Although TP53 mutations have been widely studied in lung cancer, the majority of studies have focused on exons 5-8 of the gene. In addition, TP53 mutations in Korean patients with lung cancers have not been investigated. We searched for mutations in the entire coding exons, including splice sites of the gene, in Korean patients with non-small cell lung cancer (NSCLC). Mutations of the gene were determined by direct sequencing in 176 NSCLCs. Sixty-nine mutations (62 different mutations) were identified in 65 tumors. Of the 62 mutations, 12 were novel mutations. TP53 mutations were more frequent in males, ever-smokers and squamous cell carcinomas than in females, never-smokers and adenocarcinomas, respectively (all comparisons, P<0.001). Missense mutations were most common (52.2%), but frameshift, nonsense, and splice-site mutations were frequently observed at frequencies of 18.8%, 15.9% and 10.1%, respectively. Of the 69 mutations, 9 (13.0%) were found in the oligomerization domain. In addition, the proportion of mutations in the oligomerization domain was significantly higher in adenocarcinomas than in squamous cell carcinomas (23.5% vs. 2.9%, P=0.01). Our study provides clinical and molecular characteristics of TP53 mutations in Korean patients with NSCLCs.
Carcinoma, Non-Small-Cell Lung/*epidemiology/*genetics ; Female ; Genetic Predisposition to Disease/*epidemiology/*genetics ; Humans ; Incidence ; Korea/epidemiology ; Lung Neoplasms/*epidemiology/*genetics ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Risk Assessment/methods ; Risk Factors ; Tumor Suppressor Protein p53/*genetics

OBJECTIVEThe aim of this study was to establish a standard protocol for detection of EGFR mutations in cytologic specimens.

METHODS287 cytologic samples were collected from the patients who were suspected of having lung cancer at six hospitals in Beijing. A detection protocol for EGFR mutations was designed. Two comparative experiments were carried out for the coincidence in EGFR mutation rates between direct sequencing (Seq) and amplification refractory mutation system (ARMS) methods, and between 40 matched cytologic samples with formaldehyde-fixed paraffin embedded (FFPE) cytologic blocks and cytospin slides.

RESULTSTumor cells were found in 236 out of 287 cases (82.2%, 236/287) . Among them, there were 31 cases (13.1%, 31/236) of low tumor cell content samples and 205 cases (86.9%, 205/236) of high tumor cell content samples. 180 cases in the high tumor cell content samples (87.8%, 180/205) were diagnosed to be consistent with NSCLC. 25 out of 194 cases were ruled out or indefinite to be diagnosed as NSCLC by immunohistochemistry. By direct sequencing, the mutation rate of EGFR was 27.8% (50/180) in NSCLC samples and 28.2% (50/177) in adenocarcinoma samples (high tumor content samples) . By ARMS, the mutation rate of EGFR was 45.6% (82/180) in NSCLC samples and 46.3% (82/177) in adenocarcinoma samples (high tumor content samples). The EGFR mutation rate in low tumor content samples was 38.7% (12/31) , there was no significant difference in EGFR mutation rates between the groups of low tumor cell content samples and high tumor cell content samples (P = 0.12). The concordance rate of EGFR mutation rates was 100% between scraping tumor cells from slides samples and from FFEP blocks in the 40 matched samples. Forty-eight out of 180 definitive NSCLC patients received Gefitinib therapy. The FPS was 12 months in the gefitinib-treated ARMS⁺ group and 2 months in the ARMS⁻ group (P < 0.001), and the OS was 19 months in the gefitinib-treated ARMS⁺ group and 7 months in the ARMS⁻ group (P = 0.003), but no significant differences were found in the efficacy (PFS and OS) of Gefitinib between Seq⁺ and Seq⁻ groups (P = 0.227, P = 0.510, respectively), and Seq⁺/ARMS⁺ and Seq⁻/ARMS⁺ groups (P = 0.354, P = 0.334, respectively).

CONCLUSIONSThe detection protocol for EGFR mutations in cytological specimens introduced in this study is tested to be reliable and feasible. Pathological evaluation and immunohistochemistry are important in the detection procedure of EGFR mutations in cytologic specimens. High sensitivity methods should be selected for detection of EGFR mutations in cytologic samples.

Adenocarcinoma ; metabolism ; Carcinoma, Non-Small-Cell Lung ; metabolism ; Humans ; Lung Neoplasms ; diagnosis ; epidemiology ; metabolism ; Mutation ; Mutation Rate ; Polymerase Chain Reaction ; Receptor, Epidermal Growth Factor ; genetics ; metabolism

The role of genetic polymorphisms of NAD(P)H:quinone oxidoreductase 1 (NQO1), which is known to be related to carcinogen metabolism and oxidative status, was evaluated for lung cancer development. The genotypes of two NQO1 polymorphisms, namely, IVS1-27C>G and Ex6+40C>T, were determined in 616 lung cancer cases and 616 lung cancer-free controls and haplotypes composed of the two polymorphisms were estimated. In the evaluation of the effect of the NQO1 genotypes or diplotypes, we did not find any significant association with lung cancer risk after adjusting for body mass index and smoking status. However, when we evaluated the effect of the NQO1 diplotypes for lung cancer risk in combination with smoking, smokers without the C-T/C-T diplotype showed a significantly increased risk of lung cancer compared with nonsmokers without the C-T/C-T diplotype (adjusted OR, 2.2; 95% CI, 1.67-3.02), and smokers with the C-T/C-T diplotype showed the highest OR of lung cancer (adjusted OR, 2.7; 95% CI, 1.78-4.21). Moreover, a trend test showed an additive interaction between smoking and the NQO1 C-T/C-T diplotype (P(trend) < 0.01). The additive effect of smoking and the NQO1 C-T/C-T diplotype was more apparent in squamous cell carcinoma, although this effect was statistically significant in all lung cancer cell types (all cell types, P(trend) < 0.05). This result suggests that haplotypes of the NQO1 gene play an important role in the development of lung cancer by interaction with smoking.
Aged ; Carcinoma, Non-Small-Cell Lung/epidemiology/*genetics ; Female ; Genetic Predisposition to Disease ; Haplotypes/genetics ; Humans ; Lung Neoplasms/epidemiology/*genetics ; Male ; Middle Aged ; NAD(P)H Dehydrogenase (Quinone)/*genetics ; Polymorphism, Single Nucleotide/genetics ; Risk ; Small Cell Lung Carcinoma/epidemiology/*genetics ; Smoking/*adverse effects

OBJECTIVETo determine the interaction between indoor air pollution and mEH gene polymorphisms.

METHODSBlood samples from 222 non small cell lung cancer patients and 222 healthy people were characterized by PCR and PCR-RFLP methods. The interaction coefficients were determined through unconditional logistic regression model.

RESULTSSignificant differences in the positive rate of mEH-exon3 mutant and the heterozygote were found between case and control groups (chi(2) = 7.046, P = 0.030). But no significant difference was found in mEH-exon4 non-wild-type between groups (chi(2) = 2.674, P = 0.263). mEH-exon3 mutant (OR = 1.99; 95% CI = 1.21, 3.25) could significantly increase the risk of lung cancer. After adjusted by confounding variables, significant interactions were found between the use of coal-wall stove and the non-wild type mEH gene. The interaction coefficients were increased with the duration of exposure and quantity of coal consumed. The super multiplication models were established between non-wild type mEH gene and the exposure to soot or oil fume during cooking. The interaction coefficients were 2.75 and 7.34 respectively for exon3 and exon4. No interaction was found between non-wild type mEH gene and irritation of eye or throat during cooking.

CONCLUSIONThrough the molecular epidemiological techniques, we confirmed indoor air pollution that caused by coal burning was a noticeable lung cancer risk factor. The interaction between the polymorphisms of mEH gene and the indoor air pollution plays an important role in the carcinogenesis of lung.

Adult ; Aged ; Air Pollution, Indoor ; Carcinoma, Non-Small-Cell Lung ; epidemiology ; genetics ; China ; epidemiology ; Epoxide Hydrolases ; genetics ; Exons ; Female ; Humans ; Lung Neoplasms ; epidemiology ; Male ; Middle Aged ; Polymorphism, Genetic ; Smoking

Due to the advanced diagnostic technique and better understanding for multiple primary lung cancers (MPLC), the increasing incidence of MPLC has been reported. Very often, MPLC are misdiagnosed as metastasis because of lacking efficient molecular biomarkers for prediction and diagnosis. Studies on the molecular mechanism for tumorgenesis and progression of MPLC may therefore facilitate the discovery of biomarkers for disease diagnosis and prognosis, so that an individual and rational treatment can be achieved. We tried to further our understanding and improve the diagnostic skill for MPLC by reviewing the current status and the latest advancement of molecular markers related to MPLC.
Adenocarcinoma ; pathology ; Biomarkers, Tumor ; analysis ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; radiotherapy ; Carcinoma, Small Cell ; pathology ; Carcinoma, Squamous Cell ; pathology ; Chromosome Deletion ; DNA Damage ; Genes, Tumor Suppressor ; Humans ; Incidence ; Lung Neoplasms ; diagnosis ; epidemiology ; etiology ; genetics ; Neoplasms, Multiple Primary ; diagnosis ; epidemiology ; etiology ; genetics ; Smoking ; adverse effects

Recently, rearranged during transfection (RET) fusions have been identified in approximately 1% of non-small cell lung cancer (NSCLC). To know the prevalence of RET fusion genes in Korean NSCLCs, we examined the RET fusion genes in 156 surgically resected NSCLCs using a reverse transcriptase polymerase chain reaction. Two KIF5B-RET fusions and one CCDC6-RET fusion were identified. All three patients were females and never smokers with adenocarcinomas. RET fusion genes were mutually exclusive from EGFR, KRAS mutations and EML4-ALK fusion. RET fusion genes occur 1.9% (3 of 156) of surgically treated NSCLC patients in Koreans.
Asian Continental Ancestry Group/*genetics ; Carcinoma, Non-Small-Cell Lung/epidemiology/*genetics/surgery ; Cytoskeletal Proteins/genetics ; Female ; Humans ; Kinesin/genetics ; Lung Neoplasms/epidemiology/*genetics/surgery ; Middle Aged ; Oncogene Proteins, Fusion/*genetics ; Proto-Oncogene Proteins c-ret/*genetics ; Republic of Korea/epidemiology ; Sequence Analysis, DNA

Lung cancer is the leading cause of cancer death worldwide, with large variation of the incidence and mortality across regions. Although the mortality of lung cancer has been decreasing, or steady in the US, it has been increasing in Asia for the past two decades. Smoking is the leading cause of lung cancer, and other risk factors such as indoor coal burning, cooking fumes, and infections may play important roles in the development of lung cancer among Asian never smoking women. The median age of diagnosis in Asian patients with lung cancer is generally younger than Caucasian patients, particularly among never-smokers. Asians and Caucasians may have different genetic susceptibilities to lung cancer, as evidenced from candidate polymorphisms and genome-wide association studies. Recent epidemiologic studies and clinical trials have shown consistently that Asian ethnicity is a favorable prognostic factor for overall survival in non-small cell lung cancer (NSCLC), independent of smoking status. Compared with Caucasian patients with NSCLC, East Asian patients have a much higher prevalence of epidermal growth factor receptor (EGFR) mutation (approximately 30% vs. 7%, predominantly among patients with adenocarcinoma and never-smokers), a lower prevalence of K-Ras mutation (less than 10% vs. 18%, predominantly among patients with adenocarcinoma and smokers), and higher proportion of patients who are responsive to EGFR tyrosine kinase inhibitors. The ethnic differences in epidemiology and clinical behaviors should be taken into account when conducting global clinical trials that include different ethnic populations.
Adenocarcinoma ; ethnology ; genetics ; metabolism ; Asian Continental Ancestry Group ; genetics ; Carcinoma, Non-Small-Cell Lung ; ethnology ; genetics ; metabolism ; European Continental Ancestry Group ; genetics ; Far East ; epidemiology ; Female ; Genetic Predisposition to Disease ; Humans ; Lung Neoplasms ; ethnology ; genetics ; metabolism ; Mutation ; Oncogene Proteins, Fusion ; metabolism ; Receptor, Epidermal Growth Factor ; genetics ; metabolism ; Risk Factors ; Smoking ; adverse effects ; United States ; epidemiology ; ras Proteins ; genetics ; metabolism