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Cho, Sung-Yup,Han, Jee Yun,Na, Deukchae,Kang, Wonyoung,Lee, Ahra,Kim, Jooyoung,Lee, Jieun,Min, Seoyeon,Kang, Jinjoo,Chae, Jeesoo,Kim, Jong-Il,Park, Hansoo,Lee, Won-Suk,Lee, Charles American Association for Cancer Research 2017 Molecular cancer therapeutics Vol.16 No.10
<P>Colorectal cancer is the third most commonly diagnosed cancer in the world, and exhibits heterogeneous characteristics in terms of genomic alterations, expression signature, and drug responsiveness. Although there have been considerable efforts to classify this disease based on high-throughput sequencing techniques, targeted treatments for specific subgroups have been limited. KRAS and BRAF mutations are prevalent genetic alterations in colorectal cancers, and patients with mutations in either of these genes have a worse prognosis and are resistant to anti-EGFR treatments. In this study, we have found that a subgroup of colorectal cancers, defined by having either KRAS or BRAF (KRAS/BRAF) mutations and BCL2L1 (encoding BCLXL) amplification, can be effectively targeted by simultaneous inhibition of BCL-XL (with ABT-263) and MCL1 (with YM155). This combination treatment of ABT-263 and YM-155 was shown to have a synergistic effect in vitro as well as in in vivo patient-derived xenograft models. Our data suggest that combined inhibition of BCL-XL and MCL1 provides a promising treatment strategy for this genomically defined colorectal cancer subgroup. (C) 2017 AACR.</P>
Kwak, Soo Heon,Chae, Jeesoo,Lee, Seungbok,Choi, Sungkyoung,Koo, Bo Kyung,Yoon, Ji Won,Park, Jin-Ho,Cho, Belong,Moon, Min Kyong,Lim, Soo,Cho, Young Min,Moon, Sanghoon,Kim, Young Jin,Han, Sohee,Hwang, M American Diabetes Association 2018 Diabetes Vol.67 No.9
<P>We investigated ethnicity-specific exonic variants of type 2 diabetes (T2D) and its related clinical phenotypes in an East Asian population. We performed whole-exome sequencing in 917 T2D case and control subjects, and the findings were validated by exome array genotyping in 3,026 participants. In silico replication was conducted for seven nonsynonymous variants in an additional 13,122 participants. Single-variant and gene-based association tests for T2D were analyzed. A total of 728,838 variants were identified by whole-exome sequencing. Among nonsynonymous variants, PAX4 Arg192His increased risk of T2D and GLP1R Arg131Gln decreased risk of T2D in genome-wide significance (odds ratio [OR] 1.48, P = 4.47 x 10(-16) and OR 0.84, P = 3.55 x 10(-8), respectively). Another variant at PAX4 192 codon Arg192Ser was nominally associated with T2D (OR 1.62, P = 5.18 x 10(-4)). In T2D patients, PAX4 Arg192His was associated with earlier age at diagnosis, and GLP1R Arg131Gln was associated with decreased risk of cardiovascular disease. In control subjects without diabetes, the PAX4 Arg192His was associated with higher fasting glucose and GLP1R Arg131Gln was associated with lower fasting glucose and HbA(1c) level. Gene-based analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P = 1.0 x 10(-4)). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans.</P>
Association of HLA Genotype and Fulminant Type 1 Diabetes in Koreans
Kwak, Soo Heon,Kim, Yoon Ji,Chae, Jeesoo,Lee, Cue Hyunkyu,Han, Buhm,Kim, Jong-Il,Jung, Hye Seung,Cho, Young Min,Park, Kyong Soo Korea Genome Organization 2015 Genomics & informatics Vol.13 No.4
Fulminant type 1 diabetes (T1DM) is a distinct subtype of T1DM that is characterized by rapid onset hyperglycemia, ketoacidosis, absolute insulin deficiency, and near normal levels of glycated hemoglobin at initial presentation. Although it has been reported that class II human leukocyte antigen (HLA) genotype is associated with fulminant T1DM, the genetic predisposition is not fully understood. In this study we investigated the HLA genotype and haplotype in 11 Korean cases of fulminant T1DM using imputation of whole exome sequencing data and compared its frequencies with 413 participants of the Korean Reference Panel. The $HLA-DRB1^*04:05-HLA-DQB1^*04:01$ haplotype was significantly associated with increased risk of fulminant T1DM in Fisher's exact test (odds ratio [OR], 4.11; 95% confidence interval [CI], 1.56 to 10.86; p = 0.009). A histidine residue at $HLA-DR{\beta}1$ position 13 was marginally associated with increased risk of fulminant T1DM (OR, 2.45; 95% CI, 1.01 to 5.94; p = 0.054). Although we had limited statistical power, we provide evidence that HLA haplotype and amino acid change can be a genetic risk factor of fulminant T1DM in Koreans. Further large-scale research is required to confirm these findings.
Park, Hansoo,Cho, Sung-Yup,Kim, Hyerim,Na, Deukchae,Han, Jee Yun,Chae, Jeesoo,Park, Changho,Park, Ok-Kyoung,Min, Seoyeon,Kang, Jinjoo,Choi, Boram,Min, Jimin,Kwon, Jee Young,Suh, Yun-Suhk,Kong, Seong-H National Academy of Sciences 2015 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.112 No.40
<P><B>Significance</B></P><P>Gastric cancer (GC) is one of the major causes of cancer-related deaths worldwide, but targeted therapy for GC is limited. Here, we identified two druggable targets from genomic alteration profiling of 103 patients with GC from Asia and validated the target suitability using patient-derived GC xenograft models, which recapitulate the tumor biology observed in patients. Combination therapy of irinotecan (standard treatment) with a <I>BCL2L1</I> (<I>BCL2</I>-like 1)-targeted drug was effective in size reduction of GC tumors having amplification of the <I>BCL2L1</I> gene, and genomic mutations of deleted in liver cancer 1 (<I>DLC1</I>) were associated with increased sensitivity to a ROCK inhibitor. Therefore, our study strongly suggests that <I>BCL2L1</I> and <I>DLC1</I> can serve as targets for novel GC therapies.</P><P>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 [<I>APC</I>, <I>CTNNB1</I>, and <I>DLC1</I> (deleted in liver cancer 1)], ErbB signaling (<I>ERBB2</I>, <I>PIK3CA</I>, and <I>KRAS</I>), and p53 signaling/apoptosis [<I>TP53</I> and <I>BCL2L1</I> (BCL2-like 1)] pathways. In 18.4% of GC cases (19/103), amplification of the antiapoptotic gene <I>BCL2L1</I> was observed, and subsequently a <I>BCL2L1</I> inhibitor was shown to markedly decrease cell viability in <I>BCL2L1</I>-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 <I>DLC1</I> 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 <I>BCL2L1</I> and <I>DLC1</I> as potential druggable targets for specific subsets of GC cases.</P>