Subtype distribution, clinical presentation, and molecular spectrum of neurofibromatosis type 1-associated breast cancer.

Aim: To investigate clinical and molecular features of neurofibromatosis type 1 (NF1)-associated breast cancer (BC) in a large multicenter cohort. Methods: Clinical and histopathological data from 86 NF1 patients with BC (69 with molecular data) were collected, and 111 published cases were reviewed. NF1 variants were assessed in silico, and their distribution across neurofibromin domains was compared with the general NF1 population. Results: NF1 patients developed BC earlier than the general population (mean 49 years), with missense variant heterozygotes showing the earliest onset (43.9 vs. 49.5 years for truncating variants, p = 0.014). Tumors were frequently high-grade (49 %), HER2-enriched (31 %) or luminal B subtypes (31 %), with reduced luminal A (28 %) frequency. NF1+BC patients had more subcutaneous (p = 0.006) and plexiform neurofibromas (p < 0.00001). Compared with the general NF1 population, they lacked large deletions (0 % vs. 3 %, p = 0.0148), showed enrichment for N-HEAT missense variants (70 % vs. 42 %; p = 0.0078), and carried recurrent variants significantly enriched in NF1+BC. Structural modeling predicted deleterious effects for >70 % of variants, with proline/arginine substitutions accounting for 83 % of missense variants (vs. 44 % in the general NF1 population, p = 0.0012). Conclusions: NF1-associated BC is characterized by earlier onset, aggressive tumor features, and distinct mutational patterns. Keywords: Breast cancer; Cancer predisposition; Dominant negative effect; Genotype-phenotype correlation; NF1; Neurofibromatosis type 1; Neurofibromin; Surveillance.