GENDER EFFECT IN CANCER
M.Tevfik Dorak, MD PhD
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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). Among newly diagnosed childhood cancers, the standardised (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).
Although the male-to-female (M:F) age-adjusted incidence is >1.0 for all types of leukaemias 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 leukaemia (M:F: 1.1; Table 1 in Linet, 2003). Burkitt lymphoma is one of the childhood (and adult) tumours with the highest M:F ratio (Boerma, 2004). The M:F ratio also varies among the subtypes of central nervous system tumours, with the highest ratio apparent for ependymomas (M:F: 2.0) and primitive neuroectodermal tumours (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’ tumour. Only for extragonadal, non-intracranial germ cell tumours, 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 leukaemia, 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 gender effect is not only seen in incidence of childhood ALL but also in prognosis; males having more cancers and worse prognosis (Sather, 1981; Gustafsson & Kreuger, 1983; Lanning, 1992; Chessells, 1995; Shuster, 1998; Pui, 1999; Eden, 2000). Furthermore, second malignancies also occur more frequently in males (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's disease, 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 leukaemia / 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 leukaemia and ALL incidence (Linet & Devesa, 1991)
* The risk for second primary malignancies is higher in males following childhood CNS tumours (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 leukaemia 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). Li & Fraumeni likened this observation to male-specific susceptibility to adenovirus-induced cancers in hamsters (Yohn, 1973)
* 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; Green, 1992; Read, 1997). The most striking example is of course EBV infections in X-linked lymphoproliferative disease (Seemayer, 1993).
* The association of childhood leukaemia with cleft lip and palate is based on three male cases (Zack, 1991)
* Association of childhood leukaemia with high birthweight 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)
* 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 leukaemia (Jackson, 1999)
- Postnatal diagnostic irradiation and DNA repair genes (Infante-Rivard, 2000)
- DNA repair gene XRCC1 (Joseph, 2005)
- Xenobiotic enzyme polymorphisms (Krajinovic, 1999)
* 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)
* 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 female infants (Tamura, 1999). This may be relevant in the male-specificity of HFE-C282Y association in childhood ALL (Dorak, 1999)
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M.Tevfik Dorak, B.A. (Hons), M.D., Ph.D.
30 May 2006