• Cancer is the second leading cause of death among women and men. 1
  • A study of more than 1 million cancer cases from 45 population-based cancer registries in 17 European countries demonstrated that young women were more likely than young men to survive cancer, while in older people, men were more likely to survive. Women with cancer of the head and neck, esophagus, stomach, liver, or pancreas were less likely to die from cancer than men with the same tumor type, whereas women with bladder cancer were more likely to die from the disease than men. 2
  • Although data are somewhat inconsistent, in general, cancer risk in men is more profoundly influenced by selenium status than in women. 3 A review of prospective human studies that evaluated the influence of selenium levels on cancer risk revealed that the most consistent sex difference within Western populations was a higher risk for stomach and pancreatic cancer in men with lower selenium levels. Sex-based differences in selenium’s metabolism, tissue distribution, dose response, and molecular role in tumor biology may be involved in any potential anti-carcinogenic effects of the mineral.
  • In a study of seven kindreds with germline p53 mutations (missense and truncation), an equal number of men and women were carriers of the mutation.4  However, women were more likely than men to develop all types of cancer, and the increased incidence was not due to female breast cancer. The onset of cancer occurred earlier in female carriers, not only for breast cancer, but also for brain and lung cancer.

Lung Cancer

Epidemiology

  • As the leading cause of cancer mortality in the United States, lung cancer will kill more than an estimated 160,000 people in 2004 (including more than 68,000 women), which is more than breast, colon, and prostate cancer combined. 5
  • Since 1987, more women have died each year of lung cancer than of breast cancer, which, for the prior 40 years, was the major cause of cancer death in women. In 2004, it is anticipated that 25% of all cancer deaths in women will be from lung cancer. 5
  • Among men, lung cancer incidence and mortality have been declining since the early 1980s and 1990s, respectively. 6  The peak death rate in men in the 1990s coincided with a lag period of approximately 25 years after the highest per capita cigarette consumption. 7 Because women began regular smoking approximately 20 years after men, lung cancer incidence rates did not begin to fall in women until 1998. Mortality rates in women have stabilized since 1995 for the first time, after increasing for several decades. 6
  • Mortality rates for many cancers vary by socioeconomic characteristics. For example, lung cancer deaths among women aged 65 years or older increased seven-fold to eight-fold between 1950 and 1998, with higher mortality in higher socioeconomic groups. 8

Susceptibility

Smoking causes approximately 80% of the lung cancer deaths in women in the United States. 9 Several studies have indicated that compared to men, women who smoke are more likely to develop lung cancer at a younger age and at lower levels of exposure to cigarette smoke. 10-14 Although a recent study has fueled controversy over the existence of sex differences in lung cancer risk by reporting equal risk between the sexes, 15 sex differences are present in the histological, molecular, and physiological aspects of the disease.

Histology

      • One study reported that women are more likely than men to develop small cell lung cancer, which spreads quickly and typically yields the worst outcome, and adenocarcinoma, which involves the cells lining internal organs. 14 Adenocarcinoma accounted for about 40% of the lung cancer cases diagnosed in women in another study. 16
      • Two studies indicated that women are at lower risk than men for squamous cell lung cancer, which begins on the surface of the lungs and is easiest to treat. 17, 18

Cellular and Molecular Pathways

      • Reduced DNA repair capacity (DRC) is associated with increased risk of lung cancer. Women smokers with lung cancer are more likely than men to have a deficiency in DRC for tobacco carcinogen-induced DNA damage. 19   In addition, women are more likely to have mutations in the p53 20 and K- ras genes. 21  In fact, p53 mutations are more common in women smokers compared to women who have never smoked; this effect was not seen in men. 20
      • Nonsmoking women are more likely than nonsmoking men to develop lung cancer. Therefore, environmental factors other than smoking may play a role in lung cancer development in nonsmoking women. When exposed to an environmental carcinogen, nonsmoking women are more susceptible to DNA damage than nonsmoking men. 22
      • The gastrin-releasing peptide receptor (GRPR) has been linked to proliferation of bronchial cells in the presence of gastrin-releasing peptide, as well as tobacco following long-term use. One study demonstrated that the expression levels of GRPR mRNA were higher in non-smoking women and in women with lower levels of tobacco exposure than men. The GRPR gene is located on the X chromosome and escapes X inactivation in women, which may partly explain the proposed increased susceptibility of women to tobacco-induced lung cancer. 23
      • Genetic variations of estrogen-metabolizing enzymes contribute to cancer susceptibility. For example, mutations in the cytochrome P450 1A1 (CYP1A1) gene have been linked to lung cancer risk in smokers, mediate gender differences in lung cancer susceptibility, and have been associated with an elevated risk for developing breast, prostate, colorectal, and oral squamous cell cancer. 24 Women have a greater lung cancer risk than men if they possess the mutant CYP1A1 genotype. 25 CYP1A1 metabolization and activation of the carcinogens found in tobacco smoke lead to the formation of DNA adducts and reduced DNA repair. CYP1A1 protein expression and DNA adducts are higher in the lungs of female lung cancer patients than in males. 26
      • Myeloperoxidase (MPO) also metabolizes the carcinogens in tobacco smoke. A polymorphism upstream of the transcriptional activation site of the MPO gene affects the level of expression of the enzyme.The variant allele leads to less enzyme expression, and thus, potential protection from cancer-causing metabolites. Studies have demonstrated that the variant allele is associated with reduced risk of lung cancer in men but not in women. 27, 28
      • Oxidative DNA damage and antibodies to that damage are implicated in lung, breast, and colorectal cancer. Antibodies to oxidative DNA are 50% higher in smoking women than smoking men and may contribute to the proposed increased risk of smoking-induced lung cancer in women compared to men. 29

Physiology

    • Estrogen may partly be responsible for women’s susceptibility to lung cancer by increasing the effects of carcinogens such as tobacco smoke, cooking fumes, and radon. 30 Women who have less exposure to estrogen throughout their lifetime, such as those who undergo early menopause, may have a lower risk of lung cancer, while women who take estrogen replacement therapy may have an elevated risk. 30
    • In vitro studies demonstrated that estrogen produces a proliferative response in non-small cell lung cancer (NSCLC) cells, which indicates that estrogen might drive the carcinogenic process in the lung. 31 In a study of 13 women and 13 men with lung cancer, estrogen receptor a (ER a) was expressed more frequently in tumor and nontumor lung tissue of women, whereas the frequency of expression of ER b was similar between the sexes. 32 Differential expression of ER isoforms may contribute to variations in lung cancer development and progression in women and men.

Prognosis

  • In general, women with lung cancer have a better prognosis than men. 14
  • Compared with men, women undergoing surgery for non-small cell lung cancer (NSCLC) are more likely to be asymptomatic, nonsmokers, or light smokers. 33 Women survive longer than men after surgery for early-stage NSCLC. 33, 34 In a lung cancer trial with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib, female sex and histological adenocarcinoma correlated with better radiographic response to the drug. 35
  • Tumors with the K- ras mutation are likely to grow more aggressively than tumors that lack this mutation. 21 This is especially alarming considering that mutations in the K- ras gene are found more often in the lung tumors of women than in men.

Colorectal Cancer (CRC)

Epidemiology

  • Colorectal cancer is the third most common type of cancer and the third leading cause of cancer deaths in the United States, after breast and lung cancer in women and prostate and lung cancer in men. 36 The American Cancer Society estimates that 146,940 new CRC cases and 56,730 CRC deaths will occur in women and men in 2004. In terms of lifetime risk, approximately one in 18 women and one in 17 men will develop CRC. 5
  • Colorectal cancer takes approximately equal numbers of men’s and women’s lives each year. 37 Mortality rates for CRC have declined for men since 1985 and for women since 1950. The decrease in CRC incidence and mortality rates are largely due to detection and removal of precancerous polyps, early detection of tumors through screening, and improved treatments. 6

Susceptibility

Physiology

  • Results of observational studies 38, 39 and the Women’s Health Initiative (WHI), 40, 41 which prospectively studied the benefits and risks of the combination of estrogen plus progestin (hormone replacement therapy; HRT) on the health of thousands of postmenopausal women, demonstrated that HRT was associated with a statistically significant decrease in the incidence of CRC.
  • Further analysis of the WHI data revealed that although HRT decreased the incidence of CRC, the CRCs that were diagnosed in these women were more advanced and had more lymph node involvement than those detected in placebo controls. 41 The authors cautioned that current data do not sufficiently support the use of HRT regimens for the prevention of CRC and emphasized the importance of CRC screening for women regardless of HRT status.
  • In a recent study of 699 women, the risk of death from CRC significantly decreased in women using HRT. In HRT users, a 67% reduction in risk of death from CRC was seen in tumors of the distal colon, whereas this association was not observed in proximal tumors. 42
  • Microsatellite instability (MIS) is characterized by mutations in tandem repeats in DNA and occurs in 10-15% of colon tumors. 43 In a study of over 1,800 men and women, overall, women were more likely to have colon tumors with MIS. The extent of MIS increased with age, corresponding to decreasing circulating levels of estrogen in women. HRT reduced the risk of MSI-positive tumors; however, the exact mechanism for this effect is not known. 44
  • A case-control study of over 1,600 patients demonstrated a relationship among HRT status, 5,10-methylenetetrahydrofolate reductase(MTHFR) genotypes, and CRC risk. Reduced risk was reported in those women who expressed two polymorphisms in the MTFHR gene and did not report using HRT. In addition, the wild type version of MTFHR was associated with reduced risk of CRC in women who reported current or recent use of HRT. 45

Smoking

  • Although studies have shown that smoking is related to an increase in colorectal adenomas (precursors to most CRC), the relationship between smoking and CRC is controversial. 46 However, the potential role smoking may play in CRC incidence and mortality is important, considering that 20% of women in the U.S. smoke. 36 Recent studies reporting a direct relationship between smoking and CRC demonstrated a higher relative risk of mortality in women compared to men 47 and a higher incidence rate in post-menopausal smokers versus nonsmokers. 48 The incidence of proximal, but not distal CRC was 33% higher in postmenopausal ever-smokers than in never-smokers.
  • Microsatellite instability was found more often in CRC of smokers of both sexes; however, unstable tumors, especially those in the proximal colon, were more likely to occur in women. 43

Overweight, Obesity, and Diet

  • In the scientific literature, the connection between excess body weight and risk of CRC has been stronger for men than for women. 49 Researchers speculate that high body mass index (BMI), 49, 50 high central obesity, 49 and hyperinsulinemia 51, 52 may play a role in the development of CRC. Studies evaluating the importance of insulin, insulin-like growth factors, and insulin binding proteins have begun to decipher the molecular connection between adiposity and CRC. 53-55
  • Reports on the relationship between glycemic load (the amount of carbohydrate in food) and CRC risk have been equivocal. However, a prospective study of over 38,000 women reported that high dietary glycemic load was statistically significantly associated with increased risk. 56 Another study evaluated the influence of carbohydrates and the American diet on CRC risk in Chinese women and men residing in North America (China has a low incidence of CRC). Increased nonfiber carbohydrate component and total carbohydrate consumption was associated with increased risk of CRC in both sexes. Among women, risk was greatest for the right colon, whereas among men, risk was greatest for the rectum. 57
  • High dietary levels of trans-fatty acids, which are hypothesized to be carcinogenic, may increase the risk of CRC in postmenopausal women not taking HRT more than in pre-menopausal women or post-menopausal women taking HRT. One study reported that estrogen-positive women did not experience an increased risk of colon cancer, regardless of level of trans-fatty acids consumed. 58
  • In a study evaluating the risk factors for colorectal adenomas, reduced risk was linked to increased physical activity in men, but not women. 59

Prevention, Screening, and Treatment

  • Although CRC risk is similar for men and women, men are screened for CRC more than women. From 1987 to 1998, the use of protoscopy, flexible sigmoidoscopy (FS), or colonoscopy for CRC screening increased 11.3%for men but only 4% for women. 7 According to a recent American Cancer Society survey, far more women expressed concern about their risk for breast cancer (54%) than for CRC (10%). 60 In addition to underestimating their risk for CRC, women tend to be fearful and embarrassed about screening procedures. 61
  • Results of a survey of over 52,000 men and women indicated that morbidly obese women were less likely to be screened for CRC than obese, overweight, and normal weight women, as well as men of all weight groups. 62 Screening in the morbidly obese is critical, considering the increased risk of CRC in this population.
  • In a study of nearly 4,000 patients, men were more likely than women to receive complete FS examinations. 63 Due to angulation of the colon and perception of pain in women, the depth of insertion of the sigmoidoscope and the procedure time were shorter. In addition, fewer adenomatous polyps or cancers were detected in women, which may have been a result of decreased effectiveness of the screening. An additional study reported increased effectiveness in women with the use of an upper endoscope, rather than a standard sigmoidoscope. 64
  • A meta-analysis of 12 treatment arms involving 1,093 women and 1,355 men who received fluorouracil (5-FU)-based chemotherapy for CRC reported more frequent and severe toxicity in women than men. 65 Although data are controversial, one potential mechanism for the increased toxicity in women could be lower tumor expression of dihydropyrimidine dehydrogenase, the initial rate-limiting enzyme in the breakdown of 5-FU. 65, 66

Bladder Cancer

Epidemiology

  • In 2004, 44,640 men and 15,600 women are expected to be diagnosed with bladder cancer. 5 Men are approximately four times as likely to develop the disease than women. 36 In both sexes, bladder cancer incidence rates have leveled off from 1987 to 2000 after rising 0.7% each year from 1975 to 1987. 36
  • The bladder cancer mortality rate decreased significantly between 1973 and 1996, but this reduction primarily occurred in men. 67 Although men are more likely to develop bladder cancer than women, women have a 30% to 50% greater chance of dying of the disease. 68 One explanation for the disparity in mortality is that women are diagnosed with more advanced disease than men, which may be due to delay in diagnosis, and cultural, biological, or anatomical factors.
  • A study of 397 bladder cancer patients in the United Kingdom revealed that women from more deprived areas had worse survival and were more likely to present with advanced disease compared to women of less deprived areas. 69 The differences in survival and stage did not vary by deprivation in men.
  • African Americans are less likely to be diagnosed with bladder cancer than Caucasians, but once diagnosed, they have poorer survival. 68 A study of 497 patients diagnosed with bladder cancer demonstrated that African-American women were more likely to have invasive bladder cancer than Caucasian women; this racial difference was not seen in men. 70

Susceptibility

Cellular and Molecular Pathways

A German study of 157 patients demonstrated that expression of certain genotypes of phase II detoxification enzymes may influence sex-specific incidence of bladder cancer. Particular genotypes of arylamine N-acetyltransferase 2 and glutathione S-transferase M1 were related to an increased risk of bladder cancer in men, whereas these genotypes protected women from the disease. 71

Smoking

  • According to the Surgeon General, smoking may account for 30-40% of bladder cancer cases. 72
  • In a study of over 1,500 patients, the risk of bladder cancer was higher in women than men who smoked comparable amounts of cigarettes. For the heaviest smokers (40 cigarettes a day for 40 years), women’s risk of bladder cancer was twice that of men’s. 73 Levels of 3- and 4-aminobiphenyl-hemoglobin adducts, which are a measure of aromatic amine exposure, were higher in smoking women than men.

Non-Hodgkin’s Lymphoma (NHL)

Epidemiology

  • In 2004, 28,850 men and 25,520 women are expected to be diagnosed with NHL, and 19,410 men and 10,390 women will die of the disease. 36
  • A study of over 60,000 NHL cases diagnosed from 1978 through 1995 revealed that NHL incidence was higher in men than women below age 60, but at older ages, no sex difference in incidence was detected. 74

Susceptibility

Smoking

In a case-control study of over 1,400 patients with NHL in Italy, the risk for follicular NHL was higher among women smokers than men smokers. 75 Similarly, smoking enhanced NHL incidence in female but not male smokers in a case-control study of 180 NHL patients in France. 76 Longer duration of smoking and earlier age of smoking initiation was associated with greater incidence in these women.

Kidney Cancer

Epidemiology

Kidney cancer will be diagnosed in approximately 22,000 men and 14,000 women, and almost 8,000 men and 5,000 women will die of the disease in 2004 in the United States. 5

Susceptibility

  Alcohol

The Iowa cancer registry compared approximately 400 patients with renal cell carcinoma (RCC) with controls from the general population and found that the risk of developing RCC was decreased in women but not men who consumed more than three servings of alcohol per week; 77 however, most epidemiological studies have not demonstrated this protective effect of alcohol. 78
Physiology

  • A Swedish case-control study of 1,465 female RCC patients found that ever-parous women had a 40% increased risk of the disease; the risk increased by 15% with each additional birth after the initial pregnancy. 79 Three case-control studies have identified the protective effects of oral contraceptives against RCC. 80
  • In an immunohistochemical analysis of RCC tumors from 182 patients,15% (24 male, 3 female) of tumors expressed the androgen receptor (AR),whereas only two tumors expressed the estrogen and progesterone receptors. 81 Expression of the AR was significantly associated with lower tumor grade and stage, as well as better prognosis. The authors noted that considering AR expression was not observed in late-stage tumors, its expression is an early and transient event in renal cell tumorigenesis; however, the data do not support hormone therapy for treatment of RCC.

Prognosis

In a retrospective study of 768 RCC patients in Japan, women diagnosed with clear cell carcinoma had a significantly better prognosis than men. More women were diagnosed with Stage 1 disease and fewer women were diagnosed with Stage 4 disease than men. Also, women had better survival after recurrence than men. 82

Other Types of Cancer

Epidemiology

  • In 2004, an estimated 18,550 men and 9,710 women will be diagnosed with cancer of the oral cavity and pharynx, and 7,230 men and 4,830 women will die of the disease in the United States. In a hospital-based study of 1,009 patients, increasing levels of tobacco exposure were related to oral cancer risk in both sexes, but the linear increase in risk was significantly higher for women than for men. 83 Among the nonsmokers over age 50, a significantly higher proportion of oral cancer cases were diagnosed in women than in men. The malignant transformation rate of oral leukoplakia was significantly higher in women in a follow-up, hospital-based study of 166 patients in the Netherlands. 84
  • Liver cancer is a common cause of cancer mortality throughout the world, but it is relatively rare among adults born in the United States. 85 Approximately 19,000 people will be diagnosed with and more than 14,000 will die of liver cancer in the United States in 2004. 5  From the 1930s to the 1960s, the death rate for liver cancer was higher in women; however, since the 1960s, the rate has been higher in men. 85 Currently, approximately twice as many men than women are diagnosed with and die from liver cancer. 5
  • In 2004, 4,330 men and 3,550 women are expected to be diagnosed with Hodgkin’s lymphoma in the United States. 5 The disease will kill 700 men and 620 women. One case-control study of over 300 patients with Hodgkin’s disease found higher risk for the disease in women who had recurrent miscarriage. 86 Also, in contrast to nulliparity, parity was associated with a decrease in disease development. However, nursing modified the protective effect of parity, such that higher parity was associated with greater risk in women who had never nursed.
  • In the United States, gallbladder and other biliary cancers are expected to afflict nearly 4,000 women and 3,000 men in 2004.Approximately 2,300 women and 1,300 men will die of the disease in the same year. 5 Gallbladder cancer incidence is higher in middle-aged to elderly women and varies by region in the United States and internationally. 87
  • One study from 26 population-based central cancer registries determined that among adolescents and young adults, females are more likely to be diagnosed with melanoma of the skin and thyroid cancer than males. 88
  • The risk of infant leukemia is higher in females than males, but the risk of childhood leukemia is higher in males than females. 88-90 The higher risk of infant leukemia in females might be due to a mutation in the mixed lineage leukemia gene. 89

Prognosis

  • One study of 61 patients with B-type chronic lymphocytic leukemia in Israel demonstrated that women had a better overall prognosis than men. The majority of men with this cancer expressed the product of the multi-drug resistance gene MDR1, and most women did not, which may help explain the sex difference in prognosis. 91
  • Several studies have indicated that girls with acute lymphoblastic leukemia (ALL) have significantly better long-term outcomes than boys after undergoing the same treatment. 92-96 Authors of a study in Germany of over 100 children with ALL suggested that the higher expression of the multi-drug resistance-associated protein 3 in males with T-cell ALL may account for the poorer prognosis in boys compared to girls. 97

References

1. Anderson, R.N., Deaths: Leading Causes for 2000. National Vital Statistics Reports . 2002, National Center for Health Statistics: Hyattsville, MD.

2. Micheli, A., et al., The prognostic role of gender in survival of adult cancer patients. EUROCARE Working Group. Eur J Cancer, 1998. 34 (14 Spec No): p. 2271-8.

3. Waters, D.J., et al., Making sense of sex and supplements: differences in the anticarcinogenic effects of selenium in men and women. Mutat Res, 2004. 551 (1-2): p. 91-107.

4. Hwang, S.J., et al., Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet, 2003. 72 (4): p. 975-83.

5. Jemal, A., et al., Cancer statistics, 2004. CA Cancer J Clin, 2004. 54 (2): p. 8-29.

6. Jemal, A., et al., Annual report to the nation on the status of cancer, 1975-2001, with a special feature regarding survival. Cancer, 2004. 101 (1): p. 3-27.

7. Cancer Prevention and Early Detection Facts and Figures . 2003: American Cancer Society. http://www.cancer.org/downloads/STT/CPED2003PWSecured.pdf

8. Singh, G.K., B.A. Miller, and B.F. Hankey, Changing area socioeconomic patterns in U.S. cancer mortality, 1950-1998: Part II-Lung and colorectal cancers. J Natl Cancer Inst, 2002. 94 (12): p. 916-25.

9. Thun, M., et al. Trends in tobacco smoking and mortality from cigarette use in Cancer Prevention Studies I (1959 through 1965) and II(1982 through 1988). in Changes in cigarette-related disease risks and their implications for prevention and control. Smoking and tobacco monograph No. 8. 1997, NIH Publication No. 97-4213. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute

10. Zang, E.A. and E.L. Wynder, Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst, 1996. 88 (3-4): p. 183-92.

11. Nordlund, L.A., J.M. Carstensen, and G. Pershagen, Are male and female smokers at equal risk of smoking-related cancer: evidence from a Swedish prospective study. Scand J Public Health, 1999. 27 (1): p. 56-62.

12. Dresler, C.M., et al., Gender differences in genetic susceptibility for lung cancer. Lung Cancer, 2000. 30 (3): p. 153-60.

13. Koyi, H., G. Hillerdal, and E. Branden, A prospective study of a total material of lung cancer from a county in Sweden 1997-1999:gender, symptoms, type, stage, and smoking habits. Lung Cancer, 2002. 36 (1): p. 9-14.

14. Radzikowska, E., P. Glaz, and K. Roszkowski, Lung cancer in women: age, smoking, histology, performance status, stage, initial treatment and survival. Population-based study of 20 561 cases. Ann Oncol, 2002. 13 (7): p. 1087-93.

15. Bain, C., et al., Lung cancer rates in men and women with comparable histories of smoking. J Natl Cancer Inst, 2004. 96 (11): p. 826-834.

16. Yang, P., et al., Adenocarcinoma of the lung is strongly associated with cigarette smoking: further evidence from a prospective study of women. Am J Epidemiol, 2002. 156 (12): p. 1114-22.

17. Baldini, E.H. and G.M. Strauss, Women and lung cancer: waiting to exhale. Chest, 1997. 112 (4 Suppl): p. 229S-234S.

18. Morgan, L.C., et al., Lung cancer in New South Wales: current trends and the influence of age and sex. Med J Aust, 2000. 172 (12): p. 578-82.

19. Wei, Q., et al., Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study. J Natl Cancer Inst, 2000. 92 (21): p. 1764-72.

20. Toyooka, S., T. Tsuda, and A.F. Gazdar, The TP53 gene, tobacco exposure, and lung cancer. Hum Mutat, 2003. 21 : p. 229-239.

21. Nelson, H.H., et al., Implications and prognostic value of K-ras mutation for early-stage lung cancer in women. J Natl Cancer Inst, 1999. 91 (23): p. 2032-8.

22. Cheng, Y.W., et al., Gender difference in DNA adduct levels among nonsmoking lung cancer patients. Environ Mol Mutagen, 2001. 37 (4): p. 304-10.

23. Shriver, S.P., et al., Sex-specific expression of gastrin-releasing peptide receptor: relationship to smoking history and risk of lung cancer. J Natl Cancer Inst, 2000. 92 (1): p. 24-33.

24. Huber, J.C., C. Schneeberger, and C.B. Tempfer, Genetic modelling of the estrogen receptor metabolism as a risk factor of hormone-dependent disorders. Maturitas, 2002. 42 (1): p. 1-12.

25. Alexandrie, A.K., et al., Genetic susceptibility to lung cancer with special emphasis on CYP1A1 and GSTM1: a study on host factors in relation to age at onset, gender and histological cancer types. Carcinogenesis, 1994. 15 (9): p. 1785-90.

26. Mollerup, S., et al., Sex differences in lung CYP1A1 expression and DNA adduct levels among lung cancer patients. Cancer Res, 1999. 59 (14): p. 3317-20.

27. Schabath, M.B., et al., Genetic variants of myeloperoxidase and lung cancer risk. Carcinogenesis, 2000. 21 (6): p. 1163-6.

28. Schabath, M.B., et al., A myeloperoxidase polymorphism associated with reduced risk of lung cancer. Lung Cancer, 2002. 37 (1): p. 35-40.

29. Mooney, L.A., et al., Gender differences in autoantibodies to oxidative DNA base damage in cigarette smokers. Cancer Epidemiol Biomarkers Prev, 2001. 10 (6): p. 641-8.

30. Siegfried, J.M., Women and lung cancer: does oestrogen play a role? Lancet Oncol, 2001. 2 (8): p. 506-13.

31. Stabile, L.P., et al., Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res, 2002. 62 (7): p. 2141-50.

32. Fasco, M.J., G.J. Hurteau, and S.D. Spivack, Gender-dependent expression of alpha and beta estrogen receptors in human nontumor and tumor lung tissue. Mol Cell Endocrinol, 2002. 188 (1-2): p. 125-40.

33. de Perrot, M., et al., Sex differences in presentation, management, and prognosis of patients with non-small cell lung carcinoma. J Thorac Cardiovasc Surg, 2000. 119 (1): p. 21-6.

34. Alexiou, C., et al., Do women live longer following lung resection for carcinoma? Eur J Cardiothorac Surg, 2002. 21 (2): p. 319-25.

35. Kris, M.G., et al., Efficacy of Gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer. Jama, 2003. 290 (16): p. 2149-2158.

36. Cancer Facts and Figures 2004 . 2004: American Cancer Society. http://www.cancer.org/downloads/STT/CAFF2004PWSecured.pdf

37. National Vital Statistics Report. National Center for Health Statistics, Centers for Disease Control and Prevention. U.S. Department of Health and Human Services: Hyattsville (MD), 2001. 49 (11): p. 18.

38. Jacobs, E.J., E. White, and N.S. Weiss, Exogenous hormones, reproductive history, and colon cancer (Seattle, Washington, USA). Cancer Causes Control, 1994. 5 (4): p. 359-66.

39. Newcomb, P.A. and B.E. Storer, Postmenopausal hormone use and risk of large-bowel cancer. J Natl Cancer Inst, 1995. 87 (14): p. 1067-71.

40. Rossouw, J.E., et al., Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. Jama, 2002. 288 (3): p. 321-33.

41. Chlebowski, R.T., et al., Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med, 2004. 350 (10): p. 991-1004.

42. Mandelson, M.T., et al., Hormone replacement therapy in relation to survival in women diagnosed with colon cancer. Cancer Causes Control, 2003. 14 (10): p. 979-84.

43. Slattery, M.L., et al., Associations between cigarette smoking, lifestyle factors, and microsatellite instability in colon tumors. J Natl Cancer Inst, 2000. 92 (22): p. 1831-6.

44. Slattery, M.L., et al., Estrogens reduce and withdrawal of estrogens increase risk of microsatellite instability-positive colon cancer. Cancer Res, 2001. 61 (1): p. 126-30.

45. Curtin, K., et al., MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev, 2004. 13 (2): p. 285-92.

46. Women and Smoking: A Report of the Surgeon General . 2001, Department of Health and Human Services.

47. Colangelo, L.A., et al., Cigarette smoking and colorectal carcinoma mortality in a cohort with long-term follow-up. Cancer, 2004. 100 (2): p. 288-93.

48. Limburg, P.J., et al., Cigarette smoking and colorectal cancer: long-term, subsite-specific risks in a cohort study of postmenopausal women. Clin Gastroenterol Hepatol, 2003. 1 (3): p. 202-10.

49. Moore, L.L., et al., BMI and waist circumference as predictors of lifetime colon cancer risk in Framingham Study adults. Int J Obes Relat Metab Disord, 2004. 28 (4): p. 559-67.

50. Lin, J., et al., Body mass index and risk of colorectal cancer in women (United States). Cancer Causes Control, 2004. 15 (6): p. 581-9.

51. Tager, I.B., L. Ngo, and J.P. Hanrahan, Maternal smoking during pregnancy. Effects on lung function during the first 18 months of life. Am J Respir Crit Care Med, 1995. 152 (3): p. 977-83.

52. Trevisan, M., et al., Markers of insulin resistance and colorectal cancer mortality. Cancer Epidemiol Biomarkers Prev, 2001. 10 (9): p. 937-41.

53. Kaaks, R., et al., Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst, 2000. 92 (19): p. 1592-600.

54. Hunt, K.J., et al., Insulin-like growth factor II and colorectal cancer risk in women. Cancer Epidemiol Biomarkers Prev, 2002. 11 (9): p. 901-5.

55. Cruz-Correa, M., et al., Loss of imprinting of insulin growth factor II gene: a potential heritable biomarker for colon neoplasia predisposition. Gastroenterology, 2004. 126 (4): p. 964-70.

56. Higginbotham, S., et al., Dietary glycemic load and risk of colorectal cancer in the Women’s Health Study. J Natl Cancer Inst, 2004. 96 (3): p. 229-33.

57. Borugian, M.J., et al., Carbohydrates and colorectal cancer risk among Chinese in North America. Cancer Epidemiol Biomarkers Prev, 2002. 11 (2): p. 187-93.

58. Slattery, M.L., et al., Trans-fatty acids and colon cancer. Nutr Cancer, 2001. 39 (2): p. 170-5.

59. Terry, M.B., et al., Risk factors for advanced colorectal adenomas: a pooled analysis. Cancer Epidemiol Biomarkers Prev, 2002. 11 (7): p. 622-9.

60. Rao, K.V. and S. Goodin, Prevention and management of colorectal cancer in women. J Am Pharm Assoc (Wash), 2001. 41 (4): p. 585-95.

61. Farraye, F.A., et al., Barriers to endoscopic colorectal cancer screening: are women different from men? Am J Gastroenterol, 2004. 99 (2): p. 341-9.

62. Rosen, A.B. and E.C. Schneider, Colorectal cancer screening disparities related to obesity and gender. J Gen Intern Med, 2004. 19 (4): p. 332-8.

63. Eloubeidi, M.A., et al., Female gender and other factors predictive of a limited screening flexible sigmoidoscopy examination for colorectal cancer. Am J Gastroenterol, 2003. 98 (7): p. 1634-9.

64. Farraye, F.A., et al., Screening flexible sigmoidoscopy using an upper endoscope is better tolerated by women. Am J Gastroenterol, 2004. 99 (6): p. 1074-80.

65. Sloan, J.A., et al., Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol, 2002. 20 (6): p. 1491-8.

66. Yamashita, K., et al., Gender differences in the dihydropyrimidine dehydrogenase expression of colorectal cancers. Cancer Lett, 2002. 188 (1-2): p. 231-6.

67. Reis, L.A., et al., SEER Cancer Statistics Review, 1973-1996 . 1999, National Cancer Institute: Bethesda, MD.

68. Madeb, R. and E.M. Messing, Gender, racial and age differences in bladder cancer incidence and mortality. Urol Oncol, 2004. 22 (2): p. 86-92.

69. Moran, A., et al., Bladder cancer: worse survival in women from deprived areas. Br J Cancer, 2004. 90 (11): p. 2142-4.

70. Prout, G.R., Jr., et al., Bladder cancer: race differences in extent of disease at diagnosis. Cancer, 2000. 89 (6): p. 1349-58.

71. Schnakenberg, E., et al., Gender-specific effects of NAT2 and GSTM1 in bladder cancer. Clin Genet, 2000. 57 (4): p. 270-7.

72. The Health Consequences of Smoking: A Report of the Surgeon General . 2004, Department of Health and Human Services.

73. Castelao, J.E., et al., Gender- and smoking-related bladder cancer risk. J Natl Cancer Inst, 2001. 93 (7): p. 538-45.

74. Groves, F.D., et al., Cancer surveillance series: non-Hodgkin’s lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Inst, 2000. 92 (15): p. 1240-51.

75. Stagnaro, E., et al., Smoking and hematolymphopoietic malignancies. Cancer Causes Control, 2001. 12 (4): p. 325-34.

76. Besson, H., et al., Smoking and non-Hodgkin’s lymphoma: a case-control study in the Rhone-Alpes region of France. Cancer Causes Control, 2003. 14 (4): p. 381-9.

77. Parker, A.S., et al., Gender, alcohol consumption, and renal cell carcinoma. Am J Epidemiol, 2002. 155 (5): p. 455-62.

78. Whang, Y.E. and P.A. Godley, Renal cell carcinoma. Curr Opin Oncol, 2003. 15 (3): p. 213-6.

79. Lambe, M., et al., Pregnancy and risk of renal cell cancer: a population-based study in Sweden. Br J Cancer, 2002. 86 (9): p. 1425-9.

80. Dhote, R., et al., Risk factors for adult renal cell carcinoma. Urol Clin North Am, 2004. 31 (2): p. 237-47.

81. Langner, C., et al., Steroid hormone receptor expression in renal cell carcinoma: an immunohistochemical analysis of 182 tumors. J Urol, 2004. 171 (2 Pt 1): p. 611-4.

82. Onishi, T., et al., Gender as a prognostic factor in patients with renal cell carcinoma. BJU Int, 2002. 90 (1): p. 32-6.

83. Muscat, J.E., et al., Gender differences in smoking and risk for oral cancer. Cancer Res, 1996. 56 (22): p. 5192-7.

84. Schepman, K.P., et al., Malignant transformation of oral leukoplakia: a follow-up study of a hospital-based population of 166 patients with oral leukoplakia from The Netherlands. Oral Oncol, 1998. 34 (4): p. 270-5.

85. Wingo, P.A., et al., Long-term trends in cancer mortality in the United States, 1930-1998. Cancer, 2003. 97 (12 Suppl): p. 3133-275.

86. Glaser, S.L., et al., Reproductive factors in Hodgkin’s disease in women. Am J Epidemiol, 2003. 158 (6): p. 553-63.

87. Malik, I.A., Gallbladder cancer: current status. Expert Opin Pharmacother, 2004. 5 (6): p. 1271-7.

88. Wu, X.C., et al., Cancer incidence in adolescents and young adults in the United States, 1992-1997. J Adolesc Health, 2003. 32 (6): p. 405-15.

89. Ross, J.A. and L.L. Robison, MLL rearrangements in infant leukemia: is there a higher frequency in females? Leuk Res, 1997. 21 (8): p. 793-5.

90. Biondi, A., et al., Biological and therapeutic aspects of infant leukemia. Blood, 2000. 96 (1): p. 24-33.

91. Steiner, H., et al., Differences in rhodamine-123 efflux in B-type chronic lymphocytic leukemia suggest possible gender and stage variations in drug- resistance gene activity. Ann Hematol, 1998. 76 (5): p. 189-94.

92. Pui, C.H., et al., Sex differences in prognosis for children with acute lymphoblastic leukemia. J Clin Oncol, 1999. 17 (3): p. 818-24.

93. Shuster, J.J., et al., Prognostic significance of sex in childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study. J Clin Oncol, 1998. 16 (8): p. 2854-63.

94. Imbach, P., et al., Boys but not girls with T-lineage acute lymphocytic leukemia (ALL) are different from children with B-progenitor ALL. Population-based data results of initial prognostic factors and long-term event-free survival. Swiss Pediatric Oncology Group. J Pediatr Hematol Oncol, 1995. 17 (4): p. 346-9.

95. Hord, M.H., et al., Ethnicity and cure rates of Texas children with acute lymphoid leukemia. Cancer, 1996. 77 (3): p. 563-9.

96. Klemetsdal, B., T. Flaegstad, and J. Aarbakke, Is there a gender difference in red blood cell thiopurine methyltransferase activity in healthy children? Med Pediatr Oncol, 1995. 25 (6): p. 445-9.

97. Steinbach, D., et al., The multidrug resistance-associated protein 3 (MRP3) is associated with a poor outcome in childhood ALL and may account for the worse prognosis in male patients and T-cell immunophenotype. Blood, 2003. 102 (13): p. 4493-8.