Abstract
Genetic susceptibility to nevi may affect the risk of developing melanoma, since common and atypical nevi are the main host risk factors implicated in the development of cutaneous melanoma. Recent genome-wide studies defined a melanoma polygenic risk score based on variants in genes involved in different pathways, including nevogenesis. Moreover, a predisposition to nevi is a hereditary trait that may account for melanoma clustering in some families characterized by cases with a high nevi density. On the other hand, familial melanoma aggregation may be due to a Mendelian inheritance of high/moderate-penetrance pathogenic variants affecting melanoma risk, regardless of the nevus count. Based on current knowledge, this review analyzes the complex interplay between nevi and melanoma predisposition in a familial context. We review familial melanoma, starting from Whiteman’s divergent pathway model to overall melanoma development, distinguishing between nevi-related (cases with a high nevus count and a high polygenic risk score) and nevi-resistant (high/moderate-penetrance variant-carrier cases) familial melanoma. This distinction could better direct future research on genetic factors useful to identify high-risk subjects.
Highlights
The incidence of melanoma has more than tripled worldwide in the last few decades, with an estimated number of new cases in 2020 of about 325,000 per year [1]
In the familial atypical multiple mole melanoma (FAMMM) syndrome, which is characterized by the presence of multiple atypical and common nevi, both CDKN2A pathogenic variants and the nevus count affect the risk of melanoma in a synergistic manner
The association between UV-radiation exposure and melanocytic nevi represents the major player in this setting
Summary
The incidence of melanoma has more than tripled worldwide in the last few decades, with an estimated number of new cases in 2020 of about 325,000 per year [1]. An interesting hypothesis of “two divergent pathways” was proposed by Whiteman to try to explain the joint effects of host and environmental factors on melanoma development [8] One of this model’s pathways considers host factors (e.g., the number and type of nevi, and skin phenotype), the main drivers of the malignant transformation of a melanocyte in individuals with a nevi predisposition, through an initial stimulus of UV radiation. Beyond environmental and phenotypic factors, it is estimated that about 5–15% of affected cases have a positive family history for this malignancy [11,12] This evidence suggests that a genetic predisposition may deeply contribute to the development and progression of the disease [13], especially due to the presence of germline mutations in candidate genes at high, moderate, and low penetrance [14]. The dominant genetic traits that predispose to FAMMM syndrome are characterized by germline mutations in melanoma risk loci that are not associated with the nevus count [35]
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