Nat Genet 2017 Oct;49(10):1476-1486.
Paz Polak 1 2 3, Jaegil Kim 1, Lior Z Braunstein 1 4, Rosa Karlic 5, Nicholas J Haradhavala 1 2, Grace Tiao 1, Daniel Rosebrock 1, Dimitri Livitz 1, Kirsten Kübler 1 2 3, Kent W Mouw 3 6, Atanas Kamburov 1 2 3, Yosef E Maruvka 1 2 3, Ignaty Leshchiner 1, Eric S Lander 1 7 8, Todd R Golub 1 3 9, Aviad Zick 10, Alexandre Orthwein 11, Michael S Lawrence 1 2 3, Rajbir N Batra 12 13 14, Carlos Caldas 12 13 14, Daniel A Haber 2 3, Peter W Laird 15, Hui Shen 15, Leif W Ellisen 2 3, Alan D D’Andrea 16 17, Stephen J Chanock 18, William D Foulkes 11 19, Gad Getz 1
Biallelic inactivation of BRCA1 or BRCA2 is associated with a pattern of genome-wide mutations known as signature 3. By analyzing ∼1,000 breast cancer samples, we confirmed this association and established that germline nonsense and frameshift variants in PALB2, but not in ATM or CHEK2, can also give rise to the same signature. We were able to accurately classify missense BRCA1 or BRCA2 variants known to impair homologous recombination (HR) on the basis of this signature. Finally, we show that epigenetic silencing of RAD51C and BRCA1 by promoter methylation is strongly associated with signature 3 and, in our data set, was highly enriched in basal-like breast cancers in young individuals of African descent.