Eung Bae Lee

PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers.

Somatic mutations of phosphatase and tensin homolog deleted on chromosome ten (PTEN) in non-small cell lung cancers (NSCLCs) have been investigated in but a small number of cases. In addition, the relationship between PTEN mutations and epidermal growth factor receptor (EGFR), KRAS, and TP53 mutations has not been investigated. Therefore, we investigated the frequency of PTEN mutations in 176 surgically resected NSCLCs and analyzed the relationship between PTEN mutations and EGFR, ERBB2, KRAS, and TP53 mutations. Mutations of PTEN (exons 1-9), EGFR (exons 18-21), ERBB2 (exons 19 and 20), KRAS (exon 1), and TP53 (exons 2-11) were determined by polymerase chain reaction and direct sequencing. PTEN mutations were present in 8 (4.5%) of the 176 tumors. PTEN mutations were only found in ever-smokers and were significantly more frequent in squamous cell carcinoma than in adenocarcinoma (10.2% vs 1.7%, P=0.02). Mutations of EGFR, ERBB2, KRAS, and TP53 genes were found in 36 (20.5%), 2 (1.1%), 11 (6.3%), and 66 (37.5%) cases, respectively. Of the 8 tumors with PTEN mutations, 1 case concurrently had an EGFR mutation and 4 cases had TP53 mutations. However, PTEN mutations were not found in the tumors with KRAS mutation. Our findings indicate that PTEN mutations are relatively common in NSCLC, and thus analysis of PTEN mutations may facilitate a comprehensive understanding of the genetic alterations related to the EGFR signaling pathway.

Lys751Gln polymorphism in the DNA repair gene XPD and risk of primary lung cancer.

a Department of Internal Medicine, School of Medicine, Kyungpook National Uni ersity Hospital, Samduk 2ga 50, Taegu 700-412, South Korea b Cancer Research Institute, School of Medicine, Kyungpook National Uni ersity, Dong In 2Ga 101, Taegu 700-422, South Korea c Department of Biochemistry, School of Medicine, Kyungpook National Uni ersity, Dong In 2Ga 101, Taegu 700-422, South Korea d Department of Thoracic Surgery, School of Medicine, Kyungpook National Uni ersity Hospital, Samduk 2ga 50, Taegu 700-412, South Korea e Department of Internal Medicine, School of Medicine, Keimyung Uni ersity, Dongsan Dong 194, Taegu 700-712, South Korea f Department of Pre enti e Medicine, School of Medicine, Kyungpook National Uni ersity, Dong In 2Ga 101, Taegu 700-422, South Korea

O6‐alkylguanine‐DNA alkyltransferase gene polymorphisms and the risk of primary lung cancer

O6‐alkylguanine‐DNA alkyltransferase (AGT) plays an important role in the repair of O6‐alkylguanine adducts, which are major mutagenic lesions produced by environmental carcinogens. Polymorphisms in the AGT gene may affect the capacity to repair DNA damage and thereby have influence on individuals susceptibility to smoking‐related cancer. To test this hypothesis, we investigated the potential association of AGT polymorphisms (485Cu2009>u2009A, Leu53Leu (Cu2009>u2009T) and Leu84Phe] with the risk of lung cancer in a Korean population. The AGT genotypes were determined in 432 lung cancer patients and in 432 healthy controls who were frequency‐matched for age and gender. The 485 AA genotype was associated with a significantly increased risk for overall lung cancer as compared with the 485 CC genotype and the combined 485 CCu2009+u2009CA genotype, respectively (adjusted odds ratio (OR)u2009=u20091.83, 95% confidence interval (CI)u2009=u20091.12–2.99, Pu2009=u20090.02, and Bonferroni corrected P‐value (Pc)u2009=u20090.04; and adjusted ORu2009=u20091.67, 95% CIu2009=u20091.05–2.66, Pu2009=u20090.03, respectively). When the lung cancer cases were categorized by the tumor histology, the 485 AA genotype was associated with a significantly increased risk of adenocarcinoma (AC) and small cell carcinoma (SmCC), respectively, as compared with the combined 485 CCu2009+u2009CA genotype (adjusted ORu2009=u20092.54, 95% CIu2009=u20091.39–4.66, Pu2009=u20090.003; and adjusted ORu2009=u20092.19, 95% CIu2009=u20091.06–4.55, Pu2009=u20090.04, respectively). However, the genotype distributions of the Leu53Leu and Leu84Phe polymorphisms were not significantly different between the lung cancer cases and the controls. On a promoter assay, the 485Cu2009>u2009A polymorphism did not have an effect on the promoter activity of the AGT gene. These results suggest that the effect of the AGT 485Cu2009>u2009A polymorphism on the risk of lung cancer may be secondary to linkage disequilibrium (LD) with either another AGT variant or with a true susceptibility gene, and that the AGT 485Cu2009>u2009A polymorphism could be used as a marker for the genetic susceptibility to lung cancer.

Staple Line Coverage After Bullectomy for Primary Spontaneous Pneumothorax: A Randomized Trial

BACKGROUNDnThoracoscopic wedge resection is generally accepted as a standard surgical procedure for primary spontaneous pneumothorax. Because of the relatively high recurrence rate after surgery, additional procedures such as mechanical pleurodesis or visceral pleural coverage are usually applied to minimize recurrence, although mechanical pleurodesis has some potential disadvantages. The aim of this study was to clarify whether an additional coverage procedure on thexa0staple line after thoracoscopic bullectomy prevents postoperative recurrence compared with additional pleurodesis.nnnMETHODSnA total of 1,414 patients in 11 hospitals with primary spontaneous pneumothorax undergoing thoracoscopic bullectomy were enrolled. After bullectomy with staplers, patients were randomly assigned to either the coverage group (nxa0= 757) or the pleurodesis group (nxa0= 657). In the coverage group, the staple line was covered with absorbable cellulose mesh and fibrin glue. The pleurodesis group underwent additional mechanical abrasion on the parietal pleura.nnnRESULTSnThe coverage group and the pleurodesis group showed comparable surgical outcomes. After a median follow-up of 19.5 months, the postoperative 1-year recurrence rate was 9.5% in the coverage group and 10.7% in the pleurodesis group. The 1-year recurrence rate requiring intervention was 5.8% in the coverage group and 7.8% in the pleurodesis group. The coverage group showed better recovery from pain.nnnCONCLUSIONSnIn terms of postoperative recurrence rate, visceral pleural coverage after thoracoscopic bullectomy was not inferior to mechanical pleurodesis. Visceral pleural coverage may potentially replace mechanical pleurodesis, which has potential disadvantages such as disturbed normal pleural physiology.

AKT1 polymorphisms and survival of early stage non-small cell lung cancer†

This study was conducted to investigate the impact of polymorphisms in the AKT1 gene on the survival of early stage non‐small cell lung cancer (NSCLC) patients.

Dual roles of a variable number of tandem repeat polymorphism in the TERT gene in lung cancer

This study was conducted to determine the impact of a functional tandem repeat minisatellite (MNS16A) polymorphism in the telomerase reverse transcriptase (TERT) gene on the risk of lung cancer, as well as on survival of patients with non‐small‐cell lung cancer (NSCLC). The effect of the MNS16A variable number of tandem repeat (VNTR) polymorphism on the risk of lung cancer was evaluated in a case–control study that consisted of 937 lung cancer patients and 943 healthy controls. The effect of the polymorphism on survival outcome was evaluated in 703 patients with surgically resected NSCLC. Compared with the VNTR‐302 allele, the VNTR‐243 allele was associated with a significantly increased risk of lung cancer (adjusted odds ratio, 1.55; 95% confidence interval [CI], 1.07–2.25; Pu2003=u20030.02). In addition, the genotypes carrying at least one VNTR‐243 allele were associated with a significantly increased risk of lung cancer compared with the genotypes with no VNTR‐243 allele (adjusted odds ratio, 1.61; 95% CI, 1.09–2.38; Pu2003=u20030.02). In contrast to the effect of the polymorphism on the risk of lung cancer, the genotypes carrying at least one VNTR‐243 allele were associated with a significantly better overall survival in patients with surgically resected NSCLC (adjusted hazard ratio, 0.51; 95% CI, 0.28–0.93; Pu2003=u20030.03). These findings suggest that the MNS16A VNTR polymorphism in the TERT gene has dual, conflicting roles in lung carcinogenesis. This polymorphism may increase the risk of lung cancer development, and may improve survival in lung cancer patients. (Cancer Sci 2011; 102: 144–149)

Primary esophageal repair in Boerhaave's syndrome

Boerhaaves syndrome is the most severe disease in the esophageal perforation. The purpose of this report is to evaluate the outcome in patients who were treated with primary repair for Boerhaaves syndrome regardless of the time interval. From 1997 to July 2007, 10 patients with Boerhaaves syndrome were treated with primary repair regardless of the time interval. The interval between rupture and initial treatment was less than 24 hours in five patients (50.0%) and more than 24 hours in the other five patients (50.0%). There was no operative mortality and five postoperative leaks. Of these five patients with postoperative leaks, one received primary repair for less than 24 hours (20%) and four received operation for more than 24 hours (80%). However, postoperative leaks were managed by non-operative methods and resolved within 2 weeks. The time interval between perforation and operative intervention should not prejudice the surgeon against primary repair of Boerhaaves syndrome. Although a high incidence of postoperative leak occurred in patients who were operated on for more than 24 hours, its management is not hard to perform and its prognosis was not poor.

Comprehensive analysis of DNA repair gene polymorphisms and survival in patients with early stage non-small-cell lung cancer.

This study was conducted to analyze a comprehensive panel of single nucleotide polymorphisms (SNP) in DNA repair genes to determine the relationship between polymorphisms and the survival outcome of patients with early stage non‐small‐cell lung cancer (NSCLC). Three hundred and ten consecutive patients with surgically resected NSCLC were enrolled. Forty‐eight SNP in 27 DNA repair genes were genotyped and their associations with overall survival (OS) and disease‐free survival (DFS) were analyzed. Individually, six SNP exhibited significant associations with survival outcome. When the six SNP were combined, OS and DFS decreased as the number of bad genotypes increased (Ptrendu2003<u20030.0001 for both). Patients with three, and four or five bad genotypes had a significantly worse OS and DFS compared with those carrying zero or one bad genotypes (adjusted hazard ratio [aHR] for OSu2003=u20033.53, 95% confidence interval [CI]u2003=u20031.25–9.97, Pu2003=u20030.02, and aHR for DFSu2003=u20033.31, 95% CIu2003=u20031.41–7.76, Pu2003=u20030.006; and aHR for OSu2003=u20035.47, 95% CIu2003=u20031.87–16.00, Pu2003=u20030.002, and aHR for DFSu2003=u20034.42, 95% CIu2003=u20031.82–10.74, Pu2003=u20030.001, respectively). These findings suggest that the six SNP identified can be used as prognostic markers for patients with surgically resected early stage NSCLC. (Cancer Sci 2010; 101: 2436–2442)

Polymorphisms in apoptosis-related genes and survival of patients with early-stage non-small-cell lung cancer.

PurposeThis study was conducted to determine the association between single-nucleotide polymorphisms (SNPs) in apoptosis-related genes and survival outcomes of patients with early-stage non-small-cell lung cancer (NSCLC).MethodsThree hundred ten consecutive patients with surgically resected NSCLC were enrolled. Twenty-five SNPs in 17 apoptosis-related genes were genotyped by a sequenome mass spectrometry-based genotyping assay. The genotype associations with overall survival (OS) and disease-free survival (DFS) were analyzed.ResultsThree SNPs (TNFRSF10B rs1047266, TNFRSF1A rs4149570, and PPP1R13L rs1005165) were significantly associated with survival outcomes on multivariate analysis. When the three SNPs were combined, OS and DFS were decreased as the number of bad genotypes increased (Ptrend for OS and DFSxa0=xa07xa0×xa010−5 and 1xa0×xa010−4, respectively). Patients with one bad genotype, and patients with two or three bad genotypes had significantly worse OS and DFS compared with those with no bad genotypes [adjusted hazard ratio (aHR) for OSxa0=xa02.27, 95% confidence interval (CI)xa0=xa01.22–4.21, Pxa0=xa00.01, aHR for DFSxa0=xa01.74, 95% CIxa0=xa01.08–2.81, Pxa0=xa00.02; aHR for OSxa0=xa04.11, 95% CIxa0=xa02.03–8.29, Pxa0=xa08xa0×xa010−5; and aHR for DFSxa0=xa02.89, 95% CIxa0=xa01.64–5.11, Pxa0=xa03xa0×xa010−4, respectively].ConclusionThree SNPs in apoptosis-related genes were identified as possible prognostic markers of survival in patients with early-stage NSCLC. The SNPs, and particularly their combined genotypes, can be used to identify patients at high risk for poor disease outcome.

Loss of heterozygosity on the long arm of chromosome 21 in non–small cell lung cancer

BACKGROUNDnIn Down syndrome, the incidence of solid tumors including lung cancer is considerably lower than that of the general population. The low risk of lung cancer in individuals with Down syndrome may be related to the gene-dosage effect of the extra chromosome 21. It may suggest that tumor suppressor genes playing a role in the pathogenesis of lung cancer may be present on chromosome 21.nnnMETHODSnA total of 39 surgically resected non-small cell lung cancers were analyzed using nine microsatellite markers for 21q. Loss of heterozygosity was considered to be present when the signal intensity of the allele in tumor DNA was less than 50% of that in the corresponding normal DNA.nnnRESULTSnLoss of heterozygosity for at least one locus was detected in 22 of 39 tumors (56.4%). Allelic loss was frequently detected at three distinct regions: at the locus D21S1432 on 21q21.1, the region between D21S1435 and D21S1442 on 21q21.2 to 21.3, and the region between D21S1270 and D21S1445 on 21q22.1.nnnCONCLUSIONSnThese results indicate that loss of heterozygosity on 21q may play an important role in the pathogenesis of non-small cell lung cancer.