Melanocytic Nevi as Biomarkers of Breast Cancer Risk

In this week’s issue of PLOS Medicine, Jiali Han and colleagues [1] and Marina Kvaskoff and colleagues [2] describe prospective studies of melanocytic nevi and breast cancer risk among middle-aged women. Melanocytic nevi, commonly known as moles, are a heterogeneous group of benign tumors of the skin, which are commonly acquired in childhood and adolescence and which may disappear with increasing age [3]. Nevi are a common phenotypic trait and a recognized risk factor for malignant melanoma [4], but have not, to our knowledge, been investigated previously as a risk factor for breast cancer. In these separate, large cohort studies, investigators have observed, unexpectedly, small but significant increases in breast cancer risk across categories reflecting greater numbers of melanocytic nevi. The analysis conducted by Han and colleagues [1] draws its participants from the Nurses’ Health Study (NHS) cohort, comprising 74,523 white women in the United States who were aged 40–65 y in 1986 when they responded to a selfadministered questionnaire that asked each respondent to count and report the number of nevi of diameter $3 mm on her left arm, inspected from shoulder to wrist. Participants were followed through 2010, accruing more than 1.5 million person-years, and in that time 5,483 cases of invasive breast cancer were ascertained. Following adjustment for known breast cancer risk factors, participants reporting the most nevi (15+) were 35% more likely to be diagnosed with breast cancer than their counterparts who reported no nevi (p for trend = 0.003). The analysis conducted by Kvaskoff and colleagues [2] was carried out using data from the E3N Teachers’ Study Cohort, and included 89,902 women in France who were aged 39–66 when they enrolled in the study between 1989–1991. At baseline, participants were asked to report on their number of moles using qualitative categories as follows: ‘‘none,’’ ‘‘a few,’’ ‘‘many,’’ or ‘‘very many.’’ The cohort was followed through 2008; a total of 5,956 incident breast cancer cases were ascertained over nearly 1.4 million personyears. In age-adjusted models, women reporting the most nevi were observed to have 13% higher breast cancer risk than their counterparts without nevi (p for trend = 0.04). This association was attenuated and the trend no longer significant when investigators adjusted for benign breast disease or family history of breast cancer. A non-statistically significant increase in breast cancer risk of 8% was observed after adjusting for established breast cancer risk factors and measures of ultraviolet radiation exposure. While their findings are broadly consistent, subgroup findings in the two studies were different. Kvaskoff and colleagues found no significant association in postmenopausal women, but observed that, among premenopausal women, those who had reported ‘‘very many’’ nevi were 34% more likely to be diagnosed with breast cancer compared to counterparts who reported ‘‘none’’ even after adjustment for all potential confounders (p for trend = 0.03, p for heterogeneity = 0.04). In contrast, Han and colleagues found no significant modification of the risk association by menopausal status. The association between nevi and breast cancer risk is unlikely to be causal. Both melanocytic nevi and melanoma are derived from melanin-producing cells in dermal or epidermal tissues [5]; in contrast, most breast cancers are thought to arise from epithelial cells of ductal or lobular origin [6]. Given their distinct origins and locations, nevi are unlikely to act as intermediates or causal agents in the pathway to breast cancer; it seems likely instead that the observed associations reflect a shared cause or causes.