Details

Autor(en) / Beteiligte

• Pulver, Emilia M
• Mukherjee, Chirantani
• van de Kamp, Gerarda
• Roobol, Stefan J
• Rother, Magdalena B
• van der Gulden, Hanneke
• de Bruijn, Roebi
• Lattanzio, Maria Valeria
• van der Burg, Eline
• Drenth, Anne Paulien
• Verkaik, Nicole S
• Hahn, Kerstin
• Klarenbeek, Sjoerd
• de Korte-Grimmerink, Renske
• van de Ven, Marieke
• Pritchard, Colin E J
• Huijbers, Ivo J
• Xia, Bing
• van Gent, Dik C
• Essers, Jeroen
• van Attikum, Haico
• Ray Chaudhuri, Arnab
• Bouwman, Peter
• Jonkers, Jos

Titel

A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair

Ist Teil von

• Cancer research (Chicago, Ill.), 2021-12, Vol.81 (24), p.6171-6182

Ort / Verlag

United States

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• The tumor suppressor gene encodes a multidomain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks, which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, missense variants affecting its PALB2-interacting coiled-coil domain are considered variants of uncertain clinical significance (VUS). Using genetically engineered mice, we show here that a BRCA1 coiled-coil domain VUS, p.L1363P, disrupts the interaction with PALB2 and leads to embryonic lethality. p.L1363P led to a similar acceleration in the development of -deficient mammary tumors as loss, but the tumors showed distinct histopathologic features, with more stable DNA copy number profiles in p.L1363P tumors. Nevertheless, p.L1363P mammary tumors were HRR incompetent and responsive to cisplatin and PARP inhibition. Overall, these results provide the first direct evidence that a BRCA1 missense variant outside of the RING and BRCT domains increases the risk of breast cancer. SIGNIFICANCE: These findings reveal the importance of a patient-derived BRCA1 coiled-coil domain sequence variant in embryonic development, mammary tumor suppression, and therapy response. .