In-Jae Oh

Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients

PURPOSE Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer, largely because of a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SCC, we probed somatic genome alterations of lung SCC by using samples from Korean patients. PATIENTS AND METHODS We performed whole-exome sequencing of DNA from 104 lung SCC samples from Korean patients and matched normal DNA. In addition, copy-number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated. RESULTS This cancer cohort is characterized by a high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of exposure to cigarette smoke. Seven genes demonstrated statistical enrichment for mutation: TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA). Comparative analysis between Korean and North American lung SCC samples demonstrated a similar spectrum of alterations in these two populations in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SCC. CONCLUSION These findings provide new steps toward the identification of genomic target candidates for precision medicine in lung SCC, a disease with significant unmet medical needs.

Efficacy of Gemcitabine in Patients with Non–Small Cell Lung Cancer According to Promoter Polymorphisms of the Ribonucleotide Reductase M1 Gene

Purpose: High ribonucleotide reductase M1 (RRM1) expression in resected lung cancers has been associated with better clinical outcomes. However, gemcitabine-treated patients with high tumoral RRM1 expression generally evidence poor prognoses due to the decreased efficacy of gemcitabine therapy. This study was designed in accordance with the hypothesis that polymorphisms (−37 and −524) of the RRM1 promoter gene sequence, which regulate RRM1 expression, could influence the efficacy and prognosis of lung cancer patients treated with gemcitabine-based chemotherapy. Experimental Design: A retrospective dataset of 97 patients with advanced non–small cell lung cancer treated with gemcitabine regimens as a first-line treatment was studied in this work. The allelotyping of RRM1 promoter polymorphisms was conducted via real-time PCR using genomic DNA obtained from peripheral WBC. Results: The RRM1 promoter allelotype was RR37CC-R524TT in 58 patients, RR37AC-RR524CT in 29 patients, and other allelotypes in 10 patients. The response rate for gemcitabine-containing chemotherapy was 49.5%. The response rate was significantly higher in the RR37AC-RR524CT group (65.5%) compared with the group containing other allelotypes (42.6%; P = 0.039). Overall survival and progression-free survival did not differ significantly by allelotype. Conclusions: We detected significant differences in response rates to gemcitabine-based chemotherapy according to the allelotypes of the RRM1 promoter sequence, which could be determined using the germline DNA. Further functional and clinical studies will be required before this can be used as a predictive marker.

Differences in classification of COPD group using COPD assessment test (CAT) or modified Medical Research Council (mMRC) dyspnea scores: a cross-sectional analyses

BackgroundThe GOLD 2011 document proposed a new classification system for COPD combining symptom assessment by COPD assessment test (CAT) or modified Medical Research Council (mMRC) dyspnea scores, and exacerbation risk. We postulated that classification of COPD would be different by the symptom scale; CAT vs mMRC.MethodsOutpatients with COPD were enrolled from January to June in 2012. The patients were categorized into A, B, C, and D according to the GOLD 2011; patients were categorized twice with mMRC and CAT score for symptom assessment, respectively. Additionally, correlations between mMRC scores and each item of CAT scores were analyzed.ResultsClassification of 257 patients using the CAT score vs mMRC scale was as follows. By using CAT score, 60 (23.3%) patients were assigned to group A, 55 (21.4%) to group B, 21 (8.2%) to group C, and 121 (47.1%) to group D. On the basis of the mMRC scale, 97 (37.7%) patients were assigned to group A, 18 (7.0%) to group B, 62 (24.1%) to group C, and 80 (31.1%) to group D. The kappa of agreement for the GOLD groups classified by CAT and mMRC was 0.510. The mMRC score displayed a wide range of correlation with each CAT item (r = 0.290 for sputum item to r = 0.731 for dyspnea item, p < 0.001).ConclusionsThe classification of COPD produced by the mMRC or CAT score was not identical. Care should be taken when stratifying COPD patients with one symptom scale versus another according to the GOLD 2011 document.

Retreatment of gefitinib in patients with non-small-cell lung cancer who previously controlled to gefitinib: a single-arm, open-label, phase II study.

Most patients with non-small-cell lung cancer (NSCLC) who initially respond to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) eventually experience progression of disease. Based on previous trials which showed second response after switching to another EGFR-TKI, we hypothesized that the reintroduction of gefitinib would lead to disease control rate (DCR) in more than 30% of patients. This was a single-arm, open-label, prospective, phase II trial of gefitinib for the treatment of advanced or metastatic NSCLC. Eligible patients had previously responded to, or had experienced disease stabilization with, initial gefitinib treatment for at least 3 months. Prior to retreatment, progressive disease (PD) should be observed, with at least one cytotoxic treatment following initial gefitinib failure. Twenty-three patients were recruited and defined as the intention to treat (ITT) group. Most of the enrolled patients were female (86.9%), never-smokers (91.3%), and adenocarcinoma patients (95.7%). Responses to initial gefitinib were partial response (PR) in 10 cases (43.5%) and stable disease (SD) in 13 cases (56.5%). PR and DCR were observed in 21.7% (5 patients) and 65.2% (15 patients) in the ITT group. Among 14 DNA samples, 13 cases had either exon 19 deletion or L858R point mutation, whereas one patient evidenced the wild-type EGFR gene. Re-initiation of EGFR-TKI can be considered as an option after failure of chemotherapy for those patients who previously controlled to EGFR-TKI treatment.

Lung cancer patients who are asymptomatic at diagnosis show favorable prognosis: A Korean Lung Cancer Registry Study

PURPOSE AND METHODS The outcomes of lung cancer patients who were asymptomatic at diagnosis have never been reported as part of a large-scale study. A national survey of lung cancer in South Korea registered a total of 8788 patients diagnosed in 2005. We report the results herein, with an emphasis on the prognosis of the asymptomatic lung cancer patients. RESULTS Adenocarcinoma was the most frequent (36.1%) histopathologic type, followed by squamous cell carcinoma (32.1%), large cell carcinoma (1.5%), and small cell carcinoma (13.5%). In most cases, lung cancer was detected with subjective symptoms, but 6.5% of cases had no symptoms indicative of lung cancer at the time of diagnosis. Compared to symptomatic patients, asymptomatic patients were younger, more often female, non-smokers, and more frequently presented with adenocarcinoma. Initial treatments were surgery (22.1%), radiation therapy (7.8%), chemo-radiation therapy (5.4%), and chemotherapy (38%), while 26.6% of patients were recorded to have supportive care only. Asymptomatic patients received surgery in 60.0% of cases, and they showed significantly longer survival times than symptomatic patients. Absence of symptoms at diagnosis significantly reduced the risk of death from non-small cell lung cancer, regardless of patient age, patient gender, stage at diagnosis, smoking history, or whether treatment was performed, but did not reduce the risk of death from small cell lung cancer. CONCLUSIONS Adenocarcinoma has grown to be the leading histopathologic type of lung cancer in South Korea. Absence of symptom at diagnosis is a favorable prognostic factor for patients with non-small cell lung cancer.

p53 codon 72 polymorphism and the risk of lung cancer in a Korean population.

The aim of this study was to assess whether p53 codon 72 polymorphism is associated with an increased risk of lung cancer (LC) in a South Korean population. We conducted a population-based, large-scale, case-control study including 3939 patients with LC and 1700 controls. P53 codon 72 polymorphism was determined by real-time polymerase chain reaction (PCR). The frequencies of p53 codon 72 polymorphisms (Arg/Arg, Arg/Pro, and Pro/Pro) in LC were 37.0%, 46.2%, and 16.7%, respectively; frequencies in the controls were 43.2%, 45.6%, and 11.2%, respectively (p<0.01). The Arg/Pro and Pro/Pro genotype were significantly associated with increased risk of LC (odds ratio (OR)=1.22, 95% confidence interval (CI)=1.06-1.14 and OR=1.83, 95% CI=1.48-2.26, respectively) compared with the Arg/Arg genotype. Risk was compared in different subgroups. The OR of Pro/Pro genotype was significantly higher in small cell lung cancer (SCC) and squamous cell carcinoma (SQC) than in adenocarcinoma (ADC). Higher OR of Pro/Pro genotype was also seen among males. However, relationships between gender, age, smoking, and genotypes were not found. P53 codon 72 polymorphism was associated with an increased risk of LC in this Korean population; the association was especially noteworthy in SQC, SCC, and males.

Plasma C-reactive protein and endothelin-1 level in patients with chronic obstructive pulmonary disease and pulmonary hypertension.

Pulmonary hypertension is a frequent complication of chronic obstructive pulmonary disease (COPD) and associated with a worse survival and increased risk of hospitalization for exacerbation of COPD. However, little information exists regarding the potential role of systemic inflammation in pulmonary hypertension of COPD. The purpose of the present study was to investigate the degree of C-reactive protein (CRP) and endothelin-1 (ET-1) levels in COPD patient with and without pulmonary hypertension. The levels of CRP and ET-1 were investigated in 58 COPD patient with pulmonary hypertension and 50 patients without pulmonary hypertension. Pulmonary hypertension was defined as a systolic pulmonary artery pressure (Ppa) ≥35 mmHg assessed by Doppler echocardiography. Plasma CRP and ET-1 levels were significantly higher in patients with pulmonary hypertension than in patients without hypertension. There were significant positive correlations between the plasma ET-1 level and CRP level in the whole study groups. For COPD patients, systolic Ppa correlated significantly with plasma CRP levels and plasma ET-1 levels. These findings support a possibility that CRP and ET-1 correlate to pulmonary hypertension in COPD patients.

Treatment outcome of combination therapy including clarithromycin for Mycobacterium avium complex pulmonary disease.

Background/Aims The frequency of nontuberculous mycobacteria pulmonary disease in HIV-negative patients is increasing; the most common pathogen in Korea is the Mycobacterium avium complex (MAC). However, few studies have evaluated the treatment outcome of MAC pulmonary disease in Korea. Methods The efficacy of a clarithromycin-containing regimen for MAC pulmonary disease was studied in 42 patients treated for more than 6 months between January 2005 and December 2008. All patients were treated with a regimen consisting of clarithromycin, rifampin, and ethambutol. Streptomycin was added in 10 patients. Results Among the 42 patients, a negative culture conversion was achieved in 33 (78.6%), and the median duration of treatment in these patients was 19 months (interquartile range [IQR], 16 to 22). Of the 33 patients with a negative culture conversion, 14 completed treatment. During the follow-up period (median, 10 months; IQR, 4 to 20) for the 14 patients, one relapsed at 24 months after treatment completion. The culture conversion rate was significantly higher in patients who were treated with more than 500 mg/day clarithromycin (87.1% vs. 54.5%, p = 0.038). Conclusions The combined regimen including clarithromycin was effective against MAC pulmonary disease. High-dose clarithromycin of more than 500 mg/day may improve the outcome of patients with MAC pulmonary disease.

Methylenetetrahydrofolate reductase C677T polymorphism in patients with lung cancer in a Korean population

BackgroundThis study was designed to investigate an association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of lung cancer in a Korean population.MethodsWe conducted a large-scale, case-control study involving 3938 patients with newly diagnosed lung cancer and 1700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. Statistical significance was estimated by logistic regression analysis.ResultsThe MTHFR C677T frequencies of CC, CT, and TT genotypes were 34.5%, 48.5%, and 17% among lung cancer patients, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677CT and TT genotype showed a weak protection against lung cancer compared with the homozygous CC genotype, although the results did not reach statistical significance. The age- and gender-adjusted odds ratio (OR) of overall lung cancer was 0.90 (95% confidence interval (CI), 0.77-1.04) for MTHFR 677 CT and 0.88 (95% CI, 0.71-1.07) for MTHFR 677TT. However, after stratification analysis by histological type, the MTHFR 677CT genotype showed a significantly decreased risk for squamous cell carcinoma (age- and gender-adjusted OR, 0.78; 95% CI, 0.64-0.96). The combination of 677 TT homozygous with 677 CT heterozygous also appeared to have a protection effect on the risk of squamous cell carcinoma. We observed no significant interaction between the MTHFR C677T polymorphism and age and gender or smoking habit.ConclusionsThis is the first reported study focusing on the association between MTHFR C677T polymorphisms and the risk of lung cancer in a Korean population. The T allele was found to provide a weak protective association with lung squamous cell carcinoma.

Hippo pathway effector YAP inhibition restores the sensitivity of EGFR-TKI in lung adenocarcinoma having primary or acquired EGFR-TKI resistance.

The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) is significantly limited by various resistance mechanisms to those drugs. The resistance to EGFR-TKI is largely divided by two classes; acquired resistance after EGFR-TKI treatment, and primary resistance marked by cancer cells dependence on other oncogene, such as KRAS. YAP has emerged as critical oncogene in conferring drug resistance against targeted therapy. In this study, we evaluated the role of YAP in primary and acquired EGFR-TKI resistance using gefitinib-resistant A549 and PC9 cells and their parental cell lines. Our study revealed that EGFR-TKI resistance is associated with enhanced YAP activity. Notably, YAP activation was independent of the Hippo pathway. We confirmed that AXL is a downstream target of YAP that confers EGFR-TKI resistance. And our results showed that YAP can induce ERK activation in lung adenocarcinoma. The combination of YAP inhibition with EGFR-TKI overcomes primary and acquired EGFR-TKI resistance. We also found increased YAP expression in human lung cancer after acquiring EGFR-TKI resistance. Collectively, we suggest a novel EGFR-TKI resistance mechanism involving YAP activation and suggest targeting YAP and EGFR simultaneously may be a breakthrough treatment of primary and acquired EGFR-TKI resistant lung cancer.