A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer Journal Article
| Authors: | Polak, P.; Kim, J.; Braunstein, L. Z.; Karlic, R.; Haradhavala, N. J.; Tiao, G.; Rosebrock, D.; Livitz, D.; Kübler, K.; Mouw, K. W.; Kamburov, A.; Maruvka, Y. E.; Leshchiner, I.; Lander, E. S.; Golub, T. R.; Zick, A.; Orthwein, A.; Lawrence, M. S.; Batra, R. N.; Caldas, C.; Haber, D. A.; Laird, P. W.; Shen, H.; Ellisen, L. W.; D'Andrea, A. D.; Chanock, S. J.; Foulkes, W. D.; Getz, G. |
| Article Title: | A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer |
| Abstract: | 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. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. |
| Keywords: | controlled study; unclassified drug; major clinical study; promoter region; single nucleotide polymorphism; somatic mutation; frameshift mutation; genetics; missense mutation; mutation; cancer patient; allele; genetic predisposition to disease; breast cancer; neoplasm proteins; genetic association; mutational analysis; breast neoplasms; brca1 protein; brca2 protein; dna methylation; gene expression regulation; tumor suppressor gene; gene expression regulation, neoplastic; epigenetics; genes, brca1; genes, brca2; breast tumor; breast carcinoma; tumor protein; atm protein; checkpoint kinase 2; gene regulatory network; gene silencing; tumor gene; genetic predisposition; transcriptome; nonsense mutation; germ-line mutation; african; gene regulatory networks; genes, neoplasm; nucleic acid binding protein; germline mutation; allelic imbalance; recombinational dna repair; recombination repair; basal like breast cancer; humans; human; female; priority journal; article; rad51c protein |
| Journal Title: | Nature Genetics |
| Volume: | 49 |
| Issue: | 10 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2017-10-01 |
| Start Page: | 1476 |
| End Page: | 1486 |
| Language: | English |
| DOI: | 10.1038/ng.3934 |
| PUBMED: | 28825726 |
| PROVIDER: | scopus |
| PMCID: | PMC7376751 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 November 2017 -- Source: Scopus |
