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Lung cancer mortality in Xuan Wei County (XWC) is among the highest in China. Lung cancer in XWC is associated with exposure, in poorly vented homes, to coal smoke containing high levels of polycyclic aromatic hydrocarbons (PAHs). We have previously investigated mutations in the p53 tumor suppressor gene and the K-ras oncogene in lung carcinomas and in sputum samples from individuals exposed to smoky coal emissions in XWC. This paper summarizes the results concerning p53 and K-ras mutations from these studies, in relation to mutations found in lung cancer patients not exposed to smoky coal emissions. [ABSTRACT FROM AUTHOR]

Abstract: Prenatal exposure to tobacco smoke has been associated with an increased risk of pediatric malignancies, yet the transplacental induction of genetic alterations by tobacco smoke carcinogens and their implication to childhood diseases remain poorly understood. We characterized mutations in the HPRT gene in umbilical cord blood T-lymphocytes of self-reported 103 never-smoking mothers and 104 smoking mothers (54 mothers smoked throughout and 50 mothers quit smoking during pregnancy). The results showed the illegitimate V(D)J recombinase-mediated deletion of HPRT exons 2–3 was the most prominent alteration occurring in 48.2% (26/54) of mutants from neonates of the smoking mothers who smoked during pregnancy, compared with 28.0% (14/50) from those of smoking mothers who quit smoking during pregnancy (p =0.035, Fisher''s exact test), 34.9% (36/103) from never-smoking mothers (p =0.08), or 32.7% (50/153) of those of neonates born from the latter two groups of mothers combined (p =0.043). There was no significant difference in the frequency of this deletion between neonates of the never-smoking mothers and the smoking mothers who quit smoking during pregnancy (34.9% versus 28.0%, respectively, p =0.39). The results show an increase in illegitimate V(D)J recombinase-mediated deletion of HPRT exons 2–3 in cord blood T-lymphocytes of newborns of mothers who smoked during pregnancy, compared with the group of mothers who did not smoke during pregnancy, implying an increase in illegitimate V(D)J recombinase-mediated alteration, a genetic recombination event associated with childhood malignancies, may be induced in utero during pregnancy by maternal exposure to tobacco smoke-derived genotoxicants. [Copyright &y& Elsevier]

Mutations in the p53 tumor suppressor gene are frequent in breast tumors but the implication of p53 mutations in breast cancer development remains poorly understood. In this study, we applied laser capture microdissection (LCM) microscope to histologically review and sample cells from paraffin-embedded breast tissue sections obtained from six cases of ductal carcinoma in situ (DCIS) and ten cases of atypical ductal hyperplasia (ADH). p53 mutations were detected, using single stranded conformational polymorphism (SSCP) and sequencing, in cell samples of three cases with DCIS and five cases with ADH. p53 mutations are therefore present in DCIS and ADH of the breast, considered as pre-malignant precursors to breast cancer, and some of them may represent early events in breast cancer development. [Copyright &y& Elsevier]

Lung cancer mortality rate in nonsmoking women in Xuan Wei (XW) County is the highest in China. The XW lung cancer rate is associated with exposure to coal smoke, containing high concentrations of polycyclic aromatic hydrocarbons (PAHs), in unvented homes. Here we investigated codon 12 K-ras mutations in lung tumors or sputum samples from 102 XW lung cancer patients (41 nonsmoking women and 61 smoking men). In addition, we analyzed specimens from 50 lung cancer patients (14 nonsmoking women, 33 smoking men and three nonsmoking men), from Beijing and Henan (B&H), where natural gas is the main domestic fuel. K-ras mutations were found in nine women (21.9%) and 14 men (22.9%) from XW, with G to T transversions accounting for 66.7 and 85.7%, respectively. Among B&H patients, one woman (7.1%) and six men (16.7%) had K-ras mutations, with G to T transversions accounting for 66.7% of the mutations in the men. Therefore, the frequency and type of K-ras mutations in XW nonsmoking women are similar to those of K-ras mutations found in both XW and B&H smoking men. On the other hand, the mutation frequency in XW women is higher than, although not statistically significant from, that in the B&H nonsmoking women (P=0.28, two-sided Fisher''s Exact Test). These results suggest an association between exposure to coal smoke and the increased K-ras mutation frequency in XW nonsmoking female lung cancer patients. They also suggest that the mutagens and/or mechanisms of mutations in these nonsmoking women are similar to those responsible for K-ras mutations in cigarette smoking lung cancer patients, which are probably induced largely by chemicals such as PAHs. [Copyright &y& Elsevier]

Aberrant methylation in gene promoter regions leads to transcriptional inactivation of cancer-related genes and plays an integral role in tumorigenesis. This alteration has been investigated in lung tumors primarily from smokers, whereas only a few studies involved never-smokers. Here, we applied methylation-specific polymerase chain reaction to compare the frequencies of the methylated promoter of p16 and O6-methylguanine-DNA methyltransferase (MGMT) genes in lung tumors from 122 patients with non--small cell lung cancer, including 81 smokers and 41 never-smokers. Overall, promoter methylation was detected in 52.5% (64 of 122) and 30.3% (37 of 122) of the p16 and MGMT genes, respectively. Furthermore, the frequency of promoter methylation was significantly higher among smokers, compared with never-smokers, for both the p16 [odds ratio (OR) = 3.28; 95% confidence interval (CI) = 1.28-8.39; P = .013] and MGMT (OR = 3.93; 95% CI = 1.27-12.21; P = .018) genes. The trend for a higher promoter methylation frequency of these genes was also observed among female smokers compared with female never-smokers. Our results suggest an association between tobacco smoking and an increased incidence of aberrant promoter methylation of the p16 and MGMT genes in non--small cell lung cancer. [ABSTRACT FROM AUTHOR]

Summary: Lung cancer rates in Xuan Wei County are among the highest in China and have been associated with exposure to indoor smoky coal emissions that contain high levels of polycyclic aromatic hydrocarbons (PAHs). The NBS1 gene product participates in DNA double-strand break repair and DNA damage-induced checkpoint activation, which are critical for maintaining genomic integrity. The p53 tumor suppressor gene is known to play key roles both in the maintenance of genomic stability in mammalian cells and in DNA damage surveillance. We examined the association between two common NBS1 polymorphisms (Leu34Leu, Gln185Glu) and lung cancer risk in a population-based case-control study in Xuan Wei, China. Individuals homozygous for the NBS1 34Leu or NBS1 185Glu variants were found to have an increased risk of lung cancer (odds ratio [OR] 2.15, 95% confidence interval [CI]: 0.91–5.10 and OR 2.53, 95% CI: 1.05–6.08, respectively). A haplotype containing the variant alleles from both NBS1 SNPs was associated with increased risk of lung cancer compared with the most common haplotype. Further, the associations were particularly pronounced among cases with over expression of p53 protein. These results suggest that NBS1 could be important in the pathogenesis of lung cancer in this population. However, additional studies in other populations with substantial environmental exposures to PAHs are needed to confirm our findings. [Copyright &y& Elsevier]

The p53 gene is frequently mutated in lung tumors, and mutations may be caused by both polycyclic aromatic hydrocarbons (PAHs) and nitrosamines found in tobacco smoke. The two major forms of lung cancer, adenocarcinoma (AC) and squamous cell carcinoma (SCC), are known to differ in the proportion of tumors exhibiting p53 mutation, and may also differ in the mutational spectra produced. Previous studies comparing p53 mutational spectra between AC and SCC of the lung have been limited by small sample size. We examined p53 mutations in exons 5–8 in 202 cases of AC and 82 cases of SCC from smoking lung cancer patients in the Western Pennsylvania region. The percent of cases with p53 mutation was significantly lower in ACs (40/202, 20%) compared to SCCs (29/82, 35%, P=0.006). The proportion of mutations present that were G to T transversions was not significantly different between the two tumor types (52% of p53 mutations in AC compared to 32% in SCC). G to A transitions either did not differ in frequency in the two types of lung cancer (20% of mutations in AC and 24% of mutations in SCC). A distinct spectrum was observed, however, in the p53 mutation pattern in the two types of lung cancer. ACs showed a strong preference for a mutational hotspot at codons 248 and 249, while squamous cell tumors showed mutational events spread throughout exons 5–8, with a preference for codon 267. Mutations at codon 267 in SCC were all C to T transitions that occurred at CpG sites. Both tumor types demonstrated preferential mutation of the non-transcribed strand (100% of all G to T transversions and 55% of the G to A transitions). These results suggest that p53 mutations in both types of lung tumors may arise from adduction by both PAHs and nitrosamines. Mutations arising in ACs appear selectively in regions of p53 that produce more rigid proteins, suggesting a drastic change in p53 function is needed to result in ACs, while less constrained changes in p53 function can result in SCCs. Mutation in p53 was not found to be related to patient survival in this group of patients, while tumor size and degree of differentiation were poor survival predictors. [Copyright &y& Elsevier]