A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer

Polak P*, Kim J*, Braunstein LZ*, Karlic R, Haradhavala NJ, Tiao G, Rosebrock D, Livitz D, K├╝bler K, Mouw KW, Kamburov A, Maruvka YE, Leshchiner I, Lander ES, Golub TR, Zick A, Orthwein A, Lawrence MS, Batra RN, Caldas C, Haber DA, Laird PW, Shen H, Ellisen LW, D'Andrea AD, Chanock SJ, Foulkes WD#, Getz G#^
Nature Genetics 49 (10) :1476-1486 (2017)


Biallelic inactivation of BRCA1/2 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 ATM or CHEK2, can also give rise to the same signature. Missense BRCA1/2 variants known to impair homologous recombination (HR) were accurately classified by this signature. Finally, we show that epigenetic silencing of RAD51C and BRCA1 by promoter methylation are strongly associated with Signature 3 and, in our dataset, were highly enriched in basal-like breast cancers in young patients of African descent.

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