GENDER EFFECT IN CANCER
M. Tevfik Dorak, MD PhD
Automated Medline Search for gender effect in cancer susceptibility using (cancer susceptibility & sex factors)
A childhood ALL GWAS identifies novel sex-specific risk variants (Singh et al, 2016)
Gender Differences in Cancer Susceptibility: An Inadequately Addressed Issue (Dorak & Karpuzoglu, 2012)
Markle & Fish: SeXX Matters in Immunity (Trends Immunol 2014)
Voskul R: Sex Differences in Autoimmune Diseases (Biol Sex Diff 2011)
Latest Reports by Dorak et al on Genetic Associations in Childhood Leukemia with Sex Effect:
A childhood ALL GWAS identifies novel sex-specific risk variants (Singh et al, 2016)
Gender Differences in Cancer Susceptibility: An Inadequately Addressed Issue (Dorak & Karpuzoglu, 2012)
Ucisik-Akkaya E, Davis CF, Gorodezky C, Alaez C, Dorak MT. HLA complex-linked heat shock protein genes
and childhood acute lymphoblastic leukemia. Cell Stress Chaperones, 2010 (PubMed)
Davis CF & Dorak MT.An extensive analysis of the hereditary hemochromatosis gene HFE and neighboring histone genes:
associations with childhood leukemia. Annals of Hematology, 2010 (PubMed)
Do TN, Ucisik-Akkaya E, Davis CF, Morrison BA, Dorak MT. 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 Mol Basis Disease, 2010 (PubMed)
Dorak MT, Mackay RK, Relton CL, Worwood M, Parker L, Hall AG. Hereditary hemochromatosis gene (HFE) variants are associated with birth weight and
Do TN, Ucisik-Akkaya E, Davis CF, Morrison BA, Dorak MT. TP53 R72P and MDM2 SNP309 polymorphisms in modification of
childhood acute lymphoblastic leukemia susceptibility. Cancer Genetics Cytogenetics 2009;195(1):31-6 (PubMed)
*** Please address reprint requests to the e-mail address at MT Dorak’s Web Profile ***
Following section is taken from Childhood Cancer Epidemiology:
Sex Differential in Childhood Cancer
The gender effect in incidence of childhood cancer is well-established and consistent worldwide (Ashley, 1969; Greenberg & Shuster, 1985; Linet & Devesa, 1991; Little J, 1999; Pearce & Parker, 2001; Desandes, 2004). Tower and Spector provide graphs or leukemia rates worldwide for each sex separately which show the increased risk for boys clearly (Tower & Spector, 2007). Among newly diagnosed childhood cancers, the standardized (with European reference) incidence rates for all participating registries in Europe yields a boys to girls ratio for adjusted rates is on average 1.22. The incidence of ALL among children younger than 15 years of age is consistently higher among males (approximately 20%) relative to females. For the 15-19 year olds, however, the male preponderance was greater, with males having a 2-fold higher ALL incidence than females (SEER Report, see also Average Annual Age-Specific Incidence Rates per Million, SEER, 19931997). The male predominance is a feature of cancer incidence in all ages (Cartwright, 2002; Boyle & Ferlay, 2005 & 2007; Cook, 2009). Late-effects in childhood cancer survivors also show sex effect (associations between female sex and cognitive dysfunction after cranial irradiation, cardiovascular outcomes, obesity, radiation-associated differences in pubertal timing, development of primary hypothyroidism, breast cancer as a second malignant neoplasm and suggests an increased prevalence for the development of osteonecrosis among females) (Armstrong, 2007).
Although the male-to-female (M:F) age-adjusted incidence is >1.0 for all types of leukemias and lymphomas, the ratio is highest (M:F: 3.0) for non-Hodgkin lymphoma, similar for ALL and HD (both M:F: 1.3), and lowest for acute myeloid leukemia (M:F: 1.1; Table 1 in Linet, 2003). Burkitt lymphoma is one of the childhood (and adult) tumors with the highest M:F ratio (Boerma, 2004). The M:F ratio also varies among the subtypes of central nervous system tumors, with the highest ratio apparent for ependymomas (M:F: 2.0) and primitive neuroectodermal tumors (M:F: 1.7), but there is little difference between male and female age-adjusted incidences for astrocytomas and other gliomas (Table 2 in Linet, 2003). Boys and girls have a similar incidence of retinoblastoma and Wilms tumor. Only for extragonadal, non-intracranial germ cell tumors, malignant melanoma and some carcinomas, notably those of the adrenal cortex and thyroid (Inskip, 2001), including radioactive iodine-induced form (Cardis, 2005), and alveolar soft part sarcoma (Bu, 2005), there is an excess among girls (UK National Childhood Cancer Statistics, 2004). For M-to-F ratio in each childhood cancer, see Table 13.1 in UK National Childhood Cancer Statistics (see also Table 4 in Linet, 2003). Reasons are unknown for the male predominance in incidence of non-Hodgkin lymphoma and ependymomas; the higher incidences among young females for thyroid cancer and malignant melanoma; and the lack of gender-related differences in incidences of acute myeloid leukemia, astrocytomas, and other gliomas, but etiologic leads to consider include exposures that differ by gender, effects of hormonal influences, and gender-related genetic differences (Linet, 2003). The sex effect is not only seen in incidence of childhood ALL but also in prognosis; males having more relapse, worse prognosis and secondary cancer (Sather, 1981; Gustafsson & Kreuger, 1983; Woodcock, 1984; Lanning, 1992; Chessells, 1995; Shuster, 1998; Pui, 1999; Eden, 2000; Devarahally, 2003).
The susceptibility by sex at different ages is a phenomenon rarely addressed in the analyses of epidemiological studies, yet the risks for males of certain ages can be between two- and fivefold greater than females, which is in need of further investigation (Cartwright, 2002). As one possible mechanism of the male-female differential in childhood cancers, in particular Hodgkin lymphoma, greater frequency of an asymptomatic carrier state in this sex has been suggested but not investigated (Vianna & Polan, 1978).
Following observations have been made in relation to gender effect in childhood leukemia / cancers and may be relevant in the explanation of this phenomenon:
* The male excess in childhood ALL is consistent worldwide and the populations with a lower M:F ratio tend to have low total leukemia and ALL incidence (Linet & Devesa, 1991)
* The risk for second primary malignancies is higher in males following childhood CNS tumors (Devarahally, 2003)
* Male survivors of childhood cancer have a lower proportion of livebirth and a reversed male-to-female ratio in their offspring suggesting a male deficit among their children (Green, 2003)
* Paternal exposure to chemicals (dibromochloropropane and dioxin) (Potashnik, 1984; Mocarelli, 2000; Jonbloet, 2002) decreases the sex (M/F) ratio in the offspring although the opposite effect has also been reported (Karmaus, 2002). Parental smoking during the periconceptional period also decreases male-to-female ration at birth (see a commentary at a CCC newsletter)
* In the original Oxford Study of Childhood Cancer (Hewitt, 1966), out of 14 survivors of threatened abortions who developed a malignancy in the first six months, only one was a male
* In the original Oxford Study of Childhood Cancer (Hewitt, 1966), unaffected sibs of familial cases of childhood leukemia have a low male-to-female ratio (0.71)
* Male children of untreated diabetic or prediabetic mothers have a higher risk of being stillborn (Gellis & Hsia, 1950)
* Seasonality in childhood HD is restricted to males only in one study (Fraumeni & Li, 1969).
* If infections have anything to do with childhood cancers, boys are more vulnerable to childhood infections than girls (Washburn, 1965; Schlegel, 1969; Purtilo, 1979; Schmitz, 1983; Rechavi, 1992; Green, 1992; Read, 1997). The most striking example is of course EBV infections in X-linked lymphoproliferative disease (Seemayer, 1993)
* The association of childhood leukemia with cleft lip and palate is based on three male cases (Zack, 1991)
* Association of childhood leukemia with high birth weight is more pronounced in a subgroup of female children of older mothers with a high socioeconomic status (Fasal, 1971; Paltiel, 2004). This has been shown in twin females too (Jackson, 1969)
* A more recent population-based study showed that in childhood ALL, the birth weight association is male-specific (Dorak, 2007)
* Miscarriage association in childhood ALL is stronger and statistically significant in boys only (Dorak, 2007)
* Familial aggregation of NHL is male-specific (Chatterjee, 2004)
* Genetic susceptibility studies have shown gender-specific associations:
- Blood groups ABO frequencies differ between male and female patients in leukemia (Jackson, 1999)
* The growth rate of the embryo is higher for males than females in different species including humans (Mittwoch, 1993). Because accelerated rates of cell division and proliferation may increase the predisposed to the development of cancer (Preston-Martin, 1990), this inherent feature of males may explain some of the gender effect in (childhood) cancers.
* The primary sex ratio at fertilization may be as high as 165:100 (see for example: Tricomi, 1960; Shettles, 1964; Serr & Ismajovich, 1963; Lee & Takano, 1970; McMillen, 1979; Kellokumpu-Lehtinen & Pelliniemi, 1984; Vatten, 2004; C3 Newsletter 13/2) but it falls down to 106:100 at birth in humans (and similarly in most mammals). A continuation of this process (elimination of excess males) is the increased morbidity and mortality of male infants and children (well-known male disadvantage (Stevenson, 2000) or fragile male (Kraemer, 2000), which has evolutionary explanations (Trivers & Willard, 1973; Wells, 2000; Dorak, 2002)). It can be speculated that the excess risk in males for childhood cancers and infections may be due to the continuing elimination of excess males.
* Homozygosity for HLA-DR haplotypes (one of which associated with risk for childhood ALL in males) shows a deficit in newborn males (Dorak, 2002)
* A finding that may be relevant in gender effect is that newborn boys have a higher homozygote TT frequency for MTHFR 677C>T SNP (Rozen, 1999). However, the 677T allele is protective for childhood ALL (Wiemels, 2001; Robien & Ulrich, 2003)
* One of the major groups of oxidative enzymes involved in drug metabolism, the CYP450 enzymes, have differential activity between males and females (Harris, 1995; Anderson, 2002). CYP3A4 activity, for example, is higher in women than in men (Harris, 1995). Likewise, GST activity also shows gender-specific differences (Singhal, 1992)
* In adults, MDR activity is higher in males with chronic lymphoid leukemia (Steiner, 1998). It has been suggested that this may be one reason for the less aggressive clinical course in women.
* Penetrance of mutations in DNA mismatch repair genes MLH1/MSH2 is significantly higher in males (approximately 80%) than in females (40%) (Mitchell, 2002). DNA mismatch repair gene mutations usually cause adult colon cancer in heterozygous form but a variety of childhood cancer in homozygous forms (Lucci-Cordisco, 2003)
* In animal studies, sensitivity to mutagenic carcinogens and the risk of radiation carcinogenesis are greater in males (Hattis, 2004)
* An in vitro study showed a higher radiosensitivity of lymphocytes from males regardless of age and ethnicity (Wang, 2000)
* Maternal serum ferritin levels are at 36 weeks of gestation correlate with umbilical cord serum ferritin of male but not female infants (Tamura, 1999). This may be relevant in the male-specificity of HFE-C282Y association in childhood ALL (Dorak, 1999)
* * * * * * * * * * * * * * * * * * * *
Observations in adult cancers:
- High levels of serum Hsp70 is associated with increased risk of lung cancer in Japan but only in males (Suzuki, 2006).
- Colon cancer development is more common in males with inflammatory bowel disease than in females (Soderlung, 2010).
- MICA STR association with nasopharyngeal cancer is male-specific (Tian, 2006).
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