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Nov 28, 2012 - sion (Ostrer, 2001; Rinn et al., 2004; Mank et al., 2010; Arnold and Lusis .... ratios across different strata (Paul and Donner, 1989). Recently, a.
REVIEW ARTICLE published: 28 November 2012 doi: 10.3389/fgene.2012.00268

Gender differences in cancer susceptibility: an inadequately addressed issue M. Tevfik Dorak 1 * and Ebru Karpuzoglu 2 1 2

Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, USA College of Veterinary Medicine, University of Georgia, Athens, GA, USA

Edited by: M. J. Mosher, Western Washington University, USA Reviewed by: Yiran Guo, Children’s Hospital of Philadelphia, USA Satyanarayana M. R. Rao, Jawaharlal Nehru Center for Advanced Scientific Research, India *Correspondence: M. Tevfik Dorak , Department of Environmental and Occupational Health, Robert Stempel College of Public Health and Social Work, Florida International University, 11200 SW 12th Street, AHC2 No. 584, Miami, FL 33199, USA. e-mail: [email protected]

The gender difference in cancer susceptibility is one of the most consistent findings in cancer epidemiology. Hematologic malignancies are generally more common in males and this can be generalized to most other cancers. Similar gender differences in non-malignant diseases including autoimmunity, are attributed to hormonal or behavioral differences. Even in early childhood, however, where these differences would not apply, there are differences in cancer incidence between males and females. In childhood, few cancers are more common in females, but overall, males have higher susceptibility. In Hodgkin lymphoma, the gender ratio reverses toward adolescence. The pattern that autoimmune disorders are more common in females, but cancer and infections in males suggests that the known differences in immunity may be responsible for this dichotomy. Besides immune surveillance, genome surveillance mechanisms also differ in efficiency between males and females. Other obvious differences include hormonal ones and the number of X chromosomes. Some of the differences may even originate from exposures during prenatal development. This review will summarize well-documented examples of gender effect in cancer susceptibility, discuss methodological issues in exploration of gender differences, and present documented or speculated mechanisms. The gender differential in susceptibility can give important clues for the etiology of cancers and should be examined in all genetic and non-genetic association studies. Keywords: genetic predisposition to disease, sex factors, genetic epidemiology, sex hormones, sex chromosomes, cancer susceptibility

Gender differences in susceptibility to a disease is a very useful piece of information that can be used to develop a causal hypothesis for the disease, or to define subgroups at highest risk for preventive action (Zahm and Fraumeni, 1995). The gender differential in cancer incidence rates is comparable to ethnic and racial disparity in magnitude, and yet, most studies fail to look for it. In genetic epidemiologic studies, if examined, it is common that genders do not have equal susceptibility to diseases. Exploration of gender disparity in disease susceptibility has not become common practice even in diseases that show sex differential in their incidence rates. Here, we will document this phenomenon in cancer susceptibility with examples, discuss possible mechanisms, and review basic methodology for its examination.

DESCRIPTIVE EPIDEMIOLOGY OF GENDER DIFFERENCES IN CANCER SUSCEPTIBILITY Epidemiology is sometimes considered to be an unhealthy science because of frequently documented inconsistencies in findings and replication failures. It is relatively infrequent that a finding will be sustained in follow-up studies. However, gender differential in cancer occurrence is one very consistent finding in descriptive epidemiology. For a very long-time, it has been recognized that males are more prone to develop cancer, and particularly hematologic malignancies (Ashley, 1969; Pearce and Parker, 2001; Cartwright et al., 2002; Cook et al., 2009; Edgren et al., 2012). Prognosis in

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childhood cancers is also worse in boys than girls (Eden et al., 2000), and second malignancies occur more frequently in boys who have survived cancer (Devarahally et al., 2003). In adult malignancies, again, males have worse overall survival and higher mortality rates (Molife et al., 2001; Cook et al., 2011). GENDER DIFFERENCES IN UNITED STATES DATA

The sex differential in primary cancer susceptibility can be quantified by comparison of incidence rates in males and females. The latest analysis of the National Cancer Institute Surveillance Epidemiology and End Results (SEER) database showed that incidence rates per 100,000 people and age-adjusted to the 2000 US standard population for all cancers in the United States for 2004–2008 are 553.0 for males and 416.5 for females yielding an incidence rate ratio (IRR) of 1.33 for all cancers (Siegel et al., 2012). Although these numbers are inclusive of sex-specific cancers such as breast and prostate, their exclusion does not alter the IRR (1.35). Likewise, the lifetime probability of developing cancer is 44.85% for males, and 38.08% for females. The probability is higher for males despite a shorter life expectancy. The same analysis also showed that the cancer mortality rates were higher in males: 223.0 versus 153.2 (ratio = 1.46). Most importantly, the common cancers have the highest male-to-female (M:F) ratio: colorectal cancers: 1.35; lung and bronchus: 1.52; non-Hodgkin lymphoma (NHL): 1.44; (urinary) bladder: 4.0. Another recent

November 2012 | Volume 3 | Article 268 | 1

Dorak and Karpuzoglu

Gender differences in cancer susceptibility

analysis of SEER identified Kaposi sarcoma as having the highest M:F IRR (28.7; Cook et al., 2009). Other than breast cancer, which rarely occurs in males, only a few cancers are more common in females. Gall bladder, anus, and thyroid tumors consistently show an M:F ratio less than 1.0 (Cook et al., 2009). In Table 1, we present sex-specific incidence rates in the US and worldwide for selected cancers. GENDER DIFFERENCES ARE SEEN WORLDWIDE

The increased M:F ratio for incident cancer is not unique to a particular country, population, or region. The analysis of age- and sex-specific cancer incidence data from Cancer Incidence in Five Continents provided by the International Agency for Research on Cancer (IARC) documented the universal nature of the sex disparity in cancer (Edgren et al., 2012). In 32 of 35 cancer sites, males had a higher incidence rates consistently across geographical regions. The three exceptions were thyroid, gallbladder, and anus cancer that had higher incidence rates in females. The most drastic occurrences of male excess were noted for laryngeal and hypopharyngeal cancer, which showed around sixfold excess in males. In this global dataset, sex differences were statistically significant at all sites (P < 0.0001). When age in adult life is taken into account, some variation is evident, especially for skin cancer and salivary gland cancer with both becoming more common in males in increasing age groups. NHL, along with its globally consistent high M:F ratio, showed consistency also in all age groups: M:F ratio equals 1.42 with little variation in age groups (range = 1.36–1.59). CHILDHOOD CANCERS SHOW GENDER DIFFERENCES TOO

In childhood cancer, males are again at a higher risk than females. The sex differential in the incidence of childhood cancer is well established and consistent worldwide (Ashley, 1969; Greenberg and Shuster, 1985; Linet and Devesa, 1991; Pearce and Parker, 2001; Cartwright et al., 2002; Desandes et al., 2004). The M:F ratio

Table 1 | Selected cancers with the highest and lowest male-to-female ratios*. Cancer

Male-to-female ratio SEER (USA)

IARC (world)

Larynx

5.17

6.36

Hypopharynx

4.13

5.75

Kaposi sarcoma

28.7

4.87

Lip

7.16

4.25

Urinary bladder

3.92

4.12

Gall bladder and biliary tract

0.57

0.94

Anus

0.81

0.85

Thyroid

0.39

0.33

*SEER data from Cook et al. (2009), Siegel et al. (2012); GLOBCAN (world) data from Edgren et al. (2012). In SEER data, all ages combined, the cancer burden was higher in males than females for total cancer (male-to-female incidence rate ratio = 1.37; 95% CI = 1.37–1.38. For the world data, all sex differences were statistically significant (P < 0.0001).

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for all incident cancers is around 1.2. Exceptions to the male excess in childhood cancer include infant leukemia, thyroid carcinoma, malignant melanoma, and alveolar soft part sarcoma. As in adults, NHL shows a stable male excess in all age groups during childhood and adolescent period (range = 1.7–3.2), whereas Hodgkin lymphoma (HL) shows an interesting age-dependent variation in its M:F ratio (Ries et al., 1999). The overall incidence of HL in children is greater in females than in males (M:F ratio = 0.8), but the sex distribution is age-dependent, with the striking M:F ratio in HL in younger ages when the disease is rare reversing for adolescents when it becomes more common (Spitz et al., 1986). The SEER data from 1990 to 1995 period show M:F ratios of 5.3 (