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GENDER EFFECT IN CANCER
M. Tevfik Dorak, MD PhD
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See Dorak, 2007: Birth weight and miscarriage
associations in childhood cancer with gender effect
and Dunn, 2007 for the
molecular basis of gender effect in autoimmunity
Gender
and Health: WHO Technical paper (WHO/FRH/WHD/98.16)
Physiological
and Pharmacological Differences Between the Sexes
Disease
Control Priorities Project > Disease
Control Priorities in Developing Countries > Gender Differentials in Health
Sex Differences in
Measles Mortality
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).
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 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 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)
* In leukemia, prognosis is worse in
boys compared to boys (Sather,
1981; Gustafsson
& Kreuger, 1983; Lanning,
1992; Chessells,
1995; Shuster,
1998; Pui,
1999; Eden,
2000)
* The
risk for second primary malignancies is higher in males following childhood CNS
tumors (Devarahally,
2003)
* In twin
studies, there is a deficit of twin boys with cancer (Hewitt,
1966; Hewitt,
1970, Inskip,
1991; Rodvall,
1992)
* 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)
* Advanced maternal age and risk
association is seen only in boys in two studies (Fasal,
1971; Reynolds,
2002)
* 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)
* Females have a greater risk of
developing thyroid cancer than males following postnatal irradiation (Hempelmann,
1975; Inskip,
2001; Cardis,
2005)
* 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)
- DNA repair gene XRCC1
(Joseph, 2005); MSH3
(Infante-Rivard,
2000); APEX1
(Infante-Rivard,
2003)
- Xenobiotic enzyme polymorphisms (Krajinovic, 1999;
Sinnett,
2000)
- HLA-DRB4
and HFE associations (Dorak, 1999a
& 1999b;
2005)
* 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, males are more
susceptible to oxidative damage (Ma,
1998). In humans, gender effect in oxidative damage has also been suggested
(Proteggente,
2002)
* 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)
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