A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer
Open accessAbstract
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.
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The four biallelic PALB2 and five RAD51C cases (6.5% of HRDetect-high) showed a BRCA2-null phenotype with elevated Signature 3, elevated Rearrangement Signatures 2 and 5, and no Rearrangement Signature 3.
“the four biallelic PALB2 and five RAD51C cases (6.5% of HRDetect-high cases) consistently showed a BRCA2-null phenotype16 including elevated Substitution Signature 3, elevated Rearrangement Signatures 2 and 5, and no Rearrangement Signature 3”
From Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study (2019) · cites this paper as [16]
Loss of PALB2 function is linked to BRCA-deficient signatures.
“supporting previous studies linking loss of PALB2 function with BRCA-deficient signatures [7, 10, 13].”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [13]
Tumours with TP53, ATM, or CHEK2 germline variants lack BRCA-deficient signatures but have highly complex clustered chromosomal rearrangements.
“Despite the role of TP53, ATM and CHEK2 in DNA-damage signalling and double-strand breaks detection, these tumours do not show evidence of BRCA-deficient signatures, as previously described [9, 13, 19], but instead they harbour highly complex clustered chromosomal rearrangements.”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [13]
Loss of BRCA1, BRCA2, or PALB2 function produces a high mutation burden and specific signatures indicating defective homologous recombination.
“Loss of function of BRCA1, BRCA2 and PALB2 yield a high mutation burden and specific signatures inferring defective HR [7, 9, 10, 13].”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [13]
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Li, Z., Razavi, P., Li, Q., Toy, W., Liu, B., Ping, C., Hsieh, W., Sanchez-Vega, F., Brown, D. N., Da Cruz Paula, A. F., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.11.006 · Cited by 508 · see citing works
Pan-cancer landscape of homologous recombination deficiency.
Nguyen, L., W. M. Martens, J., Van Hoeck, A., & Cuppen, E. (2020) · Nature communications · doi:10.1038/s41467-020-19406-4 · Cited by 532 · see citing works
“RAD51C and PALB2 were recently linked to HRD as incidental cases using mutational signature based approaches[11, 16] and our results now confirm that biallelic inactivation of these two genes results in HRD and is actually a common cause of HRD (albeit to a lesser extent than for BRCA1/2).”
ResultReal-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine
Aguirre, A. J., Nowak, J. A., Camarda, N. D., Moffitt, R. A., Ghazani, A. A., Hazar-Rethinam, M., Raghavan, S., Kim, J., Brais, L. K., Ragon, D., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0275 · Cited by 367 · see citing works
Self-citationDegasperi, A., Amarante, T. D., Czarnecki, J., Shooter, S., Zou, X., Glodzik, D., Morganella, S., Nanda, A. S., Badja, C., Koh, G., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-0027-5 · Cited by 304 · see citing works
Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study
Staaf, J., Glodzik, D., Bosch, A., Vallon-Christersson, J., Reuterswärd, C., Häkkinen, J., Degasperi, A., Amarante, T. D., Saal, L. H., Hegardt, C., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0582-4 · Cited by 307 · see citing works
The landscape of somatic genetic alterations in breast cancers from ATM germline mutation carriers
Weigelt, B., Bi, R., Kumar, R., Blecua, P., Mandelker, D. L., Geyer, F. C., Pareja, F., James, P. A., kConFab Investigators, Couch, F. J., et al. (2018) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/djy028 · Cited by 128 · see citing works
Póti, Á., Gyergyák, H., Németh, E., Rusz, O., Tóth, S., Kovácsházi, C., Chen, D., Szikriszt, B., Spisák, S., Takeda, S., et al. (2019) · Genome Biology · doi:10.1186/s13059-019-1867-0 · Cited by 116 · see citing works
A Subset of Colorectal Cancers with Cross-Sensitivity to Olaparib and Oxaliplatin
Arena, S., Corti, G., Durinikova, E., Montone, M., Reilly, N. M., Russo, M., Lorenzato, A., Arcella, P., Lazzari, L., Rospo, G., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-2409 · Cited by 115 · see citing works
Portrait of a cancer: mutational signature analyses for cancer diagnostics
Van Hoeck, A., Tjoonk, N. H., van Boxtel, R., & Cuppen, E. (2019) · BMC Cancer · doi:10.1186/s12885-019-5677-2 · Cited by 107 · see citing works
Nones, K., Johnson, J., Newell, F., Patch, A. M., Thorne, H., Kazakoff, S. H., de Luca, X. M., Parsons, M. T., Ferguson, K., Reid, L. E., et al. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz132 · Cited by 93 · see citing works
“The tumour was ‘BRCA2-like’ with a high burden of substitution signature 3 and rearrangement signature 5 supporting previous studies linking loss of PALB2 function with BRCAdeficient signatures [7, 10, 13].”
BackgroundPeng, Y., Liao, Q., Tan, W., Peng, C., Hu, Z., Chen, Y., Li, Z., Li, J., Zhen, B., Zhu, W., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09232-8 · Cited by 104 · see citing works
Genome Sequencing during a Patient’s Journey through Cancer
Nangalia, J., & Campbell, P. J. (2019) · New England Journal of Medicine · doi:10.1056/nejmra1910138 · Cited by 66 · see citing works
- 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.
- Affiliations
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Hadassah Medical Center (IL)
- McGill University (CA)
- University of Cambridge (GB)
- Harvard University (US)
- Van Andel Institute (US)
- National Cancer Institute (US)
- McGill University Health Centre (CA)
- Corresponding author
- Getz, Gad
- ORCID
- Polak, Paz
- Kim, Jaegil
- Braunstein, Lior Z
- Karlic, Rosa
- Tiao, Grace
- Rosebrock, Daniel
- Livitz, Dimitri
- Kübler, Kirsten
- Mouw, Kent W
- Kamburov, Atanas
- Maruvka, Yosef E
- Leshchiner, Ignaty
- Lander, Eric S
- Golub, Todd R
- Zick, Aviad
- Orthwein, Alexandre
- Lawrence, Michael S
- Batra, Rajbir N
- Caldas, Carlos
- Haber, Daniel A
- Laird, Peter W
- Shen, Hui
- Ellisen, Leif W
- Chanock, Stephen J
- Foulkes, William D
- Getz, Gad
- Venue
- Nature Genetics
- Published
- 2017-08-21
- Volume
- 49
- Issue
- 10
- Pages
- 1476-1486
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC7376751
- OpenAlex
- W2749641460
- Cited by
- 531
- References
- 71
- Citations by year
- 2026: 33 · 2025: 31 · 2024: 44 · 2023: 66 · 2022: 86 · 2021: 85 · 2020: 77 · 2019: 65 · 2018: 40 · 2017: 4
- FWCI
- 33.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research UK (16942)
- National Institute for Health and Care Research (NF-SI-0515-10090, NF-SI-0611-10154)
- National Cancer Institute (U24CA143845)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- mutational signatures, breast cancer, homologous recombination deficiency, DNA repair deficiency, PARP inhibitors, BRCA1, BRCA2, PALB2, ATM, CHEK2, germline mutations, promoter methylation, RAD51C, epigenetic silencing, basal-like breast cancer, African ancestry
- MeSH terms
- Breast Neoplasms, Female, Humans, Mutation, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Germ-Line Mutation, DNA Methylation, Genes, BRCA1, Genetic Predisposition to Disease, Gene Silencing, Allelic Imbalance, Genes, BRCA2, Genes, Neoplasm, Gene Regulatory Networks, Transcriptome, Recombinational DNA Repair
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