Neurofibromatosis type 1 linked to increased risk of skin cancer

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The risks of 4 types of skin cancers among patients with neurofibromatosis type 1, a multisystem autosomal dominant genetic syndrome characterized by loss of neurofibromin, were investigated.

The risks of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), keratinocyte carcinoma, and melanoma were found to be higher among a group of 4,122 patients who had neurofibromatosis type 1 (NF1), based on findings from a new study in JAMA Dermatology.

Patients who have NF1 do not have neurofibromin, a tumor suppressor gene, and because of this, they can develop benign tumors of the skin, eyes, and nervous system and are at increased risk of cancer of the nervous system or other solid organs, they wrote. the study investigators.

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

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

NF1 patients had increased odds of BCC, SCC, and melanoma compared to the non-NF1 group. For BCC, the risk was 30% higher (odds ratio [OR], 1.30; 95% CI, 1.10-1.53; P = .02); for keratinocyte carcinoma, 31% higher (OR, 1.31; 95% CI, 1.15-1.51; P < .001); for SCC, 32% higher (OR, 1.30; 95% CI, 1.07-1.63; P = .008); and for melanoma, 127% higher (OR, 2.27; 95% CI, 1.75-2.93; P < .001).

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

A subanalysis comparing melanoma and keratinocyte carcinoma rates between white and Asian, black, or Hispanic patients found higher overall risks of both cancers among those with NF1, but there was a notable difference in those risks between the ethnicities studied.

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

In addition, NF1 suppression has been linked to RAS activation in melanogenesis and SCC pathogenesis, while RAS/MAPK activation has been associated with drug resistance in certain BCC subtypes, they noted.

“These results highlight the role of germline RAS pathway hyperactivation in skin carcinogenesis. It is unknown whether photoprotection mitigates the development of skin cancer in patients with NF1”, they concluded. “However, quantifying skin cancer risk may empower clinicians to educate NF1 patients and guide dermatologic 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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