The value of small observations in the era of big science.

We are now unequivocally in the era of big science. Genotyping costs have become so trivial and genetic variation is so important that it is almost heresy to consider launching an epidemiologic investigation without collecting germ line DNA to evaluate the contributions of genetic diversity to the pathogenesis of disease. As genetics steps into the spotlight of epidemiology, studies are bursting in size (and cost) to evaluate interactions of genes and the environment and to precisely measure the magnitude of small associations. Technology has given us epidemiology on steroids. This big science approach has evolved as a consistent research strategy even for cancers where the environmental contributions are unequivocal and dominant. Smoking causes lung cancer, human papillomavirus causes cervical cancer, and excessive UV exposure causes melanoma, but, of course, the story is a bit more complicated. There is no question that we need to learn more about the causal pathways exploited by these carcinogens and how they can be modified even when epidemiology has successfully elucidated the main causes of disease. The real question is, is there still room for small science? An example of the kind of insight that can be gained from small science is published in a recent issue of Cancer Epidemiology Biomarkers and Prevention . The study of MC1R variants and the risk of melanoma by Goldstein et al. (1) examined 16 families with melanoma that carry mutations of CDKN2A . In this study, we learn that the presence of multiple MC1R variants is associated with the risk of melanoma and that these variants contribute to the clinical presentation of patients with multiple primary melanoma. Some might argue that a study of 395 individuals is not small, but perhaps what best captures the idea of small science is the reliance on an extremely well-characterized phenotype and thoughtful comparisons that yield insight. In the Goldstein study, clinical and epidemiologic data collected over 26 years provide a unique resource to measure the genetic and environmental contributions to multiple primary melanoma, specifically in melanomaprone families who carry a mutation in CDKN2A. This study is a wafer-thin slice of a very big pie. Yet, it is precisely the care in choosing the thin slice that can provide generalizable insight. Numerous studies have shown a relationship between MC1R and the risk of melanoma (2-4) and two studies have shown that the presence of an MC1R variant increases the penetrance of CDKN2A mutation carriers (5, 6). Other studies have shown that carrying multiple variants is associated with more risk than a single variant (7). Here, as in prior studies, the relative risk for MC1R was stronger for those variants designated as red hair color compared with non–red hair color variants, and the risk seemed cumulative with additional variants. In addition, by focusing on a comparison of multiple primary versus single primary melanoma, the authors showed that MC1R is a risk factor for multiple primary melanoma and that cumulative mutations are associated with decreasing age at diagnosis, beyond the effects of a major gene like CDKN2A . This approach is another good example of how studies that concentrate on comparisons of multiple primary and single primary cancers can provide an informed perspective on risk factors from a different vantage point (8).