Neurofibromatosis Type 1 Linked to Greater Skin Cancer Risk

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Basal cell carcinoma (BCC), squamous cell carcinoma (SCC), keratinocyte carcinoma, and melanoma risks were found to be higher among a group of 4122 patients who had neurofibromatosis type 1 (NF1), according to new study findings in JAMA Dermatology.

Patients who have NF1 do not have neurofibromin, a tumor suppressor gene, and because of this, they can develop benign skin, eye, and nervous system tumors and have a higher risk of nervous system or other solid organ cancers, the study investigators wrote.

“Although patients with NF1 often present to dermatologists for skin concerns, their risk of BCC, SCC, and melanoma remains unclear,” the investigators 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 that took place between January 1, 2009, and March 31, 2021. The mean (SD) patient age was 47 (18) years, and 55.5% of study participants were women; each patient with NF1 was matched to up to 10 patients (n = 41,064) who did not have the genetic syndrome. A NF1 diagnosis was shown by International Classification of Diseases, Ninth Revision or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis codes.

Patients with NF1 had higher odds of BCC, SCC, and melanoma compared with 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; < .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; < .001).

Ages 18 to 34 years were the most common, at 30.9% in the NF1 group and 31.1% in the non-NF1 group, followed by patients aged 55 to 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 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 that compared rates of melanoma and keratinocyte carcinoma between White patients and Asian, Black, or Hispanic patients found overall higher risks of both cancers among those with NF1, but there were notable difference in those risks among the ethnicities studied.

Whereas White patients had a 116% greater risk of melanoma, Asian patients had a 150% greater risk, Hispanic patients had a 193% greater risk, and Black patients, a 344% greater 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, 102% higher.

“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, suppressing NF1 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. Whether photoprotection mitigates skin cancer development in patients with NF1 is unknown,” they concluded. “Nevertheless, quantifying skin cancer risk may empower physicians to educate patients with NF1 and guide dermatologic management.”

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