Cancer incidence and the risk for multiple primary cancers in neurofibromatosis type 1.

Neurofibromatosis 1 (NF1) is a cancer predisposition syndrome caused by pathogenic variants of the NF1 gene. Here, we analyze the incidence and risk of cancer and especially the risk of multiple primary cancers in individuals with NF1. The previously established Finnish NF1 cohort was extended to include 1,811 individuals with verified NF1 and followed up using the nationwide Finnish Cancer Registry for 30,612 person-years over 1987-2020. Standardized incidence ratios (SIRs) were used to analyze cancer incidence. A total of 296 first primary cancers occurred in individuals with NF1 during the follow-up, yielding an SIR of 4.92 (95% CI 4.38-5.52). The SIR was 4.30 (95% CI 3.27-5.54) for second primary cancers with 59 cancers observed. Therefore, the history of first primary cancer did not, in general, indicate altered risk for second primary cancer among individuals with NF1 (P=0.377). Overall, NF1 was associated with a steadily increasing cumulative risk for cancer throughout the lifetime. Women with NF1 had a 20.9% (95% CI 15.9-27.4%) lifetime risk for breast cancer with significantly increased incidence at ages <50 and ≥50 years (SIRs 4.90, 95% CI 2.99-7.56 and 2.67, 95% CI 1.76-3.89, respectively). The history of a prior cancer does not predict the overall future risk for cancer in NF1. Nevertheless, the estimates are consistent with some subpopulations having an increased risk for multiple cancers. Regarding breast cancer predisposition, the results confirm NF1 as a moderate-risk gene linked to increased incidence across all ages, i.e., not only in young women.