Yeun Jun Chung

Somatic Mutations of JAK1 and JAK3 in Acute Leukemias and Solid Cancers

Purpose: The aim of this study was to see whether JAK1, JAK3, and TYK2 genes are altered in human cancers. Experimental Design: We analyzed 494 tissues from 186 acute adulthood leukemias, 30 multiple myelomas, and 278 common solid cancers, including 90 breast, 47 gastric, 47 colon, 47 lung, and 47 hepatocellular carcinomas by single-strand conformation polymorphism analysis. Results: Overall, we found six JAK1 mutations (four in acute leukemias, one in a lung carcinoma, and one in a breast carcinoma) and three JAK3 mutations (two in breast carcinomas and one in a gastric carcinoma). Of note, three JAK1 mutations were an identical p.V658F mutation, which is homologous to JAK2 p.V617F mutation. We also found two other JAK1 mutations that occurred at very close sites (p.T782M and p.L783F). We found three of the four leukemias with JAK1 mutations expressed mutated JAK1 at the mRNA level. For JAK3 mutations, one of them was JAK3 p.V715I that is homologous to the JAK1 p.L783F. These recurrent mutations in identical and homologous sites suggest a possibility that alterations of these amino acids might be important for tumor pathogenesis. With respect to the cancer types, T-acute lymphoblastic leukemia (T-ALL) showed the highest incidence of the mutations (3 of 11; 27.3%). Conclusion: Our data indicate that both JAK1 and JAK3 mutations occur in common human cancers and that JAK1 mutation in T-ALL is a frequent event. The data suggest that some of the JAK1 and JAK3 mutations may to be functional and contributes to cancer development, especially to T-ALL development.

Simultaneous copy number gains of NUPR1 and ERBB2 predicting poor prognosis in early-stage breast cancer

BackgroundThe full extent of chromosomal alterations and their biological implications in early breast carcinogenesis has not been well examined. In this study, we aimed to identify chromosomal alterations associated with poor prognosis in early-stage breast cancers (EBC).MethodsA total of 145 EBCs (stage I and II) were examined in this study. We analyzed copy number alterations in a discovery set of 48 EBCs using oligoarray-comparative genomic hybridization. In addition, the recurrently altered regions (RARs) associated with poor prognosis were validated using an independent set of 97 EBCs.ResultsA total of 23 RARs were defined in the discovery set. Six were commonly detected in both stage I and II groups (> 50%), suggesting their connection with early breast tumorigenesis. There were gains on 1q21.2-q21.3, 8q24.13, 8q24.13-21, 8q24.3, and 8q24.3 and a loss on 8p23.1-p22. Among the 23 RARs, copy number gains on 16p11.2 (NUPR1) and 17q12 (ERBB2) showed a significant association with poor survival (P = 0.0186 and P = 0.0186, respectively). The patients simultaneously positive for both gains had a significantly worse prognosis (P = 0.0001). In the independent replication, the patients who were double-positive for NUPR1-ERBB2 gains also had a significantly poorer prognosis on multivariate analysis (HR = 7.31, 95% CI 2.65-20.15, P = 0.0001).ConclusionsThe simultaneous gain of NUPR1 and ERBB2 can be a significant predictor of poor prognosis in EBC. Our study will help to elucidate the molecular mechanisms underlying early-stage breast cancer tumorigenesis. This study also highlights the potential for using combinations of copy number alterations as prognosis predictors for EBC.

Oncoprotein HCCR-1 expression in breast cancer is well correlated with known breast cancer prognostic factors including the HER2 overexpression, p53 mutation, and ER/PR status.

BackgroundOncoprotein HCCR-1 functions as a negative regulator of the p53 and contributes breast tumorigenesis. The serum HCCR-1 assay is useful in diagnosing breast cancer and mice transgenic for HCCR developed breast cancers. But it is unknown how HCCR-1 contributes to human breast tumorigenesis.MethodsOncogene HCCR-1 expression levels were determined in normal breast tissues, breast cancer tissues and cancer cell lines. We examined whether HCCR-1 protein expression in breast cancer is related to different biological characteristics, including ER, PR, p53 genotype, and HER2 status in 104 primary breast cancer tissues using immunohistochemical analyses.ResultsHCCR-1 was upregulated in breast cancer cells and tissues compared with normal breast tissues. In this study, overexpression of HCCR-1 was well correlated with known breast cancer prognostic markers including the presence of steroid receptors (ER and PR), p53 mutation and high HER2 overexpression. HCCR-1 was not detected in the ER-negative, PR-negative, p53 negative and low HER2 breast cancer tissues. These data indicate that the level of HCCR-1 in breast cancer tissues is relatively well correlated with known breast cancer factors, including the HER2 overexpression, p53 mutation, and ER/PR status.ConclusionDetermination of HCCR-1 levels as options for HER2 testing is promising although it needs further evaluation.

Dual action of apolipoprotein E‐interacting HCCR‐1 oncoprotein and its implication for breast cancer and obesity

Obese women have an increased risk for post‐menopausal breast cancer. The physiological mechanism by which obesity contributes to breast tumourigenesis is not understood. We previously showed that HCCR‐1 oncogene contributes to breast tumourigenesis as a negative regulator of p53 and detection of HCCR‐1 serological level was useful for the diagnosis of breast cancer. In this study, we found that the HCCR‐1 level is elevated in breast cancer tissues and cell lines compared to normal breast tissues. We identified apolipoprotein E (ApoE) interacting with HCCR‐1. Our data show that HCCR‐1 inhibits anti‐proliferative effect of ApoE, which was mediated by diminishing ApoE secretion of breast cancer cells. Finally, HCCR‐1 induced the severe obesity in transgenic mice. Those obese mice showed severe hyperlipidaemia. In conclusion, our results suggest that HCCR‐1 might play a role in the breast tumourigenesis while the overexpression of HCCR‐1 induces the obesity probably by inhibiting the cholesterol‐lowering effect of ApoE. Therefore, HCCR‐1 seems to provide the molecular link between the obesity and the breast cancer risk.

Comparison of the Affymetrix SNP Array 5.0 and Oligoarray Platforms for Defining CNV

Together with single nucleotide polymorphism (SNP), copy number variations (CNV) are recognized to be the major component of human genetic diversity and used as a genetic marker in many disease association studies. Affymetrix Genome-wide SNP 5.0 is one of the commonly used SNP array platforms for SNP-GWAS as well as CNV analysis. However, there has been no report that validated the accuracy and reproducibility of CNVs identified by Affymetrix SNP array 5.0. In this study, we compared the characteristics of CNVs from the same set of genomic DNAs detected by three different array platforms; Affymetrix SNP array 5.0, Agilent 2X244K CNV array and NimbleGen 2.1M CNV array. In our analysis, Affymetrix SNP array 5.0 seems to detect CNVs in a reliable manner, which can be applied for association studies. However, for the purpose of defining CNVs in detail, Affymetrix Genome-wide SNP 5.0 might be relatively less ideal than NimbleGen 2.1M CNV array and Agilent 2X244K CNV array, which outperform Affymetrix array for defining the small-sized single copy variants. This result will help researchers to select a suitable array platform for CNV analysis.

1p36.22 region containing PGD gene is frequently gained in human cervical cancer

To identify commonly occurring DNA copy number alterations in Korean cervical cancers.

Circulating Tumor DNA in a Breast Cancer Patient's Plasma Represents Driver Alterations in the Tumor Tissue

Tumor tissues from biopsies or surgery are major sources for the next generation sequencing (NGS) study, but these procedures are invasive and have limitation to overcome intratumor heterogeneity. Recent studies have shown that driver alterations in tumor tissues can be detected by liquid biopsy which is a less invasive technique capable of both capturing the tumor heterogeneity and overcoming the difficulty in tissue sampling. However, it is still unclear whether the driver alterations in liquid biopsy can be detected by targeted NGS and how those related to the tissue biopsy. In this study, we performed whole-exome sequencing for a breast cancer tissue and identified PTEN p.H259fs*7 frameshift mutation. In the plasma DNA (liquid biopsy) analysis by targeted NGS, the same variant initially identified in the tumor tissue was also detected with low variant allele frequency. This mutation was subsequently validated by digital polymerase chain reaction in liquid biopsy. Our result confirm that driver alterations identified in the tumor tissue were detected in liquid biopsy by targeted NGS as well, and suggest that a higher depth of sequencing coverage is needed for detection of genomic alterations in a liquid biopsy.

Chromosomal aberrations and prognosis in patients with concomitant chemoradiotherapy for resected head and neck cancer

Although concomitant chemoradiotherapy (CCRT) has recently become a mainstay of a primary treatment modality in advanced head and neck squamous cell carcinoma (HNSCC), some of the patients experience CCRT failure. If we can predict the CCRT outcomes, we can reduce unnecessary CCRT avoiding risk of CCRT‑related complication. We aimed to identify genetic alteration markers related to treatment failure in HNSCC patients who underwent radical surgery and CCRT. Genome‑wide copy number alterations (CNAs) were analyzed in 18 HNSCC patients with (n=9) or without (n=9) recurrence using oligoarray‑comparative genomic hybridization and candidate CNAs were validated by quantitative RT‑PCR. A total of 15 recurrently altered regions (RARs) were identified in the 18 HNSCC cases. Among them, two RARs were significantly associated with CCRT‑failure: copy number gained RARs of 7p11.2 harboring EGFR (P=0.029) and 18p11.32 harboring TYMS gene (P=0.029). Three RARs (7p11.2, 9p21.3 and 18p11.32) were significantly associated with poor disease‑specific survival in univariate analysis, and 7p11.2 was consistently significant in the multivariate analysis (HR 40.68, P=0.003). In conclusion, we defined novel genomic alterations associated with CCRT‑failure: 7p11.2 (EGFR) and 18p11.32 (TYMS). Our results provide useful clues for the elucidation of the molecular pathogenesis of HNSCC and to predict CCRT‑failure.

Recapitulation of Candidate Systemic Lupus Erythematosus-Associated Variants in Koreans

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organ systems. Although the etiology of SLE remains unclear, it is widely accepted that genetic factors could be involved in its pathogenesis. A number of genome-wide association studies (GWASs) have identified novel single-nucleotide polymorphisms (SNPs) associated with the risk of SLE in diverse populations. However, not all the SNP candidates identified from non-Asian populations have been validated in Koreans. In this study, we aimed to replicate the SNPs that were recently discovered in the GWAS; these SNPs have not been validated in Koreans or have only been replicated in Koreans with an insufficient sample size to conclude any association. For this, we selected five SNPs (rs1801274 in FCGR2A and rs2286672 in PLD2, rs887369 in CXorf21, rs9782955 in LYST, and rs3794060 in NADSYN1). Through the replication study with 656 cases and 622 controls, rs1801274 in FCGR2A was found to be significantly associated with SLE in Koreans (odds ratio, 1.26, 95% confidence interval, 1.06 to 1.50; p = 0.01 in allelic model). This association was also significant in two other models (dominant and recessive). The other four SNPs did not show a significant association. Our data support that FCGR polymorphisms play important roles in the susceptibility to SLE in diverse populations, including Koreans.

MAP: Mutation Arranger for Defining Phenotype-Related Single-Nucleotide Variant

Next-generation sequencing (NGS) is widely used to identify the causative mutations underlying diverse human diseases, including cancers, which can be useful for discovering the diagnostic and therapeutic targets. Currently, a number of single-nucleotide variant (SNV)-calling algorithms are available; however, there is no tool for visualizing the recurrent and phenotype-specific mutations for general researchers. In this study, in order to support defining the recurrent mutations or phenotype-specific mutations from NGS data of a group of cancers with diverse phenotypes, we aimed to develop a user-friendly tool, named mutation arranger for defining phenotype-related SNV (MAP). MAP is a user-friendly program with multiple functions that supports the determination of recurrent or phenotype-specific mutations and provides graphic illustration images to the users. Its operation environment, the Microsoft Windows environment, enables more researchers who cannot operate Linux to define clinically meaningful mutations with NGS data from cancer cohorts.