restriction enzyme. Genomic DNA (200 or 25 ng) was digested in Tokyo Hospital and Teikyo University Hospital between 1998 a volume of 20 or 10 mL by Anza 22 SmaI (Thermo Fisher and June 2016. To validate a fusion-detection strategy, we added Scientific), followed by heat inactivation of restriction enzyme, 185 primary colorectal cancers, collected at The University of in accordance with the manufacturer's instructions. Digested DNA Tokyo Hospital from July 2016 through April 2017. (20 or 5 ng) was subjected to 25 or 27 cycles of multiplex PCR in a total volume of 25 mL using primeSTAR GXL DNA polymerase Microsatellite instability testing (Takara Bio), in accordance with the manufacturer's instructions. Tumor tissues and corresponding normal mucosae were BRAF was used as a positive control. The primer sets are indicated obtained from surgically resected specimens and were either in Supplementary Table S1. Methylation status was determined by snap-frozen in liquid nitrogen immediately after resection and 2% agarose gel electrophoresis of 12.5 mL of PCR products. stored at À80C or immersed in RNAlater Tissue Protect Tubes (Qiagen) overnight at 4 C followed by storage at À20 C until use. Whole-exome sequencing including mutation call, Genomic DNA was extracted from tissue samples with the DNeasy copy-number analysis, and signature analysis Blood and Tissue Kit or the QIAamp DNA Mini Kit (Qiagen) and Genomic DNA was isolated
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