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Molecular characteristics of breast tumors in patients screened for germline predisposition from a population-based observational study

Nacer, Deborah F. LU orcid ; Vallon-Christersson, Johan LU orcid ; Nordborg, Nicklas LU ; Ehrencrona, Hans LU orcid ; Kvist, Anders LU ; Borg, Åke LU and Staaf, Johan LU orcid (2023) In Genome Medicine 15. p.1-20
Abstract
Background
Pathogenic germline variants (PGVs) in certain genes are linked to higher lifetime risk of developing breast cancer and can influence preventive surgery decisions and therapy choices. Public health programs offer genetic screening based on criteria designed to assess personal risk and identify individuals more likely to carry PGVs, dividing patients into screened and non-screened groups. How tumor biology and clinicopathological characteristics differ between these groups is understudied and could guide refinement of screening criteria.

Methods
Six thousand six hundred sixty breast cancer patients diagnosed in South Sweden during 2010–2018 were included with available clinicopathological and RNA sequencing data,... (More)
Background
Pathogenic germline variants (PGVs) in certain genes are linked to higher lifetime risk of developing breast cancer and can influence preventive surgery decisions and therapy choices. Public health programs offer genetic screening based on criteria designed to assess personal risk and identify individuals more likely to carry PGVs, dividing patients into screened and non-screened groups. How tumor biology and clinicopathological characteristics differ between these groups is understudied and could guide refinement of screening criteria.

Methods
Six thousand six hundred sixty breast cancer patients diagnosed in South Sweden during 2010–2018 were included with available clinicopathological and RNA sequencing data, 900 (13.5%) of which had genes screened for PGVs through routine clinical screening programs. We compared characteristics of screened patients and tumors to non-screened patients, as well as between screened patients with (n = 124) and without (n = 776) PGVs.

Results
Broadly, breast tumors in screened patients showed features of a more aggressive disease. However, few differences related to tumor biology or patient outcome remained significant after stratification by clinical subgroups or PAM50 subtypes. Triple-negative breast cancer (TNBC), the subgroup most enriched for PGVs, showed the most differences between screening subpopulations (e.g., higher tumor proliferation in screened cases). Significant differences in PGV prevalence were found between clinical subgroups/molecular subtypes, e.g., TNBC cases were enriched for BRCA1 PGVs. In general, clinicopathological differences between screened and non-screened patients mimicked those between patients with and without PGVs, e.g., younger age at diagnosis for positive cases. However, differences in tumor biology/microenvironment such as immune cell composition were additionally seen within PGV carriers/non-carriers in ER + /HER2 − cases, but not between screening subpopulations in this subgroup.

Conclusions
Characterization of molecular tumor features in patients clinically screened and not screened for PGVs represents a relevant read-out of guideline criteria. The general lack of molecular differences between screened/non-screened patients after stratification by relevant breast cancer subsets questions the ability to improve the identification of screening candidates based on currently used patient and tumor characteristics, pointing us towards universal screening. Nevertheless, while that is not attained, molecular differences identified between PGV carriers/non-carriers suggest the possibility of further refining patient selection within certain patient subsets using RNA-seq through, e.g., gene signatures. (Less)
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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Genome Medicine
volume
15
article number
25
pages
1 - 20
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85152561658
  • pmid:37060015
ISSN
1756-994X
DOI
10.1186/s13073-023-01177-4
language
English
LU publication?
yes
id
9a9b39ae-41fc-4227-addc-c86e92032a7f
date added to LUP
2023-05-08 22:54:54
date last changed
2024-05-18 01:10:21
@article{9a9b39ae-41fc-4227-addc-c86e92032a7f,
  abstract     = {{Background<br/>Pathogenic germline variants (PGVs) in certain genes are linked to higher lifetime risk of developing breast cancer and can influence preventive surgery decisions and therapy choices. Public health programs offer genetic screening based on criteria designed to assess personal risk and identify individuals more likely to carry PGVs, dividing patients into screened and non-screened groups. How tumor biology and clinicopathological characteristics differ between these groups is understudied and could guide refinement of screening criteria.<br/><br/>Methods<br/>Six thousand six hundred sixty breast cancer patients diagnosed in South Sweden during 2010–2018 were included with available clinicopathological and RNA sequencing data, 900 (13.5%) of which had genes screened for PGVs through routine clinical screening programs. We compared characteristics of screened patients and tumors to non-screened patients, as well as between screened patients with (n = 124) and without (n = 776) PGVs.<br/><br/>Results<br/>Broadly, breast tumors in screened patients showed features of a more aggressive disease. However, few differences related to tumor biology or patient outcome remained significant after stratification by clinical subgroups or PAM50 subtypes. Triple-negative breast cancer (TNBC), the subgroup most enriched for PGVs, showed the most differences between screening subpopulations (e.g., higher tumor proliferation in screened cases). Significant differences in PGV prevalence were found between clinical subgroups/molecular subtypes, e.g., TNBC cases were enriched for BRCA1 PGVs. In general, clinicopathological differences between screened and non-screened patients mimicked those between patients with and without PGVs, e.g., younger age at diagnosis for positive cases. However, differences in tumor biology/microenvironment such as immune cell composition were additionally seen within PGV carriers/non-carriers in ER + /HER2 − cases, but not between screening subpopulations in this subgroup.<br/><br/>Conclusions<br/>Characterization of molecular tumor features in patients clinically screened and not screened for PGVs represents a relevant read-out of guideline criteria. The general lack of molecular differences between screened/non-screened patients after stratification by relevant breast cancer subsets questions the ability to improve the identification of screening candidates based on currently used patient and tumor characteristics, pointing us towards universal screening. Nevertheless, while that is not attained, molecular differences identified between PGV carriers/non-carriers suggest the possibility of further refining patient selection within certain patient subsets using RNA-seq through, e.g., gene signatures.}},
  author       = {{Nacer, Deborah F. and Vallon-Christersson, Johan and Nordborg, Nicklas and Ehrencrona, Hans and Kvist, Anders and Borg, Åke and Staaf, Johan}},
  issn         = {{1756-994X}},
  language     = {{eng}},
  month        = {{04}},
  pages        = {{1--20}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Genome Medicine}},
  title        = {{Molecular characteristics of breast tumors in patients screened for germline predisposition from a population-based observational study}},
  url          = {{http://dx.doi.org/10.1186/s13073-023-01177-4}},
  doi          = {{10.1186/s13073-023-01177-4}},
  volume       = {{15}},
  year         = {{2023}},
}