M. Tevfik Dorak

Gender differences in cancer susceptibility: an inadequately addressed issue.

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.

Genetic markers in a multi-ethnic sample for childhood acute lymphoblastic leukemia risk.

Abstract Genome-wide association studies have identified multiple risk loci for childhood acute lymphoblastic leukemia (ALL), but mostly in European/White populations, despite Hispanics having a greater risk. We re-examined single nucleotide polymorphisms (SNPs) of known associations with childhood ALL and known human leukocyte antigen (HLA) region lymphoma risk markers in a multi-ethnic population. Significant associations were found in two ARID5B variants (rs7089424 and rs10821936). We replicated a strong risk association in non-Hispanic White males with rs2395185, a protective marker for lymphoma. Another HLA region marker, rs2647012, showed a risk association among Hispanics only, while a strong protective association was found with rs1048456, a follicular lymphoma risk marker. Our study validated this new case–control sample by confirming genetic markers associated with childhood ALL, and yielded new associations with lymphoma markers. Despite positive results, our study did not provide any clues as to why Hispanics have a higher susceptibility to childhood leukemia, suggesting that environmental factors may have a strong contribution.

Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes

Hereditary hemochromatosis (HFE) variants correlating with body iron levels have shown associations with cancer risk, including childhood acute lymphoblastic leukemia (ALL). Using a multi-ethnic sample of cases and controls from Houston, TX, we examined two HFE variants (rs1800562 and rs1799945), one transferrin receptor gene (TFRC) variant (rs3817672) and three additional iron regulatory gene (IRG) variants (SLC11A2 rs422982; TMPRSS6 rs855791 and rs733655) for their associations with childhood ALL. Being positive for either of the HFE variants yielded a modestly elevated odds ratio (OR) for childhood ALL risk in males (1.40, 95% CI=0.83-2.35), which increased to 2.96 (95% CI=1.29-6.80) in the presence of a particular TFRC genotype for rs3817672 (P interaction=0.04). The TFRC genotype also showed an ethnicity-specific association, with increased risk observed in non-Hispanic Whites (OR=2.54, 95% CI=1.05-6.12; P interaction with ethnicity=0.02). The three additional IRG SNPs all showed individual risk associations with childhood ALL in males (OR=1.52-2.60). A polygenic model based on the number of variant alleles in five IRG SNPs revealed a linear increase in risk among males with the increasing number of variants possessed (OR=2.0 per incremental change, 95% CI=1.29-3.12; P=0.002). Our results replicated previous HFE risk associations with childhood ALL in a US population and demonstrated novel associations for IRG SNPs, thereby strengthening the hypothesis that iron excess mediated by genetic variants contributes to childhood ALL risk.

Examination of genetic polymorphisms in newborns for signatures of sex-specific prenatal selection

Success rate in human pregnancies is believed to be very low and sex-specific mechanisms may operate in prenatal loss. Assuming a sex-differential in prenatal loss exists, we examined genetic markers in biologically plausible targets in the HLA complex, other immune system-related and iron-regulatory genes in 388 healthy newborns from Wales (UK) using one sex as a control group for the other. Genotyping of 333 single nucleotide polymorphisms (SNPs) from 107 genes was achieved mainly by TaqMan assays. Twenty-two of autosomal SNPs showed frequency differences between 187 male and 201 female newborns either individually or as part of a haplotype. Of these, six markers (RXRB rs2076310, HLA complex haplotype HLA-DQA1 rs1142316-HLA-DRA rs7192-HSPA1B rs1061581, HIST1H1T rs198844, IFNG rs2069727, NKG2D rs10772266 and IRF4 heterozygosity) showed statistically robust differences between male and female newborns and multivariable modeling confirmed their independence. There were fewer males homozygote for combined wildtype genotypes of LIF rs929271, TP53 rs1042522 and MDM2 rs2279744 compared with females [OR = 0.3, 95% confidence interval (CI) = 0.1-0.8; P < 0.01] although these SNPs did not show any association individually. It is unlikely that SNPs have clinical utility as single markers in any trait with complex etiology but polygenic predictive models remain a possibility. If their validity is confirmed in larger studies of different populations and functional mechanisms of these preliminary associations are elucidated, these markers from the HLA complex, NKG2D region and cytokines may cumulatively have sufficient predictive value for susceptibility to prenatal selection in each sex.

Evaluating the Role of Birth Weight and Gestational Age on Acute Lymphoblastic Leukemia Risk Among Those of Hispanic Ethnicity.

High birth weight is an established risk factor for childhood acute lymphoblastic leukemia (ALL), especially in children younger than 5 years of age at diagnosis. The goal of this study was to explore the association between being born large for gestational age and the risk for ALL by race/ethnicity to determine if the role of this risk factor differed by these characteristics. The authors compared birth certificate data of 575 children diagnosed with ALL who were younger than 5 years and included in the Texas Cancer Registry, Texas Department of Health, between the years 1995 and 2003 with 11,379 controls matched by birth year. Stratified odds ratios were calculated for risk of ALL by birth weight for gestational age, categorized in 3 groups, small, appropriate, and large for gestational age (SGA, AGA, and LGA, respectively), for each race/ethnicity group. The risk of developing ALL was higher among Hispanics who were LGA (odds ratio [OR] = 1.90, 95% confidence interval [CI]: 1.34–2.68) compared with LGA non-Hispanic whites (OR = 1.27, 95% CI: 0.87–1.86) after adjusting for infant gender, year of birth, maternal age, birth order, and presence of Down syndrome. However, the difference was not statistically significant. These results suggest that there may be differences in the association between higher growth in utero and risk of childhood ALL among Hispanics versus non-Hispanic whites.

Environmental, maternal, and reproductive risk factors for childhood acute lymphoblastic leukemia in Egypt: a case-control study

BackgroundAcute lymphocytic leukemia (ALL) is the most common pediatric cancer. The exact cause is not known in most cases, but past epidemiological research has suggested a number of potential risk factors. This study evaluated associations between environmental and parental factors and the risk for ALL in Egyptian children to gain insight into risk factors in this developing country. Methods: We conducted a case-control design from May 2009 to February 2012. Cases were recruited from Children’s Cancer Hospital, Egypt (CCHE). Healthy controls were randomly selected from the general population to frequency-match the cumulative group of cases by sex, age groups (<1; 1 – 5; >5 – 10; >10xa0years) and region of residence (Cairo metropolitan region, Nile Delta region (North), and Upper Egypt (South)). Mothers provided answers to an administered questionnaire about their environmental exposures and health history including those of the father. Odds ratios (ORs) and 95xa0% confidence intervals (CI) were calculated using logistic regression with adjustment for covariates.ResultsTwo hundred ninety nine ALL cases and 351 population-based controls frequency-matched for age group, gender and location were recruited. The risk of ALL was increased with the mother’s use of medications for ovulation induction (ORadju2009=u20092.5, 95xa0% CI =1.2 –5.1) and to a lesser extend with her age (ORadju2009=u20091.8, 95xa0% CIu2009=u20091.1 – 2.8, for mothers ≥ 30xa0years old). Delivering the child by Cesarean section, was also associated with increased risk (ORadju2009=u20092.01, 95xa0% CI =1.24–2.81).ConclusionsIn Egypt, the risk for childhood ALL appears to be associated with older maternal age, and certain maternal reproductive factors.

A cautionary note on the reporting of genetic association study results.

We would like to point out a practice that is becoming widespread in reporting of associations. Odd ratios (OR) are commonly converted to percentages presumably for the benefit of the lay audience. Due to the substitution of odds for probabilities and the asymmetrical distribution of protective and risk ORs, this practice leads to misleading reporting. This is particularly troubling in genetic association studies where associations may be reported as a risk association with one allele of a biallelic single nucleotide polymorphism or a protective association with the other allele. These two versions of the same association are identical in magnitude, but the current practice results in reporting different effect sizes in percentages. Here, we suggest that direct conversion of ORs to percentages should be discontinued, and we also remind that there are useful transformations readily available as replacements. Effect size in retrospective case-control association studies is customarily reported as an odds ratio (OR). ORs lie between zero and infinity, with unity indicating no association. For protective associations, the OR is between 0 and 1. Risk associations yield an OR of greater than 1, the upper limit being infinity. Since many people think more easily in terms of probabilities than odds, ORs are often converted into percentage changes in risk, especially in press releases. It is now common practice to state a protective OR of 0.6 as 40% reduction in risk, assuming a rare disease. The reciprocal risk association with the alternative allele yields an OR of 1.67 and this would be reported as a 67% increase in risk. On the other hand, a protective association with an OR of 0.60, and a risk association with an OR of 1.40 would be reported as 40% decrease and increase, respectively, in risk. The impression given is that these two associations in opposite directions are similar in magnitude, but actually they are not. Finally, the notion of fold-change and percentage increase are often intertwined, so OR1⁄4 3.0 is transformed to a 300% increase in risk, but OR1⁄4 2.0 to a 100% increase. In each of these scenarios, conversion of ORs to percentages leads to erroneous reports. This odd situation derives from nature of the case-control study design, the asymmetry of the scales of protective and risk ORs, and the centering around the value 1 for neutrality. To be translated into meaningful percentages, ORs must be transformed so that risk and protective ORs lie within identical and finite scales. Percentage-based metrics are justifiable if the metric has zero value under statistical independence, maximum value unity, and minimum value minus unity independent of the marginal distributions. Such metrics are readily available.1 One of them is the Yule’s Q value, which was originally described as an association coefficient.2 Yule defined Q in terms of the 2 2 contingency table, equating Q with the difference between the number of concordant pairs and discordant pairs expressed as a percentage of the number of untied pairs in the table. In terms of the odds ratio, Q1⁄4 (OR 1)/(ORþ 1), which transforms all ORs to [ 1, þ 1] scale with symmetry around zero. The Q value is recognized as a measure of allelic association in genetics3 but not commonly used in epidemiologic association studies. When this transformation is used as the measure of association as suggested by Yule, OR1⁄4 1.4 represents not 40% increase in risk, but 16.7% departure from the null relationship. Fifty percent departure is conferred by an association with OR1⁄4 3.0.

Iron Excess and Cancer

In the last two decades, strong observational and experimental evidence has been presented for the role of iron excess in cancer development. The hereditary hemochromatosis gene HFE variants that increase body iron levels are associated with increased cancer risk. The first such association was reported by us in childhood acute lymphoblastic leukemia. With the identification of molecular mechanisms of potentiation of carcinogenesis by iron, epidemiologic associations have been gaining more weight. Experimental data also increase the credibility of suggestions that iron excess can both initiate (genotoxic effect) and promote (via its effect on immune function) cancer development. Both environmental and genetic factors may lead to iron excess but the effect is strongest in combination. Iron excess may contribute to cancer development in many different ways, most of which yet unappreciated and most relevant of those possible connections are discussed in this chapter. Since reduction in smoking, alcohol and red meat consumption eliminates excessive exposure to iron, eating fruits and vegetables does not expose the body to too much bioavailable iron and perhaps replaces other iron-rich food stuff and avoidance of excess iron levels reduces infections, iron is indirectly involved in the success of these preventive measures. Perhaps it is time to emphasize lower exposure to environmental iron directly as an important factor to reduce the cancer burden in the industrialized world.

Environment, Genetic Immunology and Childhood Cancer

Childhood cancers make up 1% of the total cancer burden. Despite their rarity, they cause highest disease mortality in childhood. Research on the etiology of childhood cancers has been hampered by small sample sizes, lack of appropriate controls, reliance on case-control studies and difficulties with the definition of environment and measurement of environmental exposures. Only few and small studies have explored gene and environment interactions in childhood cancers. Consistent epidemiologic associations with male sex, birth weight, maternal reproductive history, allergic and autoimmune disorders, and infection frequency in early childhood as well as HLA associations may be exploited to gain further insight into the etiology. Currently available data suggest the involvement of immune surveillance in the development of childhood leukemia. Genetic epidemiologic approach should provide clues for the genetic risk factors when larger national and international cohort studies are completed. These studies should ideally consider the strong sex effect, potential parental effects and environmental factors including prenatal environment.