Dear Editor, the number of melanocytic nevi is one of the strongest risk factors for melanoma,1 yet the reasons for the interpersonal variability in their number are largely unknown. Both nevi and melanoma show somatic mutations in the RAS pathway components, most commonly in BRAF.2 Germline mutations in these same genes cause a group of developmental syndromes termed RASopathies,3 some of which characteristically display melanocytic nevi.4 However, the effects of germline RAS pathway mutations on the number of nevi are poorly understood.
To determine how the number of melanocytic nevi is influenced by the RAS pathway, we analyzed the numbers of nevi in Cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (CS). CFC is caused by mutations in the downstream elements of the RAS pathway, including BRAF, MAP2K1, and MAP2K2, or rarely KRAS,5, 6 while CS results from mutations in an upstream core component of the pathway, HRAS (Figure 1).7
Figure 1.
The RAS pathway showing genes mutated in CFC and CS patients in this study.
The Institutional Review Board at University of California Davis approved the study. After informed consent, 16 individuals with CFC and 24 with CS were enrolled8. Photography of nevi was performed (Canfield Scientific). The photographs were examined for the number of nevi by two authors independently and without knowledge of the mutation status. Fitzpatrick skin phototype was determined based on the photographs and a questionnaire regarding tendency to burn and tan. A two sample t-test and linear regression models were used.
The mean age for individuals with CFC was 15.1 years (range 6–35 years) and with CS 14.5 years (range 6–31 years)8. The majority of individuals with CFC reported a BRAF mutation (BRAF in 13/16 or 81.3%, MAP2K1 in 1/16 or 6.3%, MAP2K2 in 1/16 or 6.3%, unknown 2/16 or 12.5%) and individuals with CS an HRAS mutation (p.G12S in 16/25 or 64.0%, p.G12C in 2/25 or 8.0%, and p.G12A, p.G13C, p.G13D, p.A146V, and p.K117R in in 1/25 or 4.0% each, unknown 2/25 or 6.3%)8.
A marked difference was noted in the number of nevi in CFC versus CS (Figure 2, Table 1). The average number of nevi on the back was 47.8 in CFC (SEM 14.0) and 8.1 in CS (SEM 1.8, p=0.002). The number of nevi in CS corresponds to published population-based data of 8.4 nevi on average on the back of children and adolescents in the United States.9 The average number of nevi on the face was also increased in CFC (24.3 in CFC, SEM 7.3, vs 4.0 in CS, SEM 0.8, p=0.001). The number of nevi was higher for patients with older age (beta estimate = 1.8, 95% I 0.3 – 3.3, p = 0.02). Moreover, the number of nevi was significantly higher for phototypes I-III in CFC compared to CS but not for phototypes IV-VI (p = 0.01). There were no significant differences in painful sunburns (p=1.0), sun bathing habits (p=1.0), or hours spent outdoors between CFC and CS patients (p=0.48).
Figure 2.
Increase in the number of nevi in an individual with CFC (upper) compared with an individual with CS (lower). Both individuals are females between ages 22–23.
Table 1.
Number of nevi in CFC and CS.
| CFC | SEM or range | CS | SEM or range | |
|---|---|---|---|---|
| Age | 15.1 | 6–35 | 14.5 | 6–31 |
| Number of nevi on back | 47.8 | 14 | 8.1 | 1.8 |
| Phototype I | 6.0 | n/a1 | n/a | n/a |
| Phototype II | 77.0 | 17.3 | 2.4 | 0.4 |
| Phototype III | 53.7 | 31.5 | 9.2 | 2.6 |
| Phototype IV | 16.0 | 5.0 | 10.3 | 3.7 |
| Phototype V | 15.0 | n/a1 | 35.0 | n/a1 |
| Phototype VI | 4.0 | n/a | 9.0 | n/a |
| Number of nevi on face | 24.3 | 7.3 | 4.0 | 0.8 |
one individual only, therefore SEM not applicable
BRAF p.V600E is a well-known somatic driver of nevogenesis. This study expands our knowledge on germline regulators of nevus count, by suggesting that germline mutations in BRAF, MAP2K1 and MAP2K2, but not the upstream core component of the RAS pathway HRAS, predispose to and influence the number of nevi. Moreover, increased numbers of nevi especially in individuals with phototype I-III in CFC suggest that UV radiation may enhance the effects of the germline mutations in the downstream components of the RAS pathway on nevogenesis. The results increase our knowledge on the genetic background and development of nevi, the potential precursors of melanoma. While future studies are warranted to determine whether the risk of melanoma is increased in CFC, protection from UV radiation and regular skin exams are appropriate for individuals with CFC.
Acknowledgements
We are grateful for patients and families for participating in this study and Negar Foolad and Jed Smith for assistance with the study.
Funding sources: Dermatology Foundation, through Career Development Award in Dermatopathology (MK); National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health through grant #K23AR074530 (MK) and grant #R01AR062165 (KAR)
Abbreviations used
- SEM
standard error of mean
Footnotes
Conflicts of interest: None declared.
IRB approval status: Reviewed and approved by UC Davis IRB; approval #960347
Clinicaltrials.gov (or equivalent) listing (if applicable): Not applicable.
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