Neurofibromatosis type 1 linked to increased risk of skin cancer

The risks of 4 types of skin cancers have been studied in patients with neurofibromatosis type 1, an autosomal dominant multisystem genetic syndrome characterized by a loss of neurofibromin.

Risks of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), keratinocytic carcinoma and melanoma were found to be higher in a group of 4,122 patients with neurofibromatosis type 1 (NF1), according to new study findings in JAMA Dermatology.

Patients with NF1 lack neurofibromin, a tumor suppressor gene, and because of this they may develop benign tumors of the skin, eyes, and nervous system and have a higher risk of cancer of the system. nerves or other solid organs, the study researchers wrote.

“Although patients with NF1 often consult dermatologists for skin problems, their risk for CBC, SCC, and melanoma remains unclear,” the researchers wrote. “Biallelic loss of NF1 (OMIM 613113) leads to hyperactivation of RAS signaling pathways.

The Clinformatics Data Mart provided data for this retrospective cohort study which took place between January 1, 2009 and March 31, 2021. The mean (SD) age of the patients was 47 (18) years and 55.5% of study participants were women; each patient with NF1 was matched to a maximum of 10 patients (n=41,064) who did not have the genetic syndrome. A diagnosis of NF1 was demonstrated by International Classification of Diseases, Ninth Revision Where International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnostic codes.

Patients with NF1 had a higher risk of BCC, SCC and melanoma compared to the non-NF1 group. For CBC, the risk was 30% higher (odds ratio [OR], 1.30; 95% CI, 1.10-1.53; P = 0.02); for keratinocyte carcinoma, 31% higher (OR, 1.31; 95% CI, 1.15-1.51; P P = 0.008); and for melanoma, 127% higher (OR, 2.27; 95% CI, 1.75-2.93; P

Ages 18-34 were the most common, at 30.9% in the NF1 group and 31.1% in the non-NF1 group, followed by patients aged 55-64 (16.9%) and 45 to 54 (15.9%) years and 35 to 44 (16.9%) and 45 to 54 years (15.7%), respectively. Asian, black, and Hispanic patients outnumbered white patients in each group, at 25% versus 75% in the NF1 group and 24.7% versus 75.2% in the non-NF1 group.

A subanalysis that compared rates of melanoma and keratinocytic carcinoma between white patients and Asian, Black, or Hispanic patients found overall higher risks of both cancers in those with NF1, but there was a notable difference in these risks between the ethnic groups studied.

While white patients had a 116% higher risk of melanoma, Asian patients had a 150% higher risk, Hispanic patients had a 193% higher risk, and black patients had a 344% higher risk. And while white and Asian patients had comparable increased risks of keratinocyte carcinoma, at 25% each, Hispanic patients had a 103% higher risk and black patients had a 102% higher risk.

“Whole exome sequencing has established NF1 as the third most frequently mutated gene in melanomas,” the researchers noted. “About 12% to 18% of melanomas and 45% to 93% of desmoplastic melanomas harbor NF1 alterations.

Moreover, NF1 deletion has been linked to RAS activation in CSC melanogenesis and pathogenesis, while RAS/MAPK activation has been associated with drug resistance in some BCC subtypes, they noted.

“These results highlight the role of RAS germline pathway hyperactivation in skin carcinogenesis. It is unknown whether photoprotection attenuates the development of skin cancer in patients with NF1,” they concluded. “Nevertheless, quantifying skin cancer risk may allow physicians to educate patients with NF1 and guide dermatological management.”


Trinh P, Li S, Sarin K. Neurofibromatosis type 1 and skin cancer risk. JAMA Dermatol. 2022;158(10):1214-1216. doi:10.1001/jamadermatol.2022.3083

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