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Background Gynecologic malignancy is one of the leading causes of mortality in female adults worldwide. Comprehensive genomic analysis has revealed a list of molecular aberrations that are essential to tumorigenesis, progression, and metastasis of gynecologic tumors. However, targeting such alterations has frequently led to treatment failures due to underlying genomic complexity and simultaneous activation of various tumor cell survival pathway molecules. A compilation of molecular characterization of tumors with pharmacological drug response is the next step toward clinical application of patient-tailored treatment regimens. Results Toward this goal, we establish a library of 139 gynecologic tumors including epithelial ovarian cancers (EOCs), cervical, endometrial tumors, and uterine sarcomas that are genomically and/or pharmacologically annotated and explore dynamic pharmacogenomic associations against 37 molecularly targeted drugs. We discover lineage-specific drug sensitivities based on subcategorization of gynecologic tumors and identify TP53 mutation as a molecular determinant that elicits therapeutic response to poly (ADP-Ribose) polymerase (PARP) inhibitor. We further identify transcriptome expression of inhibitor of DNA biding 2 (ID2) as a potential predictive biomarker for treatment response to olaparib. Conclusions Together, our results demonstrate the potential utility of rapid drug screening combined with genomic profiling for precision treatment of gynecologic cancers.

Tumor genetic heterogeneity may underlie poor clinical outcomes because diverse subclones could be comprised of metastatic and drug resistant cells. Targeted deep sequencing has been used widely as a diagnostic tool to identify actionable mutations in cancer patients. In this study, we evaluated the clinical utility of estimating tumor heterogeneity using targeted panel sequencing data. We investigated the prognostic impact of a tumor heterogeneity (TH) index on clinical outcomes, using mutational profiles from targeted deep sequencing data acquired from 1,352 patients across 8 cancer types. The TH index tended to be increased in high pathological stage disease in several cancer types, indicating clonal expansion of cancer cells as tumor progression proceeds. In colorectal cancer patients, TH index values also correlated significantly with clinical prognosis. Integration of the TH index with genomic and clinical features could improve the power of risk prediction for clinical outcomes. In conclusion, deep sequencing to determine the TH index could serve as a promising prognostic indicator in cancer patients.

In the present study, we explored the possible association between KIF1B polymorphisms and inflammatory demyelinating disease (IDD) susceptibility. Eleven single nucleotide polymorphisms (SNPs) were selected for the present study based on the literature, as well as linkage disequilibrium, minor allele frequency, and location. The SNPs were genotyped in 178 IDD subjects consisting of 99 neuromyelitis optica subjects, 79 multiple sclerosis subjects, and 237 healthy controls (Total N = 415). We next preformed logistic analysis to validate associations between the KIF1B polymorphisms and the risk of IDD. Statistical analyses revealed that rs17396382 and ht4 were significantly associated with IDD susceptibility with odds ratios of 2.22 and 2.17 (P = 0.001 and 0.004; P corr = 0.01 and 0.03, respectively). In addition, although P values for six variants (rs3748576, rs7520935, rs2275424, rs11576866, rs17411502, and rs11121552) and one haplotype (ht1) did not reach the threshold of significance after correction for multiple testing, the SNPs showed a nominal association in primary analysis (P = 0.02 ~ 0.04). Our results suggest that rs17396382 and ht4 might be involved in IDD pathogenesis.

Asthma is a global health problem which threatens approximately 300 million patients worldwide. Among them, up to 20 % of the asthma patients are classified as aspirin exacerbated respiratory disease (AERD). Interleukin-1 receptor associated kinase (IRAK2) is associated with necrosis factor kappa B (NF-кB) pathway via interleukin-1 (IL-1) signaling. NF-кB pathway is known to be involved in asthma development, and several interleukin and IRAK family members have also been reported to be associated with asthma or AERD. Since IRAK2 plays an important role in the asthma etiology, we hypothesized that the genetic variants of IRAK2 may be associated with AERD. This study genotyped a total of 25 common single nucleotide polymorphisms (SNPs) in 163 AERD cases and 429 aspirin-tolerant asthma (ATA) controls. As a result, no significant association was found between the genetic variants of IRAK2 and AERD (P > 0.05). In further regression analysis for the forced expiratory volume in 1 s (FEV1) decline, an important phenotype for diagnosing AERD, although one haplotype (BL1_ht3) showed a nominal association with FEV1 decline (P = 0.04), the significance disappeared after correction for multiple testing (P > 0.05). Despite limitations in our study and need for replications, our results suggest that the genetic variants of IRAK2 might not be associated with AERD and the obstructive symptoms in asthma.

The human HLA class II histocompatibility antigen, DR alpha chain (HLA-DRA) is a member of the MHC class II gene family that activates T cells allowing secretion in various cytokines to immune responses. Thus, we explored whether the genetic variations in HLA-DRA gene can influence susceptibility for aspirin exacerbated respiratory disease (AERD). To carry out the investigation, 22 single nucleotide polymorphisms (SNPs) in HLA-DRA were genotyped in 592 Korean asthma patients. Logistic and regression analyseis wereas used to evaluate the P-values for associations of HLA-DRA polymorphisms with AERD and a relevant phenotype, the fall rate of forced expiratory volume in the 1st second (FEV1). Logistic analyses revealed that two variants, rs6911777 and HLA_DRA_BL1_ht3 were initially associated with AERD via dominant and recessive models (P = 0.05 and 0.01, respectively), however, the signals did not reach the threshold of significance after multiple corrections. Furthermore, we observed that fall rate of FEV1 by aspirin provocation was marginally different between AERD cases and aspirin-tolerant asthma (ATA) controls (mean = 24.63 vs 3.54, respectively). This study provides result of first association analysis between the variants of HLA-DRA and the risk of AERD, and conclusions derived from the study do not support significant roles of polymorphisms in HLA-DRA with AERD.

The human FYVE, RhoGEF and PH domain containing 6 (FGD6) gene regulates mechanisms that are implicated in airway bronchospasm, and therefore, may be a risk factor for aspirin exacerbated respiratory disease (AERD). This study aims to investigate the association between FGD6 variations and AERD in a Korean asthma cohort. A total of 34 single nucleotide polymorphisms (SNPs) were selected for genotyping based on previously reported polymorphisms in the HapMap database. Genotyping was carried out using TaqMan assay and nine major haplotypes from two haplotype blocks were obtained in 163 AERD cases and 429 aspirin-tolerant asthma (ATA) controls. Genotype frequency distributions of FGD6 polymorphisms and haplotypes were analyzed using logistic and regression models. Findings from logistic and regression analyses revealed a lack of association of FGD6 genetic variations with AERD and fall rate of FEV1 (P > 0.05 in co-dominant, dominant and recessive models). This preliminary report provides evidences that variations in the FGD6 gene do not influence the risk of AERD and its relevant phenotype in a Korean population. This report may contribute to the etiology of aspirin hypersensitivity in Korean asthma patients.

Human v-Fos Finuel-Biskis-Jinkins (FBJ) murine osteosarcoma viral oncogene homolog (FOS) is located in 14q24.3. The FOS protein is a constituent of the activating protein-1 (AP-1) and its increased expression in the hepatocellular carcinoma (HCC) have been reported. In this study, the association of FOS polymorphisms with the HBV infection and HCC occurrence were evaluated in Korean patients. After re-sequencing in 24 unrelated healthy individuals, two common single nucleotide polymorphisms (SNPs) in regulatory regions that were selected based on linkage disequilibrium were genotyped in a total of 1,093 Korean subjects including 656 HBV chronic carriers, who were further stratified into chronic hepatitis/liver cirrhosis (CH/LC, n = 339) and HCC (n = 317) groups, and 437 spontaneously recovered (SR) controls. Logistic regression and Cox relative hazard analysis showed no significant association of regulatory polymorphisms and haplotypes in FOS with HBV clearance and HCC development (P > 0.05, respectively).

Aspirin exacerbated respiratory disease (AERD) induces bronchoconstriction in asthmatic patients characterized with a clinical condition of severe decline in forced expiratory volume in one second (FEV1) after ingestion of aspirin. Two genes consisting a heterodimer, transporter 1 and 2, ATP-binding cassette, sub-family B (MDR/TAP) (TAP1 and TAP2) within the major histocompatibility complex (MHC) region, have been implicated in immunodeficiency and bronchiectasis development. To investigate the associations of TAP1 and TAP2 genetic polymorphisms with AERD and phenotypic FEV1 decline, a total of 43 common single-nucleotide polymorphisms (SNPs) including 12 SNPs of TAP1 and 31 SNPs of TAP2 were genotyped in 93 AERD patients and 96 aspirin-tolerant asthma controls. Interestingly, regression analysis revealed that polymorphisms and haplotypes of TAP2 were associated with FEV1 decline by aspirin provocation (P=0.002-0.04), with about twofold decline rate of FEV1 in most of minor homozygotes compared with major homozygotes. In addition, nominal evidences of association between TAP2 and AERD development were observed (P=0.02-0.04). However, TAP1 polymorphisms showed no relations to both AERD and FEV1 decline after aspirin challenge (P0.05). Although further functional evaluations and replications are required, our preliminary findings provide supporting information that variants of TAP2 might be predisposing factors for FEV1 decline-related symptoms.

Aspirin exacerbated respiratory disease (AERD) is a clinical condition characterized by severe decline in forced expiratory volume in one second (FEV1) following the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin. The exacerbated inflammatory response in Fancc-deficient mice has been reported to be associated with hemopoietic responses that are also related to AERD pathogenesis. To investigate associations of FANCC polymorphisms with AERD and related phenotypes, this study genotyped 25 common single nucleotide polymorphisms (SNPs) in a total of 592 Korean asthmatics including 163 AERD and 429 aspirin-tolerant asthma (ATA) subjects. Logistic analysis revealed that genetic polymorphisms of the FANCC gene might not be directly related to AERD development and nasal polyposis (P > 0.05). However, the FEV1 decline by aspirin provocation showed significant associations with FANCC polymorphisms (P = 0.006-0.04) and a haplotype (unique to rs4647416G > A, P = 0.01 under co-dominant, P = 0.006 under recessive model). In silico analysis showed that the "A" allele of rs4647376C > A, which was more prevalent in AERD than in ATA, could act as a potential branch point (BP) site for alternative splicing (BP score = 4.16). Although replications in independent cohorts and further functional evaluations are still needed, our preliminary findings suggest that FANCC polymorphisms might be associated with the obstructive symptoms in allergic diseases.

Development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The transferrin (TF) gene encodes a blood plasma protein that delivers iron ion in the body. The iron uptake level has been shown to be different in HCC tumor regions, indicating a possible association between iron uptake level and HCC. To investigate whether genetic polymorphisms of TF are related with HBV clearance and/or HCC occurrence, we sequenced genomes of 24 individuals and detected 37 variants. Subsequently, eight single nucleotide polymorphisms (SNPs) in TF including 4 in the promoter region, 1 in 5′UTR and 3 in coding regions were selected and genotyped in 1,101 Korean subjects including 428 spontaneously recovered (SR) patients as controls and 673 chronic carriers (CC) as cases. Results of logistic analyses adjusted for age and gender, however, revealed no significant associations of polymorphisms and haplotypes in the TF gene with HBV clearance and HCC occurrence (P > 0.05). Since age of HBV infection is a risk factor in progression to HCC, further Cox proportional regression analysis for age of HCC as a relative hazard was performed; but no association between TF polymorphisms and onset age of HCC was found (P > 0.05). Although TF gene polymorphisms have been previously reported to be associated with various diseases, our findings indicate that genetic variations of the TF gene do not influence HBV clearance and HCC occurrence in a Korean population.

Chronic inflammation has been considered a potential risk factor for prostate cancer. Toll-like receptors (TLRs) are important in the innate immune response to pathogens and in cross talk between innate immunity and adaptive immunity. In this study, sequence variants in the TLR4 gene were investigated to determine whether they were associated with prostate cancer risk in a Korean cohort. An association study between 11 single-nucleotide polymorphisms (SNPs) of the TLR4 gene and prostate cancer was performed in 463 Korean male subjects including 240 prostate cancer patients and 223 healthy controls. SNPs were genotyped using the TaqMan assay, and their association with the risk of prostate cancer was evaluated using logistic regression analysis. The statistical analysis revealed that one SNP at the 3′UTR (rs11536889) showed significant association with the risk of prostate cancer (P corr = 0.005, OR = 1.81). One common haplotype (ht2) was also significantly associated with the risk of prostate cancer (P corr = 0.009, OR = 1.77). However, further analysis showed no association between any of the SNPs and prostate cancer prognostic factors such as the Gleason score or tumor stage. The findings of this study suggest that polymorphisms of the TLR4 gene might be associated with the risk of prostate cancer in Korean men.

Aspirin-intolerant asthma (AIA) is an asthma phenotype characterized by the development of bronchoconstriction following ingestion of aspirin. Despite the well-defined pathological trigger, the underlying mechanisms of AIA are still unclear. With the biophysical characteristics of the human EMI domain-containing protein 2 (EMID2) gene in relation to the extracellular matrix deposition and epithelial-mesenchymal transition as pivotal characteristics of airway remodeling in asthma, we hypothesized that genetic polymorphisms of EMID2 might affect the development of AIA. In this study, the allelic associations of 49 single-nucleotide polymorphisms (SNPs) of the human EMID2 gene were evaluated from 163 AIA patients and 429 aspirin-tolerant asthma (ATA) subjects as controls in a Korean population. Logistic analysis showed that five SNPs (P = 0.01–0.04, but P corr > 0.05) and EMID2_BL2_ht2 haplotype (unique to the minor alleles of rs4727494 and rs13233066; P = 0.02; P corr = 0.02) were significantly associated with AIA. More interestingly, regression analysis of the decline of forced expiratory volume in one second (FEV1) by aspirin provocation revealed that 10 SNPs (P = 0.003–0.04) and four relevant haplotypes (P = 0.002–0.02) were significantly associated with the fall rate of FEV1 by aspirin provocation, indicating that genetic polymorphisms of EMID2 could cause meaningful deficits in the upper and lower airways among AIA patients. These findings provide evidence that EMID2 may be a susceptible genetic factor for aspirin hypersensitivity among asthmatics in Korean population.

The kinesin family number 3A (KIF3A) gene on the human chromosomal 5q31-33 region, which is known as a susceptibility locus for immune diseases including asthma, plays a crucial role in generation of cilia.A treatment with aspirin in the human bronchial epithelial cells increased the mRNA expression level of KIF3A compared to that of the untreated control (P ≤ 0.01), and nasal polyp epithelia from aspirin-intolerant asthma (AIA) patients also showed a higher expression of KIF3A protein than aspirin-tolerant asthma controls. Further logistic analyses revealed that most polymorphisms of KIF3A were significantly associated with AIA (P = 0.0004-0.02; P(corr) = 0.004-0.04) and the decline of forced expiratory volume at 1 s (FEV(1))% by aspirin provocation (P = 0.004-0.04; P(corr) = 0.03).Our findings suggest that the KIF3A gene and/or its polymorphisms might have a susceptibility effect on AIA, providing a new step toward controlling aspirin intolerance in asthmatics.

Subarachnoid aneurysmal hemorrhage (SAH) due to cerebral aneurysm rupture is a very serious disease resulting in high mortality rate. It has been known that genetic factors are involved in the risk of SAH. A recent breakthrough in genomic variation called copy number variation (CNV) has been revealed to be involved in risks of human diseases. In this study, we hypothesized that CNVs can predict the risk of SAH. We used the Illumina HumanHap300 BeadChip (317 503 markers) to genotype 497 individuals in a Japanese population. Furthermore, individual CNVs were identified using signal and allelic intensities. The genetic effect of CNV on the risk of SAH was evaluated using multivariate logistic regression controlling for age and gender in 187 common CNV regions (frequency1%). From a total of 4574 individual CNVs identified in this study (9.7 CNVs per individual), we were able to discover 1644 unique CNV regions containing 1232 genes. The identified variations were validated using visual examination of the genoplot image, overlapping analysis with the Database of Genomic Variants (73.2%), CNVpartition (72.4%) and quantitative PCR. Interestingly, two CNV regions, chr4:153210505-153212191 (deletion, 4q31.3, P=0.0005, P(corr) (corrected P-value)=0.04) and chr10:6265006-6267388 (duplication, 10p15.1, P=0.0006, P(corr)=0.05), were significantly associated with the risk of SAH after multiple testing corrections. Our results suggest that the newly identified CNV regions may contribute to SAH disease susceptibility.

The objective of this study was to elucidate whether polymorphisms of the interleukin 23 receptor gene (IL23R) are associated with susceptibility to systemic lupus erythematosus (SLE) in a Korean population. We recruited 602 SLE patients and 991 healthy controls. Seven single nucleotide polymorphisms (rs1004819, rs7517847, rs10489629, rs2201841, rs1343151, rs11209032, and rs1495965) were selected for genotyping among previously reported variants used in a genome-wide association study of inflammatory bowel disease. Polymorphic sites were genotyped using the TaqMan assay. The genotype distributions of IL23R polymorphisms and haplotypes were compared between the SLE patients and healthy controls using multiple logistic regression models. None of the IL23R genetic variants differed significantly between SLE patients and healthy controls, which suggests that IL23R polymorphisms play no role in the susceptibility to SLE in the Korean population. Electronic supplementary material The online version of this article (doi:10.1007/s00296-009-0893-8) contains supplementary material, which is available to authorized users.

The myosin light chain kinase (MYLK) gene encodes both smooth muscle and nonmuscle cell isoforms. Recently, polymorphisms in MYLK have been reported to be associated with several diseases. To examine the genetic effects of polymorphisms on the risk of asthma and related phenotypes, we scrutinized MYLK by re-sequencing/genotyping and statistical analysis in Korean population (n = 1,015). Seventeen common polymorphisms located in or near exons, having pairwise r 2 values less than 0.25, were genotyped. Our statistical analysis did not replicate the associations with the risk of asthma and log-transformed total IgE levels observed among African descendant populations. However, two SNPs in intron 16 (+89872C > G and +92263T >C), which were in tight LD (|D′| = 0.99), revealed significant association with log-transformed blood eosinophil level even after correction multiple testing (P = 0.002/P corr = 0.01 and P = 0.002/P corr = 0.01, respectively). The log-transformed blood eosinophil levels were higher in individuals bearing the minor alleles for +89872C > G and +92263T > C, than in those bearing other allele. In additional subgroup analysis, the genetic effects of both SNPs were much more apparent among asthmatic patients and atopic asthma patients. Among atopic asthma patients, the log-transformed blood eosinophil levels were proportionally increased by gene-dose dependent manner of in both +89872C > G and +92263T > C (P = 0.0002 and P = 0.00007, respectively). These findings suggest that MYLK polymorphisms might be among the genetic factors underlying differential increases of blood eosinophil levels among asthmatic patients. Further biological and/or functional studies are needed to confirm our results.

Background Since subepithelial fibrosis and protruded extracellular matrix are among the histological characteristics of polyps, the emilin/multimerin domain-containing protein 2 (EMID2) gene is speculated to be involved in the presence of nasal polyps in asthma and aspirin-hypersensitive patients. Methods To investigate the association between EMID2 and nasal polyposis, 49 single-nucleotide polymorphisms (SNPs) were genotyped in 467 asthmatics of Korean ancestry who were stratified further into 114 aspirin exacerbated respiratory disease (AERD) and 353 aspirin-tolerant asthma (ATA) subgroups. From pairwise comparison of the genotyped polymorphisms, 14 major haplotypes (frequency > 0.05) were inferred and selected for association analysis. Differences in the frequency distribution of EMID2 variations between polyp-positive cases and polyp-negative controls were determined using logistic analyses. Results Initially, 13 EMID2 variants were significantly associated with the presence of nasal polyps in the overall asthma group (P = 0.0008-0.05, OR = 0.54-1.32 using various modes of genetic inheritance). Although association signals from 12 variants disappeared after multiple testing corrections, the relationship between EMID2_BL1_ht2 and nasal polyposis remained significant via a codominant mechanism (P corr = 0.03). On the other hand, the nominal associations observed between the genetic variants tested for the presence of nasal polyps in AERD (P = 0.003-0.05, OR = 0.25-1.82) and ATA (P = 0.01-0.04, OR = 0.46-10.96) subgroups disappeared after multiple comparisons, suggesting lack of associations. Conclusions These preliminary findings suggest that EMID2_BL1_ht2 may be a susceptibility marker of inflammation of the nasal passages among Korean asthma patients.

Background Marbling score (MS) is the major quantitative trait that affects carcass quality in beef cattle. In this study, we examined the association between genetic polymorphisms of the micromolar calcium-activated neutral protease gene (micro-calpain, CAPN1) and carcass traits in Korean cattle (also known as Hanwoo). Results By direct DNA sequencing in 24 unrelated Korean cattle, we identified 39 sequence variants within exons and their flanking regions in CAPN1. Among them, 12 common polymorphic sites were selected for genotyping in the beef cattle (n = 421). Statistical analysis revealed that a polymorphism in the 3'UTR (c.2151*479C>T) showed significant association with MS (P cor.= 0.02). Conclusion Our findings suggest that polymorphisms in CAPN1 might be one of the important genetic factors involved in carcass quality in beef cattle, although it could be false positive association.