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Identification of Somatic Mutations Using Whole-Exome Sequencing In Heo et al. BMC Medical Genetics (2017) 18:23 DOI 10.1186/s12881-017-0382-y RESEARCHARTICLE Open Access Identification of somatic mutations using whole-exome sequencing in Korean patients with acute myeloid leukemia Seong Gu Heo1,2, Youngil Koh3, Jong Kwang Kim4,5, Jongsun Jung6, Hyung-Lae Kim7, Sung-Soo Yoon3 and Ji Wan Park1* Abstract Background: Acute myeloid leukemia (AML) is a biologically and clinically heterogeneous cancer of the bone marrow that is characterized by the rapid growth of abnormal myeloid cells. Methods: We performed a mutational analysis to identify AML somatic mutations using the whole-exome sequencing data of 36 tumor-normal sample pairs from Korean patients with de novo AML. We explored the functional impact of the genes identified in the mutational analyses through an integrated Gene Ontology (GO) and pathway analysis. Results: A total of 11 genes, including NEFH (p = 6.27 × 10−13 and q = 1.18 × 10−8) and TMPRSS13 (p = 1.40 × 10−10 and q = 1.32 × 10−6), also demonstrated q values less than 0.1 in 36 Korean AML patients. Five out of the 11 novel genes have previously been reported to be associated with other cancers. Two gene mutations, CEBPA (p = 5.22 × 10−5) and ATXN3 (p = 9.75 × 10−4), showed statistical significance exclusively in the M2 and M3 subtypes of the French-American-British classifications, respectively. A total of 501 genes harbored 478 missense, 22 nonsense, 93 frameshift indels, and/or three stop codon deletions and these gene mutations significantly enriched GO terms for signal transduction (GO:0007165, p = 1.77 × 10−3), plasma membrane (GO:0005886, p = 3.07 × 10−4), and scaffold protein binding (GO:0097110, p = 8.65 × 10−4). The mitogen-activated protein kinase (hsa04010, 7.67 × 10−4) was the most enriched Kyoto Encyclopedia of Genes and Genomes pathway. Conclusions: Morphological AML subtypes may in part reflect subtype specific patterns of genomic alterations. Following validation, future studies to evaluate the usefulness of these genes in genetic testing for the early diagnosis and prognostic prediction of AML patients would be worthwhile. Keywords: Acute myeloid leukemia, Gene ontology, Pathway analysis, Somatic mutation, Subtype-specific mutation, Whole-exome sequencing Background studies provide important diagnostic and prognostic Acute myeloid leukemia (AML) is a highly malignant information for AML patients. However, approximately cancer of the bone marrow that is characterized by the 50% of AML patients have a normal karyotype (NK- rapid growth of abnormal myeloid cells. In 2012, AML). Although Schlenck et al. showed that the com- leukemia accounted for 2.5% and 3.2% of all new cancer bination of the mutations in FLT and NPM1 or CCAAT/ cases and deaths worldwide, respectively [1]. The inci- enhancer binding protein (C/EBP), alpha (CEBPA) could dence rate of leukemia increased from 4.7 to 5 cases per be used to predict NK-AML prognosis, most patients 10,000 Koreans from 1999–2010 [2]. AML cytogenetic did not have this mutation set [3]. This finding suggests that AML is a highly heterogeneous disease and that a large number of causal mutations have not yet been un- * Correspondence: [email protected] 1Department of Medical Genetics, College of Medicine, Hallym University, 1 covered [4]. Two systems, the French-American-British Hallymdaehak-gil, Chuncheon, Gangwon-do 24252, Republic of Korea (FAB) classification and the newer World Health Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Heo et al. BMC Medical Genetics (2017) 18:23 Page 2 of 7 Organization (WHO) classification, have been used to who had not received a bone marrow transplant prior to classify AML into subtypes. To compare our results with sampling. All subjects provided matched tumor-normal the previous studies, we used the FAB system, the most sample pairs that passed a DNA quality control (QC) test. commonly used classification in previous sequencing The Institutional Review Board for Human Research at studies for AML, including The Cancer Genome Atlas Seoul National University approved the study protocol (TCGA) whole genome sequencing (WGS) [5, 6]. AML (IRB number 1201-099-396), and all participants signed is classified into eight subtypes (M0 through M7) accord- informed consent forms for WES. A clinician conducted a ing to the FAB classification based on its morphological retrospective medical record review to obtain clinical data features: early forms in white blood cells (M0-M5), red including disease status and blood chemistry. An approxi- blood cells (M6), and platelets (M7) [3]. mately 10-mL bone marrow sample was aspirated from Next-generation sequencing technologies have extended each participant by a clinician in an aseptic environment, AML genetic studies to a genome-wide scope at a single- and genomic DNA was isolated using the QIAamp DNA base resolution. Ley et al. (2008) performed the first AML Blood Maxi Kit following the manufacturer’s instructions WGS study on one Caucasian woman with the cytogeneti- (Qiagen, Inc., Valencia, CA, USA). A 2-ml whole-saliva cally normal AML subtype M1 and reported non- sample was obtained from the same individuals for the synonymous single nucleotide variants (nsSNVs) in eight matched normal samples, and the genomic DNA was genes (i.e., CDH24, PCLKC, GPR123, EBI2, PTPRT, extracted using the Oragen DNA Self-Collection kit KNDC1, SLC15A1,andGRINL1B) and insertions in the (DNA Genotek, Inc., Ontario, Canada). coding regions of the FLT3 and NPM1 genes [7]. Mardis and his colleagues reported that 16% of 80 NK-AML Whole-exome sequencing patients had a somatic point mutation in the IDH1 gene We captured the target DNA sample using the Agilent [8]. According to a later report by Ley et al.(2010), SureSelect Human All Exon 50 Mb Kit (Agilent approximately 22% of 281 AML patients had DNMT3A Technologies Inc., Santa Clara, CA, USA). The entire mutations that were newly discovered using targeted exome regions for both the tumor and normal sam- sequencing [9]. In a Chinese study using targeted exome ples from 36 AML patients were sequenced using the sequencing, the patients with the DNMT3A Arg882 muta- HiSeq 2000 platform with a 100 bp paired-end read tion showed poor prognosis among AML-M5 individuals protocol (Illumina, Inc. San Diego, CA, USA). Each the [10]. A WGS study with eight Caucasian AML patients tumor and the normal sample were sequenced to an aver- showed clonal evolution patterns and mutations associ- age read depth of 76X. The fastq quality score and read ated with relapsed AML in the genes WAC, SMC3, DIS3, length cutoff determined by the NGS QC-toolkit were set DDX41,andDAXX [11]. Recently, TCGA analyzed 50 and to 20 and 70, respectively [12]. We aligned the filtered 150 patients with de novo AML using WGS and whole- reads to the reference assembly of human_g1k_v37 fasta exome sequencing (WES), respectively. They found 23 using BWA-0.7.5 [13] and called somatic SNVs using significantly mutated genes and 237 gene mutations that MuTect v1.1.4 according to the Catalogue of Somatic recurred in at least two patients, which were grouped into Mutations in Cancer (COSMIC) v68 database [14]. nine categories according to their biological functions [6]. We used Varscan v2.3.6 to call short indels [15]. We AML is a clinically and genetically heterogeneous obtained translational effect of variant allele, protein disease, hence discovering subtype-specific mutations change information, mutation reports in Catalog of may provide additional prognostic information for AML Somatic Mutations in Cancer, and predictions of patients. In this study, we aimed to replicate previous coding non-synonymous variants on protein function findings in the European studies and to characterize the using the Oncotator web application [16]. Preliminary re- landscape of somatic mutations present in Korean acute ports using six of 36 samples have been previously myeloid leukemia. We also performed a stratified analysis published elsewhere (Additional file 1: Table S1) [17–19]. for FAB M2- and M3-subtypes to investigate if certain mutations have subtype-specific effects. We subsequently Statistical analysis evaluated the functional properties of the significantly We performed a mutation significance test using mutated genes using an integrated systems analysis of MutSigCV v1.4 with a significance threshold of a p Gene Ontology (GO) and biological pathways. value less than 0.05. The p value was calculated with the chi-square test to determine whether the observed Methods mutations in a gene significantly exceeded the expected Patients and samples frequency of random background mutations. We add- We included 36 Korean patients with de novo AML who itionally considered a q value less than 0.1, which was an visited the Division of Hematology and Medical Oncology, analogue of the p value calculated based on the Seoul National University Hospital, from 1995 to 2013 Benjamini-Hochberg false discovery rate (FDR) [20]. To Heo et al. BMC Medical Genetics (2017) 18:23 Page 3 of 7 identify subtype-specific mutant genes, we performed the Table 1 Characteristics of the 36 acute myeloid leukemia patients test individually in each of the subgroups as follows: M2- Variables AML (n = 36) AML, acute myeloblastic leukemia with maturation, and Age, mean (SE) 46.43 (3.09) M3-AML, acute promyelocytic leukemia.
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