Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency
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Abstract
Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 4755–62. ©2017 AACR.
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Four HRDetect-low patients (4.7%) had mismatch-repair-deficient tumors.
“We note that four HRDetect-low patients (4.7%) had mismatch-repair deficient (MMRd) tumors23”
From Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study (2019) · cites this paper as [23]
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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
Self-citation
- Authors
- Davies, H., Morganella, S., Purdie, C. A., Jang, S. J., Borgen, E., Russnes, H., Glodzik, D., Zou, X., Viari, A., Richardson, A. L., Børresen-Dale, A.-L., Thompson, A., Eyfjord, J. E., Kong, G., Stratton, M. R., & Nik-Zainal, S.
- Affiliations
- Wellcome Sanger Institute (GB)
- Ninewells Hospital (GB)
- Asan Medical Center (KR)
- Oslo University Hospital (NO)
- 1Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
- Institut national de recherche en sciences et technologies du numérique (FR)
- Brigham and Women's Hospital (US)
- 4Department of Pathology, Oslo University Hospital, Oslo, Norway.
- The University of Texas MD Anderson Cancer Center (US)
- University of Iceland (IS)
- Hanyang University (KR)
- ORCID
- Venue
- Cancer Research
- Published
- 2017-09-14
- Volume
- 77
- Issue
- 18
- Pages
- 4755-4762
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2754075165
- Cited by
- 99
- References
- 29
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 9 · 2023: 13 · 2022: 12 · 2021: 12 · 2020: 16 · 2019: 18 · 2018: 12
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion, other-oa)
- HAL (submittedVersion, other-oa)
- The Royal Society of Chemistry’s Journals, Books and Databases (The Royal Society of Chemistry) (submittedVersion)
- Funders
- Wellcome Trust (WT101126/B/13/Z)
- Cancer Research UK (C60100/A23916)
- Dana-Farber/Harvard Cancer Center (NIH/NCI5 P50 CA168504-02)
- National Research Foundation of Korea (NRF2015R1A2A1A10052578)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- mismatch repair deficiency, breast cancer, mutational signatures, APOBEC mutagenesis, Lynch syndrome, anti-PD-1 therapy, immunotherapy response, tumor mutational burden
- MeSH terms
- Breast Neoplasms, DNA, Neoplasm, Female, Humans, Genome, Human, Sequence Analysis, DNA, DNA Repair Enzymes, DNA Mismatch Repair, High-Throughput Nucleotide Sequencing
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