Subtype distribution, clinical presentation, and molecular spectrum of neurofibromatosis type 1-associated breast cancer
Year: 2025
Type: article
Study design: Observational Study
Abstract: 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.
Source: The Breast
Authors: Niccolò Di Giosaffatte, Paola Daniele, Francesco Petrizzelli, Chiara Iacovino, Chiara Canciani, Maria Luisa Garau, Claudia Santoro, Valentina Trevisan, Arianna Panfili, Stefania Cavone, Valentina Guida, Maria Cecilia D'Asdia, Laura Bernardini, Silvia Majore, Alessandro Ferraris, Michele Valiante, Francesca Gensini, Francesca Clementina Radio, Giada Tortora, Matteo Cassina, Giuseppina Miele, Manuela Priolo, Fabio Sirchia, Ludovica Piccinno, Elisabetta Flex, Giuseppe Zampino, Maurizio Genuardi, Vincenzo Nigro, Leonardo Salviati, Laura Papi, Paola Grammatico, Chiara Leoni, Giulio Piluso, Sandra Giustini, Tommaso Mazza, Meena Upadhyaya, Marco Tartaglia, Eva Trevisson, Alessandro De Luca
Institutions: Casa Sollievo della Sofferenza, Azienda Ospedaliera San Camillo-Forlanini, Istituti di Ricovero e Cura a Carattere Scientifico, Sapienza University of Rome, University of Padua, University of Campania "Luigi Vanvitelli", Agostino Gemelli University Polyclinic, University of Florence, Azienda Ospedaliero-Universitaria delle Marche, Ospedale Antonio Cardarelli, University of Pavia, Istituto Superiore di Sanità, Università Cattolica del Sacro Cuore, Telethon Institute Of Genetics And Medicine, Cardiff University, Bambino Gesù Children's Hospital
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,200
Awards: G2202102753, G2463588963, G3941526188
OpenAlex ID: W4415445657