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In 1893, the Proceedings of the Royal Society of London reported that in addition to seeing an increase in the annual number of deaths ascribed to cancer, it appeared that men were the more commonly afflicted of the two sexes. Since then, it has been well established that cancer as a whole demonstrates significant sex and gender bias in incidence, prognosis, and even response to treatment. Men have a disproportionately higher incidence of many types of cancers, and are more likely to have a worse prognosis after diagnosis compared to women. In the past, socially-based gender differences such as higher rates of smoking, alcohol consumption, and occupational exposure to carcinogens were proposed as the reasons for this dichotomy; however, it is becoming clear that there are sex-specific biological risk factors as well, which remain mostly unknown. In a time where the practice of tailoring treatment and prevention to the individual, or precision medicine, is being touted as the next great medical revolution, it is imperative that scientists and physicians push to understand these sex differences in order to improve cancer therapies.

Excluding sex-specific cancers, such as ovarian or prostate cancer, it is a universal phenomenon that men are disproportionately affected by cancer. Across all surveyed geographical regions, men consistently had higher incidence rates in 32 of 35 cancer sites, with exceptions being the thyroid, gallbladder and anus. Studies in the USA, Europe, and South Korea also show that the risk of malignancy is higher for males in the majority of cancer cases, with a 2-fold greater risk of subsequent mortality than in females. Gender-dependent risk factors play a clear role for some of these cancers, but do not offer a complete explanation for the sex bias seen in many cancer sites. For example, in terms of absolute numbers, more men than women develop and die of lung cancer, which has been attributed to the higher prevalence of smoking in males than in females. However, recent studies have indicated that females may actually be more susceptible to the harmful effects of tobacco smoke, and may potentially have a higher risk of developing lung cancer due to genetic, biological, and sex hormone effects. Furthermore, there are sex differences in the incidence of childhood cancers, particularly with hematological malignancies, where sex-specific biases have been universally observed. In these cases, the sex difference cannot be explained by behavioural differences between the genders alone. Instead, biological mechanisms such as differences in hormonal regulation, gene expression, and oxidative stress have been proposed as factors contributing to the observed male bias.

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Sex hormones and their effects on various biological processes are thought to be the foremost actors in this sex disparity, as evidenced by data from humans as well as animal models. Both androgens and estrogens are proposed to modulate hepatocellular carcinoma (HCC) during its initiation, progression, and metastasis. HCC is the most common type of liver cancer and the third leading cause of cancer mortality worldwide, and demonstrates a 2- to 4-times higher incidence in males. This bias is not explained by cirrhosis risk factors such as viral hepatitis or alcohol abuse, and animal models also show a male bias, indicating a sex difference at the molecular level. Female sex hormones have been proposed to have a protective effect, as evidenced by the increased incidence of HCC in postmenopausal women who do not take hormone replacement therapy (HRT) as compared to those who do take HRT. Both estrogen and prolactin, an estrogen-responsive pituitary hormone, may in fact dampen the inflammatory milieu in the liver, which contributes to the promotion of tumors. Androgens, however, seem to have a dual role, as they have been shown to promote tumour growth contributing to HCC development in a dose-dependent manner, but can also suppress HCC metastasis. While these results suggest hormone therapy as an attractive clinical therapy, clinical trials using various anti-androgens to treat HCC have shown poor results, indicating that the role of sex hormones in HCC needs to be more fully understood for the success of hormone-targeting trials. Importantly, there may be hormone-independent factors contributing to HCC as well, which could involve sex-specific differences in hepatocyte signalling pathways and metabolism.

Differences in oxidative stress have also been suggested as a factor contributing to the increased incidence and morbidity of cancer in males. In the case of skin cancers, including squamous cell carcinoma and melanoma, males are more prone to develop the disease than age-matched females, and worldwide data shows higher melanoma mortality in men. Several publications suggest that sex differences in the ability to neutralize oxidative stress caused by reactive oxygen species (ROS) may play a significant role in this bias. Moderate ROS levels produced as a result of oxidative stress have been shown to contribute to tumour development by activating stress-induced signalling pathways involved in cell survival, proliferation and migration. Oxidative stress in epidermal melanocytes, caused by exposure to UV radiation, is thus thought to drive melanoma through DNA damage and disruption of homeostasis, inducing malignancy. Here as well, sex hormones may have an effect on melanoma through the modulation of oxidative processes. Estrogen appears to have direct antioxidant and protective effects, whereas androgens diminish the number of antioxidants and enzymes, creating an elevated ROS cellular environment that may promote metastasis. However, new evidence shows that oxidative stress could also inhibit the metastasis of melanoma to other sites, demonstrating the complexity of these processes in relation to the various states of cancer initiation and progression.

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Another proposed mechanism behind sex-specific cancer susceptibility is the difference in regulation of gene expression between males and females. Sex dimorphism at the gene, protein, and metabolite levels has been demonstrated in both animals and humans, and many sex-specific genetic associations with cancer susceptibility have been identified. Several such associations have been found for childhood acute lymphoblastic leukemia (ALL), which is both more common and more likely to result in relapse and secondary malignancies in males. One such male-specific risk association is an intronic single nucleotide polymorphism (SNP) in the interferon regulatory 4 (IRF4) gene, the overexpression of which has been implicated in certain types of lymphoid and myeloid malignancies. In vitro functional studies showed that the wildtype allele of this SNP inhibited transcription of IRF4, but the risk allele was associated with increased transcription. One hypothesis for the male-specificity of this risk allele, which remains to be examined, is that estrogen suppresses the effects of the Rel/NF-kb transcription factor family that interacts with IRF4, leading to stronger IRF4 overexpression in males. However, during childhood, sex hormone levels are very low and not very different between sexes, suggesting that there is prenatal programming of autosomal gene expression that is modulated by sex hormones. Other examples of male-specific risk factors for childhood ALL include SNPs in HLA-DRA, HLA-C, and IFNg genes, which are also associated with multiple sclerosis risk. Understanding the mechanisms behind these sex-specific risk associations may help elucidate the pathogenesis of ALL and better direct therapeutic development.

Taken together, it is apparent that sex-specific differences, which alter cancer incidence and prognosis, need to be investigated before we can leverage these differences to match therapies to individual cancer patients. One study aiming to provide a “starting point” for the consideration of sex-specific treatment strategies provided a comprehensive characterization of sex differences in the molecular signatures of 13 major cancer types. Using data collected from 3,200 patients by The Cancer Genome Atlas, the study found that two groups of cancers could be identified: one that showed a greater number of sex-biased molecular signatures, and another with a smaller number of sex-biased genes. After controlling for potential confounders whenever possible, including age, smoking status, and tumour characteristics, sex differences in expression were found in over 50% of genes identified as clinical therapeutic targets for precision medicine. Beyond any treatment implications, this study underscores the importance of understanding the mechanisms impacting the sex bias in cancers, as they may direct the success of treatment.

As scientists push to realize the potential of precision cancer medicine, it is imperative that they do not ignore the sex-based biological differences in cancer in preclinical and clinical investigations. The importance of including sex as a biological variable in the design of preclinical trials has been recognized, as has the importance of well-balanced clinical trials. Furthering the understanding of the mechanisms driving the sex bias in cancers could ultimately guide sex-specific therapeutic approaches and improve cancer treatment and outcomes for men and women alike.


References:

  1. Arnold AP and Lusis AJ. Understanding the sexome: measuring and reporting sex differences in gene systems. Endocrinology 2012; 153(6): 2551-2555.
  2. Cook MB et al. Sex disparities in cancer mortality and survival. Cancer Epidemiol Biomarkers Prev 2011; 20(8): 1629-1637.
  3. Denat L et al. Melanocytes as instigators and victims of oxidative stress. J Invest Dermatol 2014; 134(6): 1512-1518.
  4. Do TN et al. An intronic polymorphism of IRF4 gene influences gene transcription in vitro and shows a risk association with childhood acute lymphoblastic leukemia in males. Biochim Biophys Acta 2010; 1802(2): 292-300.
  5. Dorak MT and Karpuzoglu E. Gender differences in cancer susceptibility: an inadequately addressed issue. Front Genet 2012; 3: 268.
  6. Edgren G et al. Enigmatic sex disparities in cancer incidence. Eur J Epidemiol 2012; 27(3): 187-196.
  7. Forbes A et al. Response to cyproterone acetate treatment in primary hepatocellular carcinoma is related to fall in free 5 alpha-dihydrotestosterone. Eur J Cancer Clin Oncol 1987; 23(11): 1659-1664.
  8. Groupe d’étude et de traitement du carcinome hépatocellulaire. Randomized trial of leuprorelin and flutamide in male patients with hepatocellular carcinoma treated with tamoxifen. Hepatology 2004; 40(6): 1361-1369.
  9. Hartwell HJ et al. Prolactin prevents hepatocellular carcinoma by restricting innate immune activation of c-Myc in mice. Proc Natl Acad Sci USA 2014; 111(31): 11455-11460.
  10. Ma WL et al. Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis. Hepatology 2012; 56(1): 176-185.
  11. Mittelstrass K et al. Discovery of sexual dimorphisms in metabolic and genetic biomarkers. PLoS Genet 2011; 7(8): e1002215.
  12. Morrison BA et al. Multiple sclerosis risk markers in HLA-DRA, HLA-C, and IFNG genes are associated with sex-specific childhood leukemia risk. Autoimmunity 2010; 43(8): 690-697.
  13. Nosrati A and Wei ML. Sex disparities in melanoma outcomes: the role of biology. Arch Biochem Biophys 2014; 563: 42-50.
  14. Piskounova E et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 2015; 527(7577): 186-191.
  15. Yu MW et al. Role of reproductive factors in hepatocellular carcinoma: Impact on hepatitis B- and C-related risk. Hepatology 2003; 38(6): 1393-1400.
  16. Yuan Y et al. Comprehensive Characterization of Molecular Differences in Cancer between Male and Female Patients. Cancer Cell 2016; 29(5): 711-722.

 

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