Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers
(2020) In Nature Communications 11(1).- Abstract
- Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type,... (More)
- Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/04a4e502-d008-4fa8-a8bf-4e0a32ca41b2
- author
- organization
-
- Breastcancer-genetics
- LUCC: Lund University Cancer Centre
- Molecular therapeutics in breast cancer (research group)
- Division of Molecular Hematology (DMH)
- Breast/lungcancer
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Research Group Lung Cancer (research group)
- Melanoma
- Melanoma Genomics (research group)
- Breast Cancer Surgery (research group)
- Breast cancer Proteogenomics (research group)
- Biomarkers and epidemiology
- Translational Oncogenomics (research group)
- Transl oncogenomics
- Tumor Cell Biology (research group)
- Division of Translational Cancer Research
- Breast cancer treatment
- The Liquid Biopsy and Tumor Progression in Breast Cancer (research group)
- Surgery (Lund)
- Pathology, Lund
- Breast/ovarian cancer
- Familial Breast Cancer (research group)
- Division of Clinical Genetics
- publishing date
- 2020
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 11
- issue
- 1
- article number
- 3747
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:32719340
- scopus:85088573653
- pmid:32719340
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-020-17537-2
- project
- Sweden Cancerome Analysis Network - Breast (SCAN-B): a large-scale multicenter infrastructure towards implementation of breast cancer genomic analyses in the clinical routine
- language
- English
- LU publication?
- yes
- additional info
- These authors contributed equally: Dominik Glodzik, Ana Bosch, Serena Nik-Zainal, Åke Borg, Johan Staaf.
- id
- 04a4e502-d008-4fa8-a8bf-4e0a32ca41b2
- date added to LUP
- 2020-07-28 10:24:44
- date last changed
- 2024-02-16 19:31:05
@article{04a4e502-d008-4fa8-a8bf-4e0a32ca41b2, abstract = {{Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.}}, author = {{Glodzik, Dominik and Bosch, Ana and Hartman, Johan and Aine, Mattias and Vallon-Christersson, Johan and Reuterswärd, Christel and Karlsson, Anna and Mitra, Shamik and Niméus, Emma and Holm, Karolina and Häkkinen, Jari and Hegardt, Cecilia and Saal, Lao H. and Larsson, Christer and Malmberg, Martin and Rydén, Lisa and Ehinger, Anna and Loman, Niklas and Kvist, Anders and Ehrencrona, Hans and Nik-zainal, Serena and Borg, Åke and Staaf, Johan}}, issn = {{2041-1723}}, language = {{eng}}, number = {{1}}, publisher = {{Nature Publishing Group}}, series = {{Nature Communications}}, title = {{Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers}}, url = {{http://dx.doi.org/10.1038/s41467-020-17537-2}}, doi = {{10.1038/s41467-020-17537-2}}, volume = {{11}}, year = {{2020}}, }