Gender, p53, and Lung Cancer
Gender, p53, and Lung Cancer
By Jennifer E. Tseng, MD, and Li Mao, MD
Lung cancer is the leading cause of cancer death in both men and women, with an estimated incidence of 164,100 new cases of lung cancer in the United States in 2000, and an estimated 156,900 deaths.1 The rate of rise in the incidence of lung cancer in women has increased rapidly; in the 30-year period ending in 1985, there was a 396% increase in the incidence of lung cancer in women compared to a 161% increase in men.2 In recent years, lung cancer mortality in men has decreased at the rate of -1.6% per year between 1990 and 1996, while the mortality rate of lung cancer in women has only recently begun to plateau.1 Previous authors have reported that women with lung cancer were more likely to be diagnosed at an early age than men with lung cancer, more likely to be lifetime non-smokers, and, in patients who have a positive tobacco history, to smoke fewer cigarettes per day than males with lung cancer.2,3
Background
Thompson et al, in a recent analysis of 1044 patients with lung cancer, reported that a significantly higher proportion of females with lung cancer had small cell histology compared with men.4 This gender difference was more striking in younger patients; 34% of females younger than 65 years with lung cancer had small cell lung cancer (SCLC) compared to 18% of men.4 Furthermore, Ferguson et al found that women with SCLC were significantly younger than men with SCLC at the time of diagnosis, with a mean age of 57.4 years for women compared with 60.2 years for men.4 Zang et al demonstrated a higher risk of lung cancer in females when controlled for cumulative tobacco exposure.5 Potential biological mechanisms for this gender difference include differences in nicotine metabolism, gender differences in cytochrome p450 enzymes, and hormonal influences on tumor development.5,6 Bennett et al recently investigated mechanisms of genetic susceptibility in a population of women who had never smoked and found that women with exposure to environmental smoke who developed lung cancer were more likely to be deficient in glutathione S-transferase M1 due to a germline polymorphism in the GSTM1 gene.7
Intriguingly, women with SCLC have an improved survival rate compared to men with SCLC in multiple studies.2,8-10 Similarly, O’Connell et al found that females with non-small cell lung cancer (NSCLC) had a significantly improved survival compared with men, with median survivals of 12.4 months vs. 8.8 months, respectively.11 The biological reasons for these differences between males and females with lung cancer are unclear. It is possible that gender differences in susceptibility to genetic mutations are at least partially responsible for these biological differences.
Mutation in the p53 tumor suppressor gene is one of the most frequently found genetic abnormalities in human cancers. The p53 gene has been found to be mutated in a significantly higher proportion of SCLC patients compared to NSCLC (70% vs 47%, respectively).12-17 However, this conclusion was mainly based on data derived from cell lines or biased gender populations, and included small sample sizes. Previous authors have reported a trend toward a higher frequency of p53 mutations in males with NSCLC compared to females.18 In a meta analysis of 1674 patients with NSCLC for whom gender data was available, p53 alterations (protein expression and/or mutation) were more frequent in males compared to females (48.3% and 32.1%, respectively).19 However, previous studies have not detected a significant gender difference in p53 mutational frequency in SCLC, as few studies have included significant numbers of female patients with SCLC.
Primary SCLC Tumors Analyzed for p53 Mutation Status
Recently, we reported a study in which primary SCLC tumors from 65 patients (38 males and 27 females) were analyzed for p53 mutation status in order to reveal a potential gender difference.20 The mean age of this study population was 58.9 years. There was no significant difference between males and females in this series in mean age, race, or response to chemotherapy. There were non-significant trends toward greater tobacco exposure in males compared to females (72 pack-years vs 59 pack-years, respectively), heavier alcohol consumption in males compared to females, and better performance status at diagnosis in females compared to males. The only clinical variable in this series that was significantly associated with gender was stage of disease, with a higher proportion of females presenting with limited stage disease at the time of diagnosis. There was no significant association between p53 mutational status and survival, age, race, cumulative tobacco exposure, and response to chemotherapy. There was a non-significant trend toward a higher frequency of p53 mutations in patients with extensive disease stage, heavy alcohol consumption, and worse performance status. There was no significant association between overall survival and p53 mutational status. After adjusting for disease stage, there was also no significant association between gender and frequency of p53 mutation.
Thirty-seven (57%) of the 65 tumors were found to have one or more mutations, with a total of 42 mutations.20 There was a trend toward a higher frequency of p53 mutations in tumors from males; among tumors from females, 46% contained p53 mutations, compared to 65% of 37 tumors from males. Furthermore, tumors from four (17%) of the 24 males had more than one mutation in the p53 gene, compared to none of the tumors from females. Mutations were demonstrated throughout all exons analyzed; the majority of mutations (81%) were within exons 5 to 7. Thirty-one of 42 mutations (74%) were missense mutations resulting in the substitution of one amino acid for another. The remaining mutation types were as follows: 10% were small deletions or insertions causing frameshifts in coding for the p53 protein, 5% were silent mutations, 5% were located at intron/exon boundaries, and 5% were nonsense mutations resulting in the substitution of a termination codon.
Presenting Nucleotide Substitutions
The most frequent type of nucleotide substitution in both males and females was the A:T®G:C transversion, comprising 29% of all tumors, 23% of primary tumors in females, and 35% of tumors in males.20 The second most frequent nucleotide substitution overall was the G:C®T:A transversion, comprising 17% of all tumors and 21% of tumors in males but only 8% of tumors in females. In females, G:C®A:T transitions and A:T® T:A transversions were both more frequent than G:C®T:A transversions, each comprising 15% of the total. Other types of nucleotide substitutions were present in less than 10% of tumors. These differences in the patterns of nucleotide substitutions in males and females were not statistically significant.
The spectrum of nucleotide substitutions in SCLC primary tumors has been demonstrated to be more diverse than that in NSCLC primary tumors.16 In our study, A:T®G:C transitions were the most common mutation (29% of all mutations), followed by G:C®T:A transversions (17%) and G:C®A:T transitions (12%). Previous studies have demonstrated an association between patterns of nucleotide substitutions and specific mutagens involved.21-24 G:C®T:A transversions are associated with benzo[a]pyrene,21,23,24 while A:T®G:C transitions may be induced by N-ethyl-N-nitrosourea.22 In a review of p53 mutations of 92 SCLC cell lines and primary tumors, Greenblatt et al found that G:C®T:A transversions comprised 46% of the mutations while A:T to G:C transitions occurred in only 9%.16 Intriguingly, a high rate of A:T to G:C transitions in SCLC has previously been demonstrated only in a Japanese population.12 Our study was the first to demonstrate that A:T to G:C transitions in the p53 gene occur frequently in an American population with SCLC. It may be that the patients included in our study have been exposed to or are susceptible to carcinogens such as N-ethyl-N-nitrosourea, which are similar to those of Japanese patients included in the study by Takahashi et al.12
Summary
To our knowledge, this is the largest study to date analyzing p53 mutations in SCLC primary tumors which has included a significant number of female patients with SCLC. We have demonstrated a trend toward lower frequency of p53 mutations in primary SCLC tumors of females compared to males, suggesting that males with SCLC may be more susceptible to certain carcinogens in tobacco smoke that preferentially induce mutations in p53. This difference is quite intriguing, as it may partially explain biological differences in tumors of males and females with SCLC. Among patients with limited disease, females have a significantly higher rate of complete response than males.10 Given the increased risk for the development of SCLC in females, the improved survival of females with SCLC is somewhat surprising. The lower frequency of p53 mutations in SCLC tumors from females may be one possible mechanism for this improved survival. Although our study did not demonstrate a significant association between p53 mutation status and survival, this may be due to the small sample size of patients studied. It would be important to evaluate p53 mutational frequency in larger populations of patients with small cell lung cancer in order to determine whether this trend toward lower frequency of p53 mutations in females is confirmed in larger series. (Dr. Tseng is a Fellow, Medical Oncology, and Dr. Mao is an Associate Professor of Medical Oncology at M.D. Anderson Cancer Center, Houston, TX.)
References
1. Greenlee RT, Bolden S, Wingo PA. Cancer Statistics, 2000. CA Cancer J Clin 2000;50:7-33.
2. Ferguson MK, Skosey C, Hoffman PC. Sex-associated differences in presentation and survival in patients with lung cancer. J Clin Oncol 1990;8:1402-1407.
3. McDuffie HH, Klaassen DJ, Dosman JA. Female-male differences in patients with primary lung cancer. Cancer 1987;59:1825-1830.
4. Thompson S. Changing patterns of lung cancer histology with age and gender. Thorax 1998;53:10.
5. Zang EA, Wynder EL. Differences in lung cancer risk between men and women: Examination of the evidence. J Natl Cancer Inst 1996;88:183-192.
6. Bepler G. Lung cancer epidemiology and genetics. J Thorac Imaging 1999;14:228-234.
7. Bennett WP, Alavanja MC, Blomeke B, et al. Environmental tobacco smoke, genetic susceptibility, and risk of lung cancer in never-smoking women. J Natl Cancer Inst 1999;91:2009-2014.
8. Johnson BE, Steinberg SM, Phelps R, et al. Female patients with small cell lung cancer live longer than male patients. Am J Med 1988;85:194-196.
9. Osterlind K, Andersen PK. Prognostic factors in small cell lung cancer: Multivariate model based on 778 patients treated with chemotherapy with or without irradiation. Cancer Res 1986;46:4189-4194.
10. Spiegelman D, Maurer LH, Ware JH, et al. Prognostic factors in small-cell carcinoma of the lung: An analysis of 1,521 patients. J Clin Oncol 1989;7:344-354.
11. O’Connell JP, Kris MG, Gralla RJ, et al. Frequency and prognostic importance of pretreatment clinical characteristics in patients with advanced non-small-cell lung cancer treated with combination chemotherapy. J Clin Oncol 1986;4:1604-1614.
12. Takahashi T, Suzuki H, Hida T, et al. The p53 gene is very frequently mutated in small-cell lung cancer with a distinct nucleotide substitution pattern. Oncogene 1991;6:1775-1778.
13. Sameshima Y, Matsuno Y, Hirohashi S, et al. Alterations of the p53 gene are common and critical events for the maintenance of malignant phenotypes in small-cell lung carcinoma. Oncogene 1992;7:451-457.
14. Reichel MB, Ohgaki H, Petersen I, et al. p53 mutations in primary human lung tumors and their metastases. Mol Carcinog 1994;9:105-109.
15. Mitsudomi T, Oyama T, Kusano T, et al. Mutations of the p53 gene as a predictor of poor prognosis in patients with non-small-cell lung cancer. J Natl Cancer Inst 1993;85:2018-2023.
16. Greenblatt MS, Bennett WP, Hollstein M, et al. Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis. Cancer Res 1994;54:4855-4878.
17. D’Amico D, Carbone D, Mitsudomi T, et al. High frequency of somatically acquired p53 mutations in small-cell lung cancer cell lines and tumors. Oncogene 1992;7:339-346.
18. Kure EH, Ryberg D, Hewer A, et al. p53 mutations in lung tumors: Relationship to gender and lung DNA adduct levels. Carcinogenesis 1996;17:2201-2205.
19. Tammemagi MC, McLaughlin JR, Bull SB. Meta-analyses of p53 tumor suppressor gene alterations and clinicopathological features in resected lung cancers. Cancer Epidemiol Biomarkers Prev 1999;8:625-634.
20. Tseng JE, Rodriguez M, Ro J, et al. Gender differences in p53 mutational status in small cell lung cancer. Cancer Res 1999;59:5666-5670.
21. Denissenko MF, Pao A, Tang M, et al. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in p53. Science 1996;274:430-432.
22. Eckert KA, Ingle CA, Drinkwater NR. N-ethyl-N-nitrosourea induces A:T to C:G transversion mutations as well as transition mutations in SOS-induced Escherichia coli. Carcinogenesis 1989;10:2261-2267.
23. Eisenstadt E, Warren AJ, Porter J, et al. Carcinogenic epoxides of benzo[a]pyrene and cyclopenta[cd]pyrene induce base substitutions via specific transversions. Proc Natl Acad Sci U S A 1982;79:1945-1949.
24. Ruggeri B, DiRado M, Zhang SY, et al. Benzo[a]- pyrene-induced murine skin tumors exhibit frequent and characteristic G to T mutations in the p53 gene. Proc Natl Acad Sci U S A 1993;90:1013-1017.
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.