HLA MHC Genetics Genetic Epidemiology Evolution Biostatistics Homepage
GENDER EFFECT IN CANCER
Mehmet Tevfik DORAK, MD PhD
Medline Search for gender effect in cancer susceptibility using (cancer susceptibility & sex factors)
Published on 15 May 2017:
Dorak MT (2017) Cancer: Gender differences at the molecular level. In: Principles of Gender-Specific Medicine - Gender in the Genomic Era.
Elsevier Science, San Diego, CA. ISBN 9780128035061
(3rd Edition of this book is in preparation)
A childhood ALL GWAS identifies novel sex-specific risk variants (Singh et al, 2016)
Comprehensive characterization of molecular differences in cancer between male and female patients (Yuan, 2016)
Gender differences in cancer susceptibility: an inadequately addressed issue (Dorak & Karpuzoglu, 2012)
Sex disparities in cancer incidence by period and age (Cook, 2009) & Enigmatic sex disparities in cancer incidence (Edgren, 2012)
See also:
Klein & Flanagan: Sex differences in immune responses (Nat Rev Immunol 2016)
Markle & Fish: SeXX Matters in Immunity (Trends Immunol 2014)
Voskul R: Sex Differences in Autoimmune Diseases (Biol Sex Diff 2011)
Ucisik-Akkaya: Genomic signatures of sex-specific prenatal selection (Mol Hum Reprod 2010)
Dorak, 2007: Birth weight and miscarriage associations in childhood cancer with gender effect; and possible mechanism in Dorak, 2009 (Suppl Material);
Dunn, 2007 and Rubtsova, 2015 for molecular basis of gender effect in autoimmunity;
Naugler, 2007 & Lawrence, 2007 for molecular mechanism of gender disparity in liver cancer
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
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
childhood leukemia risk. Pediatric Blood & Cancer, 2009;53(7):1242-8 (Abstract / Suppl Material)
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, 1993
1997). 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)
* 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, 1995; Dorak, 1999a & 1999b; 2005), HLA-B67 association (Ng, 2006), HLA-DQA association (Taylor, 1998)
* 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 (Loft, 1992; 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)
* * * * * * * * * * * * * * * * * * * *
Observations in adult cancers:
- MDM2 SNP309 interacts with sex in its negative suppressor effect on TP53 activity (Bond, 2004; Bond, 2006; Bond & Levine, 2007)
- 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).
References relevant to gender effect in cancer:
Ahmed, S. A. and Talal, N. (1990) Sex hormones and the immune system--Part 2. Animal data Baillieres Clin Rheumatol, 4, 1 13-31.
Anderson, G. D. (2002) Sex differences in drug metabolism: cytochrome P-450 and uridine diphosphate glucuronosyltransferase J Gend Specif Med, 5, 1 25-33.
Ansar Ahmed, S., Penhale, W. J. and Talal, N. (1985) Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action Am J Pathol, 121, 3 531-51.
Asham, E. H., Loizidou, M. and Taylor, I. (1998) Endothelin-1 and tumour development Eur J Surg Oncol, 24, 1 57-60.
Ashley, D. J. (1969) A male-female differential in tumour incidence British Journal of Cancer, 23, 1 21-25.
Bagnato, A. and Spinella, F. (2003) Emerging role of endothelin-1 in tumor angiogenesis Trends Endocrinol Metab, 14, 1 44-50.
Barna, M., Komatsu, T., Bi, Z. and Reiss, C. S. (1996) Sex differences in susceptibility to viral infection of the central nervous system Journal of Neuroimmunology, 67, 1 31-39.
Biggar, R. J., Pandey, J. P., Henle, W., Nkrumah, F. K. and Levine, P. H. (1984) Humoral immune response to Epstein-Barr virus antigens and immunoglobulin allotypes in African Burkitt lymphoma patients Int J Cancer, 33, 5 577-80.
Bihl, F., Brahic, M. and Bureau, J. F. (1999) Two loci, Tmevp2 and Tmevp3, located on the telomeric region of chromosome 10, control the persistence of Theiler's virus in the central nervous system of mice Genetics, 152, 1 385-92.
Bond GL, Hirshfield KM, Kirchhoff T, Alexe G, Bond EE, Robins H, Bartel F, Taubert H, Wuerl P, Hait W, Toppmeyer D, Offit K, Levine AJ (2006) MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res 66, 10, 5104-10.
Brown, C. J. and Greally, J. M. (2003) A stain upon the silence: genes escaping X inactivation Trends Genet, 19, 8 432-8.
Bruland, T., Dai, H. Y., Lavik, L. A., Kristiansen, L. I. and Dalen, A. (2001) Gender-related differences in susceptibility, early virus dissemination and immunosuppression in mice infected with Friend murine leukemia virus variant FIS-2 J Gen Virol, 82, Pt 8 1821-7.
Bruland, T., Lavik, L. A., Dai, H. Y. and Dalen, A. (2003) A glucocorticoid response element in the LTR U3 region of Friend murine leukemia virus variant FIS-2 enhances virus production in vitro and is a major determinant for sex differences in susceptibility to FIS-2 infection in vivo J Gen Virol, 84, Pt 4 907-16.
Butterfield, R. J., Roper, R. J., Rhein, D. M., Melvold, R. W., Haynes, L., Ma, R. Z., Doerge, R. W. and Teuscher, C. (2003) Sex-specific quantitative trait loci govern susceptibility to Theiler's murine encephalomyelitis virus-induced demyelination Genetics, 163, 3 1041-6.
Butterworth, M., McClellan, B. and Allansmith, M. (1967) Influence of sex in immunoglobulin levels Nature, 214, 94 1224-1225.
Cannon, J. G. and St Pierre, B. A. (1997) Gender differences in host defense mechanisms J Psychiatr Res, 31, 1 99-113.
Cartwright, R. A., Gurney, K. A. and Moorman, A. V. (2002) Sex ratios and the risks of haematological malignancies Br J Haematol, 118, 4 1071-7.
Clutton-Brock, T. H., Albon, S. D. and Guinness, F. E. (1985) Parental investment and sex differences in juvenile mortality in birds and mammals Nature, 313, 5998 133-133.
Collins, W. M., Dunlop, W. R., Zsigray, R. M., Briles, R. W. and Fite, R. W. (1986) Metastasis of Rous sarcoma tumors in chickens is influenced by the major histocompatibility (B) complex and sex Poultry Science, 65, 9 1642-1648.
Conley, M. E. (2000) Genetics of primary immunodeficiency diseases Reviews in Immunogenetics, 2, 231-242.
Craig, I. W., Harper, E. and Loat, C. S. (2004) The genetic basis for sex differences in human behaviour: role of the sex chromosomes Ann Hum Genet, 68, Pt 3 269-84.
Cutolo, M., Seriolo, B., Villaggio, B., Pizzorni, C., Craviotto, C. and Sulli, A. (2002) Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis Ann N Y Acad Sci, 966, 131-42.
Da Silva, J. A. (1999) Sex hormones and glucocorticoids: interactions with the immune system Ann N Y Acad Sci, 876, 102-17; discussion 117-8.
Darbre, P., Page, M. and King, R. J. (1986) Androgen regulation by the long terminal repeat of mouse mammary tumor virus Mol Cell Biol, 6, 8 2847-54.
Deguchi, J., Miyamoto, M. and Okada, S. (1995) Sex hormone-dependent renal cell carcinogenesis induced by ferric nitrilotriacetate in Wistar rats Jpn J Cancer Res, 86, 11 1068-71.
Devarahally, S. R., Severson, R. K., Chuba, P., Thomas, R., Bhambhani, K. and Hamre, M. R. (2003) Second malignant neoplasms after primary central nervous system malignancies of childhood and adolescence Pediatr Hematol Oncol, 20, 8 617-25.
Dorak, M. T. and Burnett, A. K. (1992) Major histocompatibility complex, t-complex, and leukemia [Review] Cancer Causes & Control, 3, 3 273-282.
Dorak, M. T., Lawson, T., Machulla, H. K., Mills, K. I. and Burnett, A. K. (2002a) Increased heterozygosity for MHC class II lineages in newborn males Genes Immun, 3, 5 263-9.
Dorak, M. T., Lawson, T., Machulla, H. K. G., Darke, C., Mills, K. I. and Burnett, A. K. (1999a) Unravelling an HLA-DR association in childhood acute lymphoblastic leukemia Blood, 94, 2 694-700.
Dorak, M. T., Mills, K. I., Gaffney, D., Wilson, D. W., Galbraith, I., Henderson, N. and Burnett, A. K. (1994) Homozygous MHC genotypes and longevity Hum Hered, 44, 5 271-8.
Dorak, M. T., Oguz, F. S., Yalman, N., Diler, A. S., Kalayoglu, S., Anak, S., Sargin, D. and Carin, M. (2002b) A male-specific increase in the HLA-DRB4 (DR53) frequency in high-risk and relapsed childhood ALL Leuk Res, 26, 7 651-6.
Dorak, M. T., Shao, W., Mills, K. I. and Burnett, A. K. (2003) Endothelin-1 gene shows a gender-specific association with childhood acute lymphoblastic leukemia [Abstract] Blood, The 45th Annual Meeting of the American Society for Hematology (ASH). San Diego, CA.
Dorak, M. T., Sproul, A. M., Gibson, B. E., Burnett, A. K. and Worwood, M. (1999b) The C282Y mutation of HFE is another male-specific risk factor for childhood ALL Blood, 94, 11 3957-3958.
Dorak, M. T., Sproul, A. M., Machulla, H. K., Burnett, A. K. and Gibson, B. E. (2000) Confirmation of the male-specific HLA-DRB4*01 association in childhood leukemia [Abstract] Eur J Hum Immunogenet, 27, 4 262-262.
Dresler, C. M., Fratelli, C., Babb, J., Everley, L., Evans, A. A. and Clapper, M. L. (2000) Gender differences in genetic susceptibility for lung cancer Lung Cancer, 30, 3 153-60.
Dunn, G. P., Old, L. J. and Schreiber, R. D. (2004) The immunobiology of cancer immunosurveillance and immunoediting Immunity, 21, 2 137-48.
Eden, O. B., Harrison, G., Richards, S., Lilleyman, J. S., Bailey, C. C., Chessells, J. M., Hann, I. M., Hill, F. G. and Gibson, B. E. (2000) Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukemia, 1980-1997. Medical Research Council Childhood Leukemia Working Party Leukemia, 14, 12 2307-2320.
Escobar, V., Corey, L. A., Bixler, D., Nance, W. E. and Biegel, A. (1979) The human X-chromosome and the levels of serum immunoglobulin M Clin Genet, 15, 3 221-7.
Evans, J. S., Nims, T., Cooley, J., Bradley, W., Jagodzinski, L., Zhou, S., Melcher, G. P., Burke, D. S. and Vahey, M. (1997) Serum levels of virus burden in early-stage human immunodeficiency virus type 1 disease in women J Infect Dis, 175, 4 795-800.
Fasal, E., Jackson, E. W. and Klauber, M. R. (1971) Birth characteristics and leukemia in childhood J Natl Cancer Inst, 47, 3 501-9.
Fox, H. S., Bond, B. L. and Parslow, T. G. (1991) Estrogen regulates the IFN-gamma promoter J Immunol, 146, 12 4362-7.
Frank, S. A. and Hurst, L. D. (1996) Mitochondria and male disease Nature, 383, 6597 224.
Fraumeni, J. F., Jr. and Li, F. P. (1969) Hodgkin's disease in childhood: an epidemiologic study J Natl Cancer Inst, 42, 4 681-91.
Gaillard, R. C. and Spinedi, E. (1998) Sex- and stress-steroids interactions and the immune system: evidence for a neuroendocrine-immunological sexual dimorphism Domest Anim Endocrinol, 15, 5 345-52.
Gandhi, M., Bacchetti, P., Miotti, P., Quinn, T. C., Veronese, F. and R.M., G. (2002) Does patient sex affect human immunodeficiency virus levels? Clin Infect Dis, 35, 3 313-322.
Gellis, S. S. and Hsia, D. Y. (1959) The infant of diabetic mother AMA J Dis Child, 97, 1 1-41.
Green, M. S. (1992) The male predominance in the incidence of infectious diseases in children: a postulated explanation for disparities in the literature Int J Epidemiol, 21, 2 381-6.
Grossman, C. (1989) Possible underlying mechanisms of sexual dimorphism in the immune response, fact and hypothesis Journal of Steroid Biochemistry, 34, 1-6 241-251.
Grossman, C. J. (1984) Regulation of the immune system by sex steroids Endocr Rev, 5, 3 435-455.
Grossman, C. J., Roselle, G. A. and Mendenhall, C. L. (1991) Sex steroid regulation of autoimmunity J Steroid Biochem Mol Biol, 40, 4-6 649-59.
Gurney, J. G., Severson, R. K., Davis, S. and Robison, L. L. (1995) Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type Cancer, 75, 8 2186-95.
Gustafsson, G. and Kreuger, A. (1983) Sex and other prognostic factors in acute lymphoblastic leukemia in childhood Am J Pediatr Hematol Oncol, 5, 3 243-50.
Han, X., Lundberg, P., Tanamachi, B., Openshaw, H., Longmate, J. and Cantin, E. (2001) Gender influences herpes simplex virus type 1 infection in normal and gamma interferon-mutant mice J Virol, 75, 6 3048-52.
Harris, R. Z., Benet, L. Z. and Schwartz, J. B. (1995) Gender effects in pharmacokinetics and pharmacodynamics Drugs, 50, 2 222-39.
Hassold, T., Quillen, S. T. and Yamane, J. A. (1983) Sex ratio in spontaneous abortions Ann Hum Genet, 47, Part 1 39-47.
Henderson, C. J., Scott, A. R., Yang, C. S. and Wolf, C. R. (1990) Testosterone-mediated regulation of mouse renal cytochrome P-450 isoenzymes Biochemical Journal, 266, 3 675-681.
Hewitt, D., Lashof, J. C. and Stewart, A. M. (1966) Childhood cancer in twins Cancer, 19, 2 157-61.
Hewitt, D. and Stewart, A. (1970) Relevance of twin data to intrauterine selection: special case of childhood cancer Acta Genet Med Gemellol (Roma), 19, 1 83-6.
Huber, S. A. and Pfaeffle, B. (1994) Differential Th1 and Th2 cell responses in male and female BALB/c mice infected with coxsackievirus group B type 3 J Virol, 68, 8 5126-32.
Infante-Rivard, C., Mathonnet, G. and Sinnett, D. (2000) Risk of childhood leukemia associated with diagnostic irradiation and polymorphisms in DNA repair genes Environ Health Perspect, 108, 6 495-8.
Inskip, P. D., Harvey, E. B., Boice, J. D., Jr., Stone, B. J., Matanoski, G., Flannery, J. T. and Fraumeni, J. F., Jr. (1991) Incidence of childhood cancer in twins Cancer Causes & Control, 2, 315-324.
Ivanova, R., Henon, N., Lepage, V., Charron, D., Vicaut, E. and Schachter, F. (1998) HLA-DR alleles display sex-dependent effects on survival and discriminate between individual and familial longevity Hum Mol Genet, 7, 2 187-94.
Jackson, E. W., Norris, F. D. and Klauber, M. R. (1969) Childhood leukemia in California-born twins Cancer, 23, 4 913-9.
Jackson, N., Menon, B. S., Zarina, W., Zawawi, N. and Naing, N. N. (1999) Why is acute leukemia more common in males? A possible sex-determined risk linked to the ABO blood group genes Ann Hematol, 78, 5 233-6.
Juan, S. H., Chen, J. J., Chen, C. H., Lin, H., Cheng, C. F., Liu, J. C., Hsieh, M. H., Chen, Y. L., Chao, H. H., Chen, T. H., Chan, P. and Cheng, T. H. (2004) 17beta-estradiol inhibits cyclic strain-induced endothelin-1 gene expression within vascular endothelial cells Am J Physiol Heart Circ Physiol, 287, 3 H1254-61.
Kanda, N. and Tamaki, K. (1999) Estrogen enhances immunoglobulin production by human PBMCs J Allergy Clin Immunol, 103, 2 Pt 1 282-8.
Kappel, C. A., Melvold, R. W. and Kim, B. S. (1990) Influence of sex on susceptibility in the Theiler's murine encephalomyelitis virus model for multiple sclerosis J Neuroimmunol, 29, 1-3 15-9.
Kasai, S. and Tomita, T. (2003) Male specific expression of a cytochrome P450 (Cyp312a1) in Drosophila melanogaster Biochem Biophys Res Commun, 300, 4 894-900.
Kaye, S. A., Robison, L. L., Smithson, W. A., Gunderson, P., King, F. L. and Neglia, J. P. (1991) Maternal reproductive history and birth characteristics in childhood acute lymphoblastic leukemia Cancer, 68, 6 1351-1355.
Kellokumpu-Lehtinen, P. and Pelliniemi, L. J. (1984) Sex ratio in human conceptuses Obstet Gynecol, 64, 2 220-222.
Kinlen, L. (2004) Infections and immune factors in cancer: the role of epidemiology Oncogene, 23, 38 6341-8.
Klein, S. L. (2000) The effects of hormones on sex differences in infection: from genes to behavior Neurosci Biobehav Rev, 24, 6 627-38.
Kraemer, S. (2000) The fragile male BMJ, 321, 7276 1609-12.
Krajinovic, M., Labuda, D., Richer, C., Karimi, S. and Sinnett, D. (1999) Susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms Blood, 93, 5 1496-1501.
Lanning, M., Garwicz, S., Hertz, H., Jonmundsson, G., Kreuger, A., Lie, S. O., Moe, P. J., Salmi, T. T., Schroder, H., Siimes, M. A. and et al. (1992) Superior treatment results in females with high-risk acute lymphoblastic leukemia in childhood Acta Paediatr, 81, 1 66-8.
Lawrence T, Hageman T, Balkwill F (2007) Sex, cytokines, and cancer. Science 317, 5834, 51-2.
Ma, Y., Kawabata, T., Hamazaki, S., Ogino, T. and Okada, S. (1998) Sex differences in oxidative damage in ddY mouse kidney treated with a renal carcinogen, iron nitrilotriacetate Carcinogenesis, 19, 11 1983-8.
Martin, J. T. (2000) Sexual dimorphism in immune function: the role of prenatal exposure to androgens and estrogens Eur J Pharmacol, 405, 1-3 251-261.
Martin, R. W., 3rd, Hood, A. F. and Farmer, E. R. (1993) Kaposi sarcoma Medicine (Baltimore), 72, 4 245-61.
McMillen, M. M. (1979) Differential mortality by sex in fetal and neonatal deaths Science, 204, 4388 89-91.
Moehler, T. M., Ho, A. D., Goldschmidt, H. and Barlogie, B. (2003) Angiogenesis in hematologic malignancies Crit Rev Oncol Hematol, 45, 3 227-44.
Moller, A. P., Sorci, G. and Erritzoe, J. (1998) Sexual dimorphism in immune defense American Naturalist, 152, 4 605-619.
Mollerup, S., Ryberg, D., Hewer, A., Phillips, D. H. and Haugen, A. (1999) Sex differences in lung CYP1A1 expression and DNA adduct levels among lung cancer patients Cancer Res, 59, 14 3317-20.
Mozes, E. and Fuchs, S. (1974) Linkage between immune response potential to DNA and X chromosome Nature, 249, 453 167-8.
Mugford, C. A. and Kedderis, G. L. (1998) Sex-dependent metabolism of xenobiotics Drug Metab Rev, 30, 3 441-98.
Nagy, P., Jako, J., Kiss, A., Tamas, E., Telek, B. and Rak, K. (1981) Sex-linked difference in blood-group distribution among patients suffering from acute leukemias Br J Haematol, 48, 3 507-8.
Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 5834, 121-4.
Nowinski, R. C., Brown, M., Doyle, T. and Prentice, R. L. (1979) Genetic and viral factors influencing the development of spontaneous leukemia in AKR mice Virology, 96, 186-204.
Olsen, N. J. and Kovacs, W. J. (1996) Gonadal steroids and immunity Endocr Rev, 17, 4 369-84.
Otten, A. D., Sanders, M. M. and McKnight, G. S. (1988) The MMTV LTR promoter is induced by progesterone and dihydrotestosterone but not by estrogen Mol Endocrinol, 2, 2 143-7.
Paltiel, O., Harlap, S., Deutsch, L., Knaanie, A., Massalha, S., Tiram, E., Barchana, M. and Friedlander, Y. (2004) Birth weight and other risk factors for acute leukemia in the Jerusalem Perinatal Study cohort Cancer Epidemiol Biomarkers Prev, 13, 6 1057-64.
Pearce, M. S. and Parker, L. (2001) Childhood cancer registrations in the developing world: still more boys than girls Int J Cancer, 91, 3 402-6.
Polderman, K. H., Stehouwer, C. D., van Kamp, G. J., Dekker, G. A., Verheugt, F. W. and Gooren, L. J. (1993) Influence of sex hormones on plasma endothelin levels Ann Intern Med, 118, 6 429-32.
Proteggente, A. R., England, T. G., Rehman, A., Rice-Evans, C. A. and Halliwell, B. (2002) Gender differences in steady-state levels of oxidative damage to DNA in healthy individuals Free Radic Res, 36, 2 157-62.
Pui, C. H., Boyett, J. M., Relling, M. V., Harrison, P. L., Rivera, G. K., Behm, F. G., Sandlund, J. T., Ribeiro, R. C., Rubnitz, J. E., Gajjar, A. and Evans, W. E. (1999) Sex differences in prognosis for children with acute lymphoblastic leukemia J Clin Oncol, 17, 3 818-24.
Purtilo, D. T. and Sullivan, J. L. (1979) Immunological bases for superior survival of females Am J Dis Child, 133, 12 1251-1253.
Read, J. S., Troendle, J. F. and Klebanoff, M. A. (1997) Infectious disease mortality among infants in the United States, 1983 through 1987 Am J Public Health, 87, 2 192-8.
Rechavi, G., Ramot, B. and Ben-Bassat, I. (1992) The role of infection in childhood leukemia: what can be learned from the male predominance? Acta Haematol, 88, 2-3 58-60.
Robien, K. and Ulrich, C. M. (2003) 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview Am J Epidemiol, 157, 7 571-82.
Rodvall, Y., Hrubec, Z., Pershagen, G., Ahlbom, A., Bjurman, A. and Boice, J. D., Jr. (1992) Childhood cancer among Swedish twins Cancer Causes Control, 3, 6 527-32.
Rolff, J. (2002) Bateman's principle and immunity Proc R Soc Lond B Biol Sci, 269, 1493 867-72.
Rozen, R., Fraser, F. C. and Shaw, G. (1999) Decreased proportion of female newborn infants homozygous for the 677 C-->T mutation in methylenetetrahydrofolate reductase Am J Med Genet, 83, 2 142-3.
Ryberg, D., Hewer, A., Phillips, D. H. and Haugen, A. (1994) Different susceptibility to smoking-induced DNA damage among male and female lung cancer patients Cancer Research, 54, 22 5801-5803.
Sarvetnick, N. and Fox, H. S. (1990) Interferon-gamma and the sexual dimorphism of autoimmunity Mol Biol Med, 7, 4 323-31.
Sather, H., Miller, D., Nesbit, M., Heyn, R. and Hammond, D. (1981) Differences in prognosis for boys and girls with acute lymphoblastic leukemia Lancet, 1, 8223 739-743.
Schlegel, R. J. and Bellanti, J. A. (1969) Increased susceptibility of males to infection Lancet, 2, 7625 826-7.
Schmitz, H., Wigand, R. and Heinrich, W. (1983) Worldwide epidemiology of human adenovirus infections Am J Epidemiol, 117, 4 455-66.
Schuurs, A. H. and Verheul, H. A. (1990) Effects of gender and sex steroids on the immune response J Steroid Biochem, 35, 2 157-72.
Shelat, S. G., Aird, F. and Redei, E. (1997) Exposure to dehydroepiandrosterone in utero affects T-cell function in males only Neuroimmunomodulation, 4, 3 154-62.
Shields, P. G. (2002) Molecular epidemiology of smoking and lung cancer Oncogene, 21, 45 6870-6.
Singhal, S. S., Saxena, M., Awasthi, S., Ahmad, H., Sharma, R. and Awasthi, Y. C. (1992) Gender related differences in the expression and characteristics of glutathione S-transferases of human colon Biochim Biophys Acta, 1171, 1 19-26.
Sinnett, D., Krajinovic, M. and Labuda, D. (2000) Genetic susceptibility to childhood acute lymphoblastic leukemia Leuk Lymphoma, 38, 5-6 447-62.
Skuse, D. H. (2000) Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism Pediatr Res, 47, 1 9-16.
Söderlund S, Granath F, Broström O, Karlén P, Löfberg R, Ekbom A, Askling J (2010). Inflammatory bowel disease confers a lower risk of colorectal cancer to females than to males. Gastroenterology 138, 5, 1697-703.
Sordello, S., Bertrand, N. and Plouet, J. (1998) Vascular endothelial growth factor is up-regulated in vitro and in vivo by androgens Biochem Biophys Res Commun, 251, 1 287-90.
Steiner, H., Polliack, A., Kimchi-Sarfaty, C., Libster, D., Fibach, E. and Rund, D. (1998) Differences in rhodamine-123 efflux in B-type chronic lymphocytic leukemia suggest possible gender and stage variations in drug-resistance gene activity Ann Hematol, 76, 5 189-94.
Sterling, T. R., Lyles, C. M., Vlahov, D., Astemborski, J., Margolick, J. B. and Quinn, T. C. (1999) Sex differences in longitudinal human immunodeficiency virus type 1 RNA levels among seroconverters J Infect Dis, 180, 3 666-72.
Stevenson, D. K., Verter, J., Fanaroff, A. A., Oh, W., Ehrenkranz, R. A., Shankaran, S., Donovan, E. F., Wright, L. L., Lemons, J. A., Tyson, J. E., Korones, S. B., Bauer, C. R., Stoll, B. J. and Papile, L. A. (2000) Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage Arch Dis Child Fetal Neonatal Ed, 83, 3 F182-5.
Taylor, G. M., Dearden, S., Payne, N., Ayres, M., Gokhale, D. A., Birch, J. M., Blair, V., Stevens, R. F., Will, A. M. and Eden, O. B. (1998) Evidence that an HLA-DQA1-DQB1 haplotype influences susceptibility to childhood common acute lymphoblastic leukemia in boys provides further support for an infection-related aetiology Br J Cancer, 78, 5 561-565.
Tian W, Zeng XM, Li LX, Jin HK, Luo QZ, Wang F, Guo SS, Cao Y (2006) Gender-specific associations between MICA-STR and nasopharyngeal carcinoma in a southern Chinese Han population. Immunogenetics 58, 2-3, 113-21.
Vatten, L. J. and Skjaerven, R. (2004) Offspring sex and pregnancy outcome by length of gestation Early Hum Dev, 76, 1 47-54.
Verthelyi, D. (2001) Sex hormones as immunomodulators in health and disease Int Immunopharmacol, 1, 6 983-93.
Vianna, N. J. and Polan, A. K. (1978) Immunity in Hodgkin's disease: importance of age at exposure Ann Intern Med, 89, 4 550-6.
Waldron, I. (1983) Sex differences in human mortality: the role of genetic factors. Soc Sci Med, 17, 321-33.
Washburn, T. C., Medearis, D. N., Jr. and Childs, B. (1965) Sex differences in susceptibility to infections Pediatrics, 35, 57-64.
Wei, Q., Cheng, L., Amos, C. I., Wang, L. E., Guo, Z., Hong, W. K. and Spitz, M. R. (2000) Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study J Natl Cancer Inst, 92, 21 1764-72.
Wells, J. C. (2000) Natural selection and sex differences in morbidity and mortality in early life J Theor Biol, 202, 1 65-76.
Whitacre, C. C., Reingold, S. C., O'Looney, P. A. and Task Force on Gender, M. S. a. A. (1999) A gender gap in autoimmunity Science, 283, 1277-1278.
Wiemels, J. L., Smith, R. N., Taylor, G. M., Eden, O. B., Alexander, F. E. and Greaves, M. F. (2001) Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia Proc Natl Acad Sci U S A, 98, 7 4004-9.
Woodcock BE, Anderson LM, Lilleyman JS (1984) Age, sex and late relapse in childhood lymphoblastic leukemia. Scand J Haematol 33, 3, :323-5.
Yeazel, M. W., Buckley, J. D., Woods, W. G., Ruccione, K. and Robison, L. L. (1995) History of maternal fetal loss and increased risk of childhood acute leukemia at an early age. A report from the Childrens Cancer Group Cancer, 75, 7 1718-1727.
Yohn, D. S. (1973) Sex-related resistance in hamsters to adenovirus oncogenesis Prog Exp Tumor Res, 18, 138-65.
Yohn, D. S., Funk, C. A., Kalnins, V. I. and Grace, J. T., Jr. (1965) Sex-related resistance in hamsters to adenovirus-12 oncogenesis. I. Influence of thymectomy at three weeks of age J Natl Cancer Inst, 35, 4 617-24.
Yohn, D. S., Funk, C. A. and Grace, J. T., Jr. (1967) Sex-related resistance in hamsters to adenovirus-12 oncogenesis. II. Influence of virus dose J Virol, 1, 6 1186-92.
Yohn, D. S., Funk, C. A. and Grace, J. T., Jr. (1968) Sex-related resistance in hamsters to adenovirus-12 oncogenesis. III. Influence of immunologic impairment by thymectomy or cortisone J Immunol, 100, 4 771-80.
Yohn, D. S. and Funk, C. A. (1969) Sex-related resistance in hamsters to adenovirus-12 oncogenesis. IV. Gonadal hormone influences J Natl Cancer Inst, 43, 1 133-9.
Childhood Cancer Epidemiology Genetic Epidemiology
Gender and the Genome (discontinued) Gender Medicine (discontinued)
Link for bookmarking: http://www.dorak.info/epi/gender.html
Mehmet Tevfik DORAK, MD, PhD
Last edited on 21 Oct 2021
HLA MHC Genetics Genetic Epidemiology Evolution Biostatistics Homepage