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Association between breast cancer risk and disease aggressiveness : Characterizing underlying gene expression patterns

Ugalde-Morales, Emilio ; Grassmann, Felix ; Humphreys, Keith LU ; Li, Jingmei ; Eriksson, Mikael ; Tobin, Nicholas P. LU ; Borg, Åke LU ; Vallon-Christersson, Johan LU orcid ; Hall, Per and Czene, Kamila (2021) In International Journal of Cancer 148(4). p.884-894
Abstract

The association between breast cancer risk defined by the Tyrer-Cuzick score (TC) and disease prognosis is not well established. Here, we investigated the relationship between 5-year TC and disease aggressiveness and then characterized underlying molecular processes. In a case-only study (n = 2474), we studied the association of TC with molecular subtypes and tumor characteristics. In a subset of patients (n = 672), we correlated gene expression to TC and computed a low-risk TC gene expression (TC-Gx) profile, that is, a profile expected to be negatively associated with risk, which we used to test for association with disease aggressiveness. We performed enrichment analysis to pinpoint molecular processes likely to be altered in... (More)

The association between breast cancer risk defined by the Tyrer-Cuzick score (TC) and disease prognosis is not well established. Here, we investigated the relationship between 5-year TC and disease aggressiveness and then characterized underlying molecular processes. In a case-only study (n = 2474), we studied the association of TC with molecular subtypes and tumor characteristics. In a subset of patients (n = 672), we correlated gene expression to TC and computed a low-risk TC gene expression (TC-Gx) profile, that is, a profile expected to be negatively associated with risk, which we used to test for association with disease aggressiveness. We performed enrichment analysis to pinpoint molecular processes likely to be altered in low-risk tumors. A higher TC was found to be inversely associated with more aggressive surrogate molecular subtypes and tumor characteristics (P <.05) including Ki-67 proliferation status (P < 5 × 10−07). Our low-risk TC-Gx, based on the weighted sum of 37 expression values of genes strongly correlated with TC, was associated with basal-like (P < 5 × 10−13), HER2-enriched subtype (P < 5 × 10−07) and worse 10-year breast cancer-specific survival (log-rank P < 5 × 10−04). Associations between low-risk TC-Gx and more aggressive molecular subtypes were replicated in an independent cohort from The Cancer Genome Atlas database (n = 975). Gene expression that correlated with low TC was enriched in proliferation and oncogenic signaling pathways (FDR < 0.05). Moreover, higher proliferation was a key factor explaining the association with worse survival. Women who developed breast cancer despite having a low risk were diagnosed with more aggressive tumors and had a worse prognosis, most likely driven by increased proliferation. Our findings imply the need to establish risk factors associated with more aggressive breast cancer subtypes.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
breast cancer, gene expression, prognosis, subtypes, Tyrer-Cuzick risk score
in
International Journal of Cancer
volume
148
issue
4
pages
11 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85090186707
  • pmid:32856720
ISSN
0020-7136
DOI
10.1002/ijc.33270
language
English
LU publication?
yes
id
0de873df-ddf2-4437-9b70-40ea591b79d2
date added to LUP
2020-09-24 12:42:16
date last changed
2022-08-04 00:46:31
@article{0de873df-ddf2-4437-9b70-40ea591b79d2,
  abstract     = {{<p>The association between breast cancer risk defined by the Tyrer-Cuzick score (TC) and disease prognosis is not well established. Here, we investigated the relationship between 5-year TC and disease aggressiveness and then characterized underlying molecular processes. In a case-only study (n = 2474), we studied the association of TC with molecular subtypes and tumor characteristics. In a subset of patients (n = 672), we correlated gene expression to TC and computed a low-risk TC gene expression (TC-Gx) profile, that is, a profile expected to be negatively associated with risk, which we used to test for association with disease aggressiveness. We performed enrichment analysis to pinpoint molecular processes likely to be altered in low-risk tumors. A higher TC was found to be inversely associated with more aggressive surrogate molecular subtypes and tumor characteristics (P &lt;.05) including Ki-67 proliferation status (P &lt; 5 × 10<sup>−07</sup>). Our low-risk TC-Gx, based on the weighted sum of 37 expression values of genes strongly correlated with TC, was associated with basal-like (P &lt; 5 × 10<sup>−13</sup>), HER2-enriched subtype (P &lt; 5 × 10<sup>−07</sup>) and worse 10-year breast cancer-specific survival (log-rank P &lt; 5 × 10<sup>−04</sup>). Associations between low-risk TC-Gx and more aggressive molecular subtypes were replicated in an independent cohort from The Cancer Genome Atlas database (n = 975). Gene expression that correlated with low TC was enriched in proliferation and oncogenic signaling pathways (FDR &lt; 0.05). Moreover, higher proliferation was a key factor explaining the association with worse survival. Women who developed breast cancer despite having a low risk were diagnosed with more aggressive tumors and had a worse prognosis, most likely driven by increased proliferation. Our findings imply the need to establish risk factors associated with more aggressive breast cancer subtypes.</p>}},
  author       = {{Ugalde-Morales, Emilio and Grassmann, Felix and Humphreys, Keith and Li, Jingmei and Eriksson, Mikael and Tobin, Nicholas P. and Borg, Åke and Vallon-Christersson, Johan and Hall, Per and Czene, Kamila}},
  issn         = {{0020-7136}},
  keywords     = {{breast cancer; gene expression; prognosis; subtypes; Tyrer-Cuzick risk score}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{4}},
  pages        = {{884--894}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{International Journal of Cancer}},
  title        = {{Association between breast cancer risk and disease aggressiveness : Characterizing underlying gene expression patterns}},
  url          = {{http://dx.doi.org/10.1002/ijc.33270}},
  doi          = {{10.1002/ijc.33270}},
  volume       = {{148}},
  year         = {{2021}},
}