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To understand the genetic epidemiology of obesity and cancer means to consider the genetics of not only these two complex diseases but also the many risk factors associated with them and the molecular mechanisms likely to contribute to their underlying etiology. It is therefore the purpose of this chapter to highlight the following: genetic mapping studies that have been done to isolate genes related to obesity, genetic studies aimed to identify genes for obesity risk factors, and, finally, a discussion of the genes shared across or among the studies of obesity and/or its risk factors and the various cancers. This is by no means an exhaustive discussion as these are each complex traits with complex molecular mechanisms. It is, however, intended to be an overview of the genes likely to be involved in the cascade of pathways linking obesity and cancer. It is well known that obesity continues to be a leading public health concern not only in the United States but now worldwide. From 1980 to 2002, the prevalence of obesity doubled in adults aged over 20 and overweight prevalence tripled in children and adolescents aged 6–9 years. The estimates of overweight and obesity in 2003–2004 showed that 17.1% of US children and adolescents were overweight and 32.2% of adults were obese [143]. The increasing rates of obesity among children are especially alarming and suggest continuing increases in the rates of obesity-related cancers. Since being overweight in childhood predicts obesity in adulthood [208], obesity occurring in childhood may operate as a ‘cumulative’ exposure that influences cancer risk in later life. Obese children may be subject to potentially long periods of hormonal exposures that operate during adolescence to influence propensity to neoplastic diseases. In females, childhood obesity may also affect the levels of sex hormone at adolescence. A prospective study of 55-year follow-up on 508 adolescents at 13–18 years from Harvard Growth Study showed that overweight adolescent boys had a nine-fold increased risk of colorectal cancer mortality [161]. Associations between adolescent weight and cancer persisted even after adjusting for adult BMI. A 50-year follow-up of >2,000 British children showed an overall 9% increase in cancer incidence per standard deviation increase in BMI, with effects three times larger for smoking-related cancers. There is also evidence from an Israeli case–control study which indicated that being in the upper quartile of BMI at age 18 years was associated with a 42% increase for ovarian cancer [24]. However, the mechanisms underlying the association between childhood obesity and cancer are not well understood, particularly in conjunction with genetic data. In one case–control study of 40 obese and 40 non-obese prepubertal children, the obese group showed higher levels of IGF-1, insulin, and lower sex-binding hormone than that of the non-obese group [182]. This suggests that high levels of growth factors and altered sex hormone profiles are present in obese children and the exposures to an adverse metabolic milieu may begin early in life.