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Kataegis in clinical and molecular subgroups of primary breast cancer

Veerla, Srinivas LU orcid and Staaf, Johan LU orcid (2024) In npj Breast Cancer 10(1). p.1-13
Abstract
Kataegis is a hypermutation phenomenon characterized by localized clusters of single base pair substitution (SBS) reported in multiple cancer types. Despite a high frequency in breast cancer, large-scale analyses of kataegis patterns and associations with clinicopathological and molecular variables in established breast cancer subgroups are lacking. Therefore, WGS profiled primary breast cancers (n = 791) with associated clinical and molecular data layers, like RNA-sequencing data, were analyzed for kataegis frequency, recurrence, and associations with genomic contexts and functional elements, transcriptional patterns, driver alterations, homologous recombination deficiency (HRD), and prognosis in tumor subgroups defined by ER, PR, and... (More)
Kataegis is a hypermutation phenomenon characterized by localized clusters of single base pair substitution (SBS) reported in multiple cancer types. Despite a high frequency in breast cancer, large-scale analyses of kataegis patterns and associations with clinicopathological and molecular variables in established breast cancer subgroups are lacking. Therefore, WGS profiled primary breast cancers (n = 791) with associated clinical and molecular data layers, like RNA-sequencing data, were analyzed for kataegis frequency, recurrence, and associations with genomic contexts and functional elements, transcriptional patterns, driver alterations, homologous recombination deficiency (HRD), and prognosis in tumor subgroups defined by ER, PR, and HER2/ERBB2 status. Kataegis frequency was highest in the HER2-positive(p) subgroups, including both ER-negative(n)/positive(p) tumors (ERnHER2p/ERpHER2p). In TNBC, kataegis was neither associated with PAM50 nor TNBC mRNA subtypes nor with distant relapse in chemotherapy-treated patients. In ERpHER2n tumors, kataegis was associated with aggressive characteristics, including PR-negativity, molecular Luminal B subtype, higher mutational burden, higher grade, and expression of proliferation-associated genes. Recurrent kataegis loci frequently targeted regions commonly amplified in ER-positive tumors, while few recurrent loci were observed in TNBC. SBSs in kataegis loci appeared enriched in regions of open chromatin. Kataegis status was not associated with HRD in any subgroup or with distinct transcriptional patterns in unsupervised or supervised analysis. In summary, kataegis is a common hypermutation phenomenon in established breast cancer subgroups, particularly in HER2p subgroups, coinciding with an aggressive tumor phenotype in ERpHER2n disease. In TNBC, the molecular implications and associations of kataegis are less clear, including its prognostic value. (Less)
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author
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type
Contribution to journal
publication status
published
subject
in
npj Breast Cancer
volume
10
issue
1
article number
32
pages
1 - 13
publisher
Nature Publishing Group
external identifiers
  • scopus:85191263548
ISSN
2374-4677
DOI
10.1038/s41523-024-00640-8
language
English
LU publication?
yes
id
2d524f1e-04e7-4be0-9378-db8dfd3116a5
date added to LUP
2024-04-24 15:00:12
date last changed
2024-05-07 14:54:31
@article{2d524f1e-04e7-4be0-9378-db8dfd3116a5,
  abstract     = {{Kataegis is a hypermutation phenomenon characterized by localized clusters of single base pair substitution (SBS) reported in multiple cancer types. Despite a high frequency in breast cancer, large-scale analyses of kataegis patterns and associations with clinicopathological and molecular variables in established breast cancer subgroups are lacking. Therefore, WGS profiled primary breast cancers (n = 791) with associated clinical and molecular data layers, like RNA-sequencing data, were analyzed for kataegis frequency, recurrence, and associations with genomic contexts and functional elements, transcriptional patterns, driver alterations, homologous recombination deficiency (HRD), and prognosis in tumor subgroups defined by ER, PR, and HER2/ERBB2 status. Kataegis frequency was highest in the HER2-positive(p) subgroups, including both ER-negative(n)/positive(p) tumors (ERnHER2p/ERpHER2p). In TNBC, kataegis was neither associated with PAM50 nor TNBC mRNA subtypes nor with distant relapse in chemotherapy-treated patients. In ERpHER2n tumors, kataegis was associated with aggressive characteristics, including PR-negativity, molecular Luminal B subtype, higher mutational burden, higher grade, and expression of proliferation-associated genes. Recurrent kataegis loci frequently targeted regions commonly amplified in ER-positive tumors, while few recurrent loci were observed in TNBC. SBSs in kataegis loci appeared enriched in regions of open chromatin. Kataegis status was not associated with HRD in any subgroup or with distinct transcriptional patterns in unsupervised or supervised analysis. In summary, kataegis is a common hypermutation phenomenon in established breast cancer subgroups, particularly in HER2p subgroups, coinciding with an aggressive tumor phenotype in ERpHER2n disease. In TNBC, the molecular implications and associations of kataegis are less clear, including its prognostic value.}},
  author       = {{Veerla, Srinivas and Staaf, Johan}},
  issn         = {{2374-4677}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{1}},
  pages        = {{1--13}},
  publisher    = {{Nature Publishing Group}},
  series       = {{npj Breast Cancer}},
  title        = {{Kataegis in clinical and molecular subgroups of primary breast cancer}},
  url          = {{http://dx.doi.org/10.1038/s41523-024-00640-8}},
  doi          = {{10.1038/s41523-024-00640-8}},
  volume       = {{10}},
  year         = {{2024}},
}