Cutaneous nevi and internal cancer risk: Results from two large prospective cohorts of US women

Abstract

Elevated cutaneous nevus number has been linked to longer telomeres. Recently, a large systematic Mendelian randomization study identified a significant positive association between telomere length and risk of cancer. Here, we hypothesized that higher nevus count, as a phenotypic marker of longer telomere, may be associated with increased risk of internal cancer, and prospectively examined the association between nevus count and total as well as site-specific cancer risk among participants in the Nurses' Health Study (NHS, 1986(NHS, -2012 and the Nurses' Health Study 2 (NHS2, 1989-2013) using Cox proportional hazards models. During 3,900,264 person-years of follow-up, we documented a total of 23,004 internal cancer cases (15,484 in the NHS and 7,520 in the NHS2). Compared to participants who had no nevi, the multivariate hazard ratios of total cancer (excluding skin cancer) were 1.06 (95% confidence interval [CI], 1.03-1.09) for women with 1-5 nevi, 1.08 (95% CI, 1.03-1.15) for those who had 6-14 nevi and 1.19 (95% CI, 1.05-1.35) for those with 15 or more nevi (p trend <0.0001). Moreover, because nevus count has been associated with risk of breast cancer previously, we conducted a secondary analysis by excluding breast cancer from the outcomes of interest. The results were very similar to those of our primary analysis. For individual cancer, most of the associations with nevus count were positive but not statistically significant. In conclusion, we identified the number of cutaneous nevi as a phenotypic marker associated with internal cancer risk, which may be explained by telomere biology.Additional Supporting Information may be found in the online version of this article.

Genetically determined cutaneous nevi and risk of cancer

“…We also found no consistent associations with internal cancers at specific sites, except for a modest association with cancers of the head and neck, but only in the UK Biobank cohort. As such, our findings do not support earlier observational studies reporting positive associations between higher nevus counts and internal cancers 9‐12 . Our null findings suggest that the positive associations in the observational studies might be due to chance or other noncausal explanations such as bias or confounding.…”

“…As such, our findings do not support earlier observational studies reporting positive associations between higher nevus counts and internal cancers. [9][10][11][12] Our null findings suggest that the positive associations in the observational studies might be due to chance or other noncausal explanations such as bias or confounding.…”

“…11 A recent analysis in the Nurses' Health Study I and II cohorts found a modest but significant association with internal cancer overall (HR for 15 or more nevi compared to none = 1.19; 95% CI: 1.05-1.35). 12 Positive but nonsignificant associations were observed between nevus count and several types of cancer although there was heterogeneity in both the size and direction of effect across cohorts. Several mechanisms have been proposed to explain these observations, including common mutations in the mitogen-activated protein kinase (MAPK) signaling pathway or in Cyclin Dependent Kinase Inhibitor 2A (CDKN2A), and shared pathways that lead to telomere length maintenance (and increased cell proliferative potential) 13 ; however, these mechanisms remain speculative.…”

“…Several large cohort studies have reported positive associations between higher nevus counts and internal cancers including breast 9,10 and thyroid 11 . A recent analysis in the Nurses' Health Study I and II cohorts found a modest but significant association with internal cancer overall (HR for 15 or more nevi compared to none = 1.19; 95% CI: 1.05‐1.35) 12 . Positive but nonsignificant associations were observed between nevus count and several types of cancer although there was heterogeneity in both the size and direction of effect across cohorts.…”