p53mutations in lung tumours: relationship to gender and lung DNA adduct levels

Abstract

Human lung cancer exhibits a high frequency of transversion mutations at G:C base pairs of the p53 gene, possibly the result of DNA damage by cigarette smoke constituents, most notably benzo[a]pyrene. We have investigated gender differences in the p53 mutational spectrum and levels of hydrophobic DNA adducts. Tumour tissue was obtained from 115 non-small cell lung cancer tumours and examined for mutational alterations in the p53 gene (exons 4-9) using PCR and single-strand conformational polymorphism analysis. We have previously examined exons 5-8 in lung cancer. Sequence analysis of exons 4 and 9 revealed that almost 20% of the mutations were located in exons 4 and 9. The levels of hydrophobic DNA adducts in non-tumorous lung tissue of 55 of the patients were analyzed by the 32P-postlabelling assay. There were both a higher frequency of G:C-->T:A mutations and a higher average hydrophobic DNA adduct level in females than in male patients, even though the level of exposure to carcinogens from cigarette smoking was lower among the females than among the males. Frameshift mutations were more common in women than in men (30 versus 15%). These preliminary findings lend support to epidemiological evidence that women may be at greater risk than men of contracting tobacco-induced lung cancer.

Loss of heterozygosity is related to p53 mutations and smoking in lung cancer

“…Different pattern of genetic changes have previously been reported for the 2 histological types (Sato et al, 1994). We have also found a significantly higher frequency of p53 mutations in squamous cell carcinomas than adenocarcinomas (Kure et al, 1996;Skaug et al, 2000). The development of different histological types of lung tumours has been suggested to reflect a dose effect of tobacco carcinogens.…”

“…However, this was not specific for these 2 loci since similar frequencies were found at other loci investigated. The p53 mutations were found in 86 (52%) of the 165 tumours analysed (Kure et al, 1996;Skaug et al, 2000). Using logistic regression and adjusting for other variables there was a significant association between the presence of p53 mutations and occurrence of LOH at 3p, 5q, 9p, 11p and 17p (Table 3).…”

“…The p53 mutation analysis was performed using a modified single-strand conformation polymorphism (SSCP) procedure and direct sequencing as described (Kure et al, 1996;Skaug et al, 2000).…”

Epidemiology of Lung Cancer

“…25-27 Studies suggest that women may be more predisposed than men to molecular aberrations resulting from the carcinogenic effects of tobacco smoke. 28 Women smokers are more likely than men to develop adenocarcinoma of the lung, and those women who have never smoked are more likely to develop lung cancer than men who have never smoked. This phenomenon suggests a role for estrogen signaling.…”

Impact of a Cognitive-Behavioral Weight Control Program on Body Weight, Diet Quality, and Smoking Cessation in Weight-Concerned Female Smokers

“…Cigarette smoking kills an estimated 178,000 women in the U.S. annually (CDC 2005 , 1997-2001). In addition to the many negative health consequences associated with smoking for individuals of both genders, women are at higher risk for cancers of the oral cavity, pharynx, larynx, esophagus, pancreas, kidney, bladder, and uterine cervix (USDHHS 2001, Women and Smoking: A Report of the Surgeon General; Kure, Ryberg, Hewer, 1996;Prescott et al, 1998;Zang & Wynder, 1996). Women who smoke double their risk for developing coronary heart disease and increase by more than tenfold their It is predicted that over the next 30 years tobacco-related deaths among women throughout the world will more than double and by the year 2020 over a million adult women can be expected to die every year from tobacco-related illnesses (USDHHS, 2001;Chollat-Traquet, 1992).…”