PAPER

  • Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer

    Hansoo Park, Sung-Yup Cho, Hyerim Kim, Deukchae Na, Jee Yun Han, Jeesoo Chae, Changho Park, Ok-Kyoung Park, Seoyeon Min, Jinjoo Kang, Boram Choi, Jimin Min, Jee Young Kwon, Yun-Suhk Suh, Seong-Ho Kong, Hyuk-Joon Lee, Edison T. Liu, Jong-Il Kim, Sunghoon Kim, Han-Kwang Yang, and Charles Lee
    Abstract

    Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Recent high-throughput analyses of genomic alterations revealed several driver genes and altered pathways in GC. However, therapeutic applications from genomic data are limited, largely as a result of the lack of druggable molecular targets and preclinical models for drug selection. To identify new therapeutic targets for GC, we performed array comparative genomic hybridization (aCGH) of DNA from 103 patients with GC for copy number alteration (CNA) analysis, and whole-exome sequencing from 55 GCs from the same patients for mutation profiling. Pathway analysis showed recurrent alterations in the Wnt signaling [APC, CTNNB1, and DLC1 (deleted in liver cancer 1)], ErbB signaling (ERBB2, PIK3CA, and KRAS), and p53 signaling/apoptosis [TP53 and BCL2L1 (BCL2-like 1)] pathways. In 18.4% of GC cases (19/103), amplification of the antiapoptotic gene BCL2L1 was observed, and subsequently a BCL2L1 inhibitor was shown to markedly decrease cell viability in BCL2L1-amplified cell lines and in similarly altered patient-derived GC xenografts, especially when combined with other chemotherapeutic agents. In 10.9% of cases (6/55), mutations in DLC1 were found and were also shown to confer a growth advantage for these cells via activation of Rho-ROCK signaling, rendering these cells more susceptible to a ROCK inhibitor. Taken together, our study implicates BCL2L1 and DLC1 as potential druggable targets for specific subsets of GC cases.

  • Discovery of common Asian copy number variants using integrated high-resolution array CGH and massively parallel DNA sequencing

    Hansoo Park, Jong-Il Kim, Young Seok Ju, Omer Gokcumen, Ryan E Mills, Sheehyun Kim, Seungbok Lee, Dongwhan Suh, Dongwan Hong, Hyunseok Peter Kang, Yun Joo Yoo, Jong-Yeon Shin, Hyun-Jin Kim, Maryam Yavartanoo, Young Wha Chang, Jung-Sook Ha, Wilson Chong, Ga-Ram Hwang, Katayoon Darvishi, HyeRan Kim, Song Ju Yang, Kap-Seok Yang, Hyungtae Kim, Matthew E Hurles, Stephen W Scherer, Nigel P Carter, Chris Tyler-Smith, Charles Lee & Jeong-Sun Seo
    Abstract

    Copy number variants (CNVs) account for the majority of human genomic diversity in terms of base coverage. Here, we have developed and applied a new method to combine high-resolution array comparative genomic hybridization (CGH) data with whole-genome DNA sequencing data to obtain a comprehensive catalog of common CNVs in Asian individuals. The genomes of 30 individuals from three Asian populations (Korean, Chinese and Japanese) were interrogated with an ultra-high-resolution array CGH platform containing 24 million probes. Whole-genome sequencing data from a reference genome (NA10851, with 28.3× coverage) and two Asian genomes (AK1, with 27.8× coverage and AK2, with 32.0× coverage) were used to transform the relative copy number information obtained from array CGH experiments into absolute copy number values. We discovered 5,177 CNVs, of which 3,547 were putative Asian-specific CNVs. These common CNVs in Asian populations will be a useful resource for subsequent genetic studies in these populations, and the new method of calling absolute CNVs will be essential for applying CNV data to personalized medicine.

  • A highly annotated whole-genome sequence of a Korean individual

    Jong-Il Kim1, Young Seok Ju1, Hansoo Park, Sheehyun Kim, Seonwook Lee, Jae-Hyuk Yi, Joann Mudge, Neil A. Miller, Dongwan Hong, Callum J. Bell, Hye-Sun Kim, In-Soon Chung, Woo-Chung Lee, Ji-Sun Lee, Seung-Hyun Seo5, Ji-Young Yun, Hyun Nyun Woo, Heewook Lee, Dongwhan Suh, Seungbok Lee, Hyun-Jin Kim, Maryam Yavartanoo, Minhye Kwak, Ying Zheng, Mi Kyeong Lee, Hyunjun Park, Jeong Yeon Kim, Omer Gokcumen, Ryan E. Mills, Alexander Wait Zaranek, Joseph Thakuria, Xiaodi Wu, Ryan W. Kim, Jim J. Huntley, Shujun Luo, Gary P. Schroth, Thomas D. Wu, HyeRan Kim, Kap-Seok Yang, Woong-Yang Park, Hyungtae Kim, George M. Church, Charles Lee, Stephen F. Kingsmore & Jeong-Sun Seo
    Abstract

    Recent advances in sequencing technologies have initiated an era of personal genome sequences. To date, human genome sequences have been reported for individuals with ancestry in three distinct geographical regions: a Yoruba African, two individuals of northwest European origin, and a person from China. Here we provide a highly annotated, whole-genome sequence for a Korean individual, known as AK1. The genome of AK1 was determined by an exacting, combined approach that included whole-genome shotgun sequencing (27.8× coverage), targeted bacterial artificial chromosome sequencing, and high-resolution comparative genomic hybridization using custom microarrays featuring more than 24 million probes. Alignment to the NCBI reference, a composite of several ethnic clades, disclosed nearly 3.45 million single nucleotide polymorphisms (SNPs), including 10,162 non-synonymous SNPs, and 170,202 deletion or insertion polymorphisms (indels). SNP and indel densities were strongly correlated genome-wide. Applying very conservative criteria yielded highly reliable copy number variants for clinical considerations. Potential medical phenotypes were annotated for non-synonymous SNPs, coding domain indels, and structural variants. The integration of several human whole-genome sequences derived from several ethnic groups will assist in understanding genetic ancestry, migration patterns and population bottlenecks.

  • THOC5의 분열효모 이종상동체가 생장 및 mRNA export에 미치는 영향

    고은진, 윤진호
    Abstract

    THO/TREX complex plays an important role in transcriptional elongation, mRNA processing, nuclear RNA export, and genome stability. A fission yeast, Schizosaccharomyces pombe, SPBC577.04 gene encoding the ortholog of THOC5, a component of THO/TREX complex, was identified and characterized. The S. pombe thoc5 (spthoc5) is not essential for both growth and mRNA export, but deletion of the spthoc5 gene caused growth defect and slight accumulation of poly(A)+ RNA in the nucleus. And the functional spThoc5-GFP protein is localized mainly in the nucleus. Co-immunoprecipitation analysis showed that the Hpr1(THOC1) protein, an evolutionally well-conserved component of THO/TREX complex, interacted with spThoc5 as well as Tho2(THOC2), another subunit of THO complex. These results suggest that S. pombe Thoc5 as a component of THO/TREX complex is also involved in mRNA export from the nucleus.

  • FLX Pyrosequencing Analysis of the Effects of the Brown-Algal Fermentable Polysaccharides Alginate and Laminaran on Rat Cecal Microbiotas

    Choa An, Takashi Kuda, Takahiro Yazaki, Hajime Takahashi and Bon Kimura
    Abstract

    Edible brown algae are used as major food material in Far East Asian countries, particularly in South Korea and Japan. They contain fermentable dietary fibers, alginic acid (uronic acid polymer) and laminaran (β-1,3-glucan), that are fermented into organic acids by intestinal bacteria. To clarify the effect of edible algae on the intestinal environment, the cecal microbiotas of rats fed diets containing no dietary fiber (control) or 2% (wt/wt) sodium alginate or laminaran for 2 weeks were analyzed using FLX amplicon pyrosequencing with bar-coded primers targeting the bacterial 16S rRNA gene. The most abundant phylum in all groups was Firmicutes. Specifically, Allobaculum was dominant in all diet groups. In addition, Bacteroides capillosus (37.1%) was abundant in the alginate group, while Clostridium ramosum (3.14%) and Parabacteroides distasonis (1.36%) were only detected in the laminaran group. Furthermore, rats fed alginate showed simplified microbiota phylotypes compared with others. With respect to cecal chemical compounds, laminaran increased cecal organic acid levels, particularly propionic acid. Alginate increased total cecal organic acids. Cecal putrefactive compounds, such as indole, H2S, and phenol, were decreased by both alginate and laminaran. These results indicate that edible brown algae can alter the intestinal environment, with fermentation by intestinal microbiota.

  • Deep resequencing of 131 Crohn’s disease associated genes in pooled DNA confirmed three reported variants and identified eight novel variants

    Sung Noh Hong, Changho Park, Soo Jung Park, Chang Kyun Lee, Byong Duk Ye, You Sun Kim, Seungbok Lee, Jeesoo Chae, Jong-Il Kim, Young-Ho Kim, IBD Study Group of the Korean Association for the Study of Intestinal Diseases (KASID)
    Abstract

    Objective Genome wide association studies (GWAS) and meta-analyses for Crohn’s disease (CD) have not fully explained the heritability of CD, suggesting that additional loci are yet to be found and that the known loci may contain high effect rare risk variants that have thus far gone undetected by GWAS. While the cost of deep sequencing remains too high to analyse many samples, targeted sequencing of pooled DNA samples allows the efficient and cost effective capture of all variations in a target region.

    Design We performed pooled sequencing in 500 Korean CD cases and 1000 controls to evaluate the coding exon and 5′ and 3′ untranslated regions of 131 CD associated genes. The identified genetic variants were validated using genotyping in an independent set of 500 CD cases and 1000 controls.

    Results Pooled sequencing identified 30 common/low single nucleotide variants (SNVs) in 12 genes and 3 rare SNVs in 3 genes. Our results confirmed a significant association of CD with the following previously reported risk loci: rs3810936 in TNFSF15 (OR=1.83, p<2.2×10−16), rs76418789 in IL23R (OR=0.47, p=1.14×10−8) and rs2241880 in ATG16L1 (OR=1.30, p=5.28×10−6). In addition, novel loci were identified in TNFSF8 (rs3181374, OR=1.53, p=1.03×10−14), BTNL2 (rs28362680, OR=1.47, p=9.67×10−11), HLA-DQA2 (rs3208181, OR=1.36, p=4.66×10−6), STAT3 (rs1053004, OR=1.29, p=2.07×10−5), NFKBIA (rs2273650, OR=0.80, p=3.93×10−4), NKX2-3 (rs888208, OR=0.82, p=6.37×10−4) and DNAH12 (rs4462937, OR=1.13, p=3.17×10−2). A novel rare SNV, rs200735402 in CARD9, was shown to have a protective effect (OR=0.09, p=5.28×10−5).

    Conclusions Our deep resequencing of 131 CD associated genes confirmed 3 reported risk loci and identified 8 novel risk loci for CD in Koreans, providing new insights into the genetic architecture of CD.

  • Colorectal cancer-susceptibility single-nucleotide polymorphisms in Korean population

    Sung Noh Hong, Changho Park, Jong-il Kim, Duk-Hwan Kim, Hee Cheol Kim, Dong Kyung Chang, Poong-Lyul Rhee, Jae J. Kim, Jong Chul Rhee, Hee Jung Son, Young-Ho Kim
    Abstract

    Background and Aim : Considering the significant racial and ethnic diversity in genetic variation, it is unclear whether the genome-wide association studies-identified colorectal cancer (CRC)-susceptibility single-nucleotide polymorphisms (SNPs) discovered in European populations are also relevant to the Korean population. However, studies on CRC-susceptibility SNPs in Koreans are limited.

    Methods : To investigate the racial and ethnic diversity of CRC-susceptibility genetic variants, we genotyped for the established European CRC-susceptibility SNPs in 198 CRC cases and 329 controls in Korea. To identify novel genetic variants using genome-wide screening in Korea, Illumina HumanHap 370K/610K BeadChips were performed on 105 CRC patients, and candidate CRC-susceptibility SNPs were selected. Subsequently, genotyping for replication was done in 189 CRC cases and 190 controls.

    Results : Among the European CRC-susceptibility SNPs, rs4939827 in SMAD7 was associated with a significant decreased risk of Korean CRC (age-/gender-adjusted odds ratio [95% confidence interval]: additive model, 0.67 [95% CI, 0.47–0.95]; dominant model, 0.59 [95% CI, 0.39–0.91]). rs4779584 and rs10795668 were associated with CRC risk in females and males, respectively. Among candidate CRC-susceptibility SNPs selected from genome-wide screening, novel SNP, rs17051076, was found to be associated with a significantly increased risk of microsatellite instability-high CRC (age-/gender-adjusted odds ratio [95% confidence interval]: additive model, 4.25 [95% CI, 1.51–11.98]; dominant model, 3.52 [95% CI, 1.13–10.94]) in the replication study.

    Conclusions : rs4939827, rs4779584, and rs10795668 may contribute to the risk of CRC in the Korean population as well as in European populations. Novel rs17051076 could be associated with microsatellite instability-high CRC in Koreans. These associations support the ethnic diversity of CRC-susceptibility SNPs and should be taken into account in large-scale studies.

  • A copy number variation in PKD1L2 is associated with colorectal cancer predisposition in korean population

    Changho Park, Jong-Il Kim, Sung Noh Hong, Hey Mi Jung, Tae Jun Kim, Seungbok Lee, Seong Jin Kim, Hee Cheol Kim, Duk-Hwan Kim, Belong Cho, Jin-ho Park, Joohon Sung, Dong-Sung Lee, Mingon Kang, Hee Jung Son, Young-Ho Kim
    Abstract

    Recently reported genome-wide association studies have identified more than 20 common low-penetrance colorectal cancer (CRC) susceptibility loci. Recent studies have reported that copy number variations (CNVs) are considered important human genomic variants related to cancer, while the contribution of CNVs remains unclear. We performed array comparative genomic hybridization (aCGH) in 36 CRC patients and 47 controls. Using breakpoint PCR, we confirmed the breakpoint of the PKD1L2 deletion region. High frequency of PKD1L2 CNV was observed in CRC cases. We validated the association between PKD1L2 variation and CRC risk in 1,874 cases and 2,088 controls (OR = 1.44, 95% CI = 1.04–1.98, p = 0.028). Additionally, PKD1L2 CNV is associated with increased CRC risk in patients younger than 50 years (OR = 2.14, 95% CI 1.39–3.30, p = 5.8 × 10−4). In subgroup analysis according to body mass index (BMI), we found that the CN loss of PKD1L2 with BMI above or equal to 25 exhibited a significant increase in CRC risk (OR = 2.29, 95% CI 1.29–4.05, p = 0.005). PKD1L2 CNV with BMI above or equal to 25 and age below 50 is associated with a remarkably increased risk of colorectal cancer (OR = 5.24, 95% CI 2.36–11.64, p= 4.8 × 10−5). Moreover, we found that PKD1L2 variation in obese patients (BMI ≥ 25) was associated with poor survival rate (p = 0.026). Our results suggest that the common PKD1L2 CNV is associated with CRC, and PKD1L2 CNV with high BMI and/or age below 50 exhibited a significant increased risk of CRC. In obese patients, PKD1L2 variation was associated with poor survival.

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