Ten percent of children with retinoblastoma inherit a RB1 gene mutation from a parent. In this circumstance, the condition is referred to as familial retinoblastoma. Every cell in the body of these children contains a RB1 gene mutation, the “first hit.” [6] The mutation to the other copy of the RB1 gene, the “second hit,” occurs in a retinal cell sometime after conception. The inherited gene mutation is highly penetrant and nearly all, about 95 %, of such children develop retinoblastoma.

Another 30 % of children with retinoblastoma also harbor a RB1 mutation in all of their cells and are at the same risk for developing retinoblastoma as children who inherit a mutation. However, these children do not have a parent with the mutation. Rather, their RB1 mutation occurred as a new germ line mutation. Although these children did not inherit the gene from an affected parent, they will be able to pass the mutation onto their children. This is called sporadic heritable retinoblastoma.

The remaining 60 % of retinoblastoma patients have nonheritable disease. Their retinoblastoma develops as the result of two somatic RB1 mutations that occur in a single cell sometime after conception.

Variation in incidence among countries, regions, and ethnic groups or over time can provide clues to etiology. Environmental (defined here as nongenetic) factors are implicated in cancers that show great variation in incidence.

The rates of retinoblastoma vary about 50-fold across the continents [9], a degree of variability higher than that for several adult cancers, namely, stomach, colon, cervical and pancreatic cancer, and lower than that for lung and esophageal cancer, among others. Incidence in North America and in much of Europe is relatively uniform, somewhat higher in Central and South America, and varies more widely in Asia and Africa [9]. Overall, the rates are higher in less industrialized countries than in more industrialized countries. In addition, there are enormous variations within some countries. The data suggest variation by economic development, with higher rates in poorer regions of countries such as Brazil and Mexico [10]. Clearly the differences in the incidence rates of retinoblastoma between regions of higher and lower incidences may be due to other factors such as ethnic origin, genetic susceptibilities, and cultural and behavioral practices. A closer examination of the differences in incidence may identify specific risk factors for development of retinoblastoma.

Males and females in most countries of the world have similar incidence rates (Figs. 4.7 and 4.8). Interestingly, in almost every Central and South American country, girls have an elevated incidence when compared to their male counterparts [9].

To summarize the extent of variation, it is useful to consider the areas with the highest incidence worldwide [9]. The highest incidence of retinoblastoma is noted in Mali (Bamako), followed by (in descending order) Uganda (Kampala), Zimbabwe (African ancestry), Hawaii (native Hawaiians), India (Madras), Vietnam (Hanoi), the Chinese population of Singapore, New Zealand (essentially equal rates among non-Maoris and Maoris), Spain (Valencia), the Philippines, Colombia (Cali), Ecuador (Quito), Nigeria (Ibadan), Costa Rica, Peru (Lima), Norway, Brazil (Belem), and Denmark (Table 4.1). All of these populations have annual incidences above 15 cases per million children ages 0–4 years. Some global differences are particularly intriguing or paradoxical, given expected similarities in ethnicity and presumed shared environmental exposures: for example, Australia and New Zealand have very different rates which cannot be explained by ethnic differences (Fig. 4.6); one province in Spain has rates much higher than the rest of Europe, higher even than Spain’s former colonies (i.e., the Philippines, Latin America), many of whom also have high rates; some Scandinavian countries (but not Sweden) have rates equivalent to those of Northern Brazil (where a large proportion of the population is of African not European ancestry); and the Chinese in Singapore have a much higher rate than Malays in Singapore or Chinese in China or Hong Kong. There is no clear pattern, but there is a suggestion that environmental factors may play a role, though genetic susceptibility to particular environmental and behavioral risk factors may explain some of the differences.

Sporadic heritable retinoblastoma results from a new germ line mutation that is of paternal origin in over 90 % of patients [12, 13]. By virtue of being a new germ line mutation, the mutation occurs before the child’s conception. Based on these two facts, it seems logical that the search for genetic and nongenetic risk factors for sporadic heritable retinoblastoma should focus on the father’s genes and his exposures before the child’s conception [14]. However, associations with mother’s exposures have been observed as well. Although these associations may turn out not to be real, our understanding of retinoblastoma genetics and etiology is still evolving and we should not dismiss the possibility of effects of maternal exposure. It would be reasonable to hypothesize preconception exposure to mutagens, variants of metabolizing genes that prolong the duration or increase the level of a mutagen in the body and variants of DNA repair genes that result in less efficient repair of DNA damage as possible risk factors.