Cancer in Neurofibromatosis Type 1

Predispositions to malignant and benign tumors are hallmarks of neurofibromatosis type I, particularly malignant peripheral nerve sheath tumor (corresponding to a 10% lifetime risk, often with very aggressive biology) and optic pathway glioma (OPG, frequently identified as an incidental asymptomatic finding on brain scans of people with NF1). Commonly, NF1-associated OPG requires surveillance only, but where active treatment is needed, NF1-specific management includes the avoidance of radiotherapy where possible, due to the high risk of second tumors within the radiation field. Less dramatic increases in the incidence of more common tumors in the general population are also observed. The increased breast cancer risk of younger women with NF1 warrants additional screening compared to that offered to females in the general population. Recognized genotype–phenotype correlations in NF1-associated malignancy are relatively few, but individuals with type I whole gene deletion appear at greater risk, and the co-deletion of SUZ12 is implicated. A higher risk of tumors has also been observed in patients with NF1 due to missense substitutions of codons 844–848, in line with their overall more severe phenotype. Conversely, malignancy risk for NF1 variants associated with “café-au-lait only” or other milder phenotypes appears lower, though this is not yet definitively established.