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Molecular analyses of triple-negative breast cancer in the young and elderly
BACKGROUND: Breast cancer in young adults has been implicated with a worse outcome. Analyses of genomic traits associated with age have been heterogenous, likely because of an incomplete accounting for underlying molecular subtypes. We aimed to resolve whether triple-negative breast cancer (TNBC) in...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874480/ https://www.ncbi.nlm.nih.gov/pubmed/33568222 http://dx.doi.org/10.1186/s13058-021-01392-0 |
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author | Aine, Mattias Boyaci, Ceren Hartman, Johan Häkkinen, Jari Mitra, Shamik Campos, Ana Bosch Nimeus, Emma Ehinger, Anna Vallon-Christersson, Johan Borg, Åke Staaf, Johan |
author_facet | Aine, Mattias Boyaci, Ceren Hartman, Johan Häkkinen, Jari Mitra, Shamik Campos, Ana Bosch Nimeus, Emma Ehinger, Anna Vallon-Christersson, Johan Borg, Åke Staaf, Johan |
author_sort | Aine, Mattias |
collection | PubMed |
description | BACKGROUND: Breast cancer in young adults has been implicated with a worse outcome. Analyses of genomic traits associated with age have been heterogenous, likely because of an incomplete accounting for underlying molecular subtypes. We aimed to resolve whether triple-negative breast cancer (TNBC) in younger versus older patients represent similar or different molecular diseases in the context of genetic and transcriptional subtypes and immune cell infiltration. PATIENTS AND METHODS: In total, 237 patients from a reported population-based south Swedish TNBC cohort profiled by RNA sequencing and whole-genome sequencing (WGS) were included. Patients were binned in 10-year intervals. Complimentary PD-L1 and CD20 immunohistochemistry and estimation of tumor-infiltrating lymphocytes (TILs) were performed. Cases were analyzed for differences in patient outcome, genomic, transcriptional, and immune landscape features versus age at diagnosis. Additionally, 560 public WGS breast cancer profiles were used for validation. RESULTS: Median age at diagnosis was 62 years (range 26–91). Age was not associated with invasive disease-free survival or overall survival after adjuvant chemotherapy. Among the BRCA1-deficient cases (82/237), 90% were diagnosed before the age of 70 and were predominantly of the basal-like subtype. In the full TNBC cohort, reported associations of patient age with changes in Ki67 expression, PIK3CA mutations, and a luminal androgen receptor subtype were confirmed. Within DNA repair deficiency or gene expression defined molecular subgroups, age-related alterations in, e.g., overall gene expression, immune cell marker gene expression, genetic mutational and rearrangement signatures, amount of copy number alterations, and tumor mutational burden did, however, not appear distinct. Similar non-significant associations for genetic alterations with age were obtained for other breast cancer subgroups in public WGS data. Consistent with age-related immunosenescence, TIL counts decreased linearly with patient age across different genetic TNBC subtypes. CONCLUSIONS: Age-related alterations in TNBC, as well as breast cancer in general, need to be viewed in the context of underlying genomic phenotypes. Based on this notion, age at diagnosis alone does not appear to provide an additional layer of biological complexity above that of proposed genetic and transcriptional phenotypes of TNBC. Consequently, treatment decisions should be less influenced by age and more driven by tumor biology. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-021-01392-0. |
format | Online Article Text |
id | pubmed-7874480 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-78744802021-02-11 Molecular analyses of triple-negative breast cancer in the young and elderly Aine, Mattias Boyaci, Ceren Hartman, Johan Häkkinen, Jari Mitra, Shamik Campos, Ana Bosch Nimeus, Emma Ehinger, Anna Vallon-Christersson, Johan Borg, Åke Staaf, Johan Breast Cancer Res Research Article BACKGROUND: Breast cancer in young adults has been implicated with a worse outcome. Analyses of genomic traits associated with age have been heterogenous, likely because of an incomplete accounting for underlying molecular subtypes. We aimed to resolve whether triple-negative breast cancer (TNBC) in younger versus older patients represent similar or different molecular diseases in the context of genetic and transcriptional subtypes and immune cell infiltration. PATIENTS AND METHODS: In total, 237 patients from a reported population-based south Swedish TNBC cohort profiled by RNA sequencing and whole-genome sequencing (WGS) were included. Patients were binned in 10-year intervals. Complimentary PD-L1 and CD20 immunohistochemistry and estimation of tumor-infiltrating lymphocytes (TILs) were performed. Cases were analyzed for differences in patient outcome, genomic, transcriptional, and immune landscape features versus age at diagnosis. Additionally, 560 public WGS breast cancer profiles were used for validation. RESULTS: Median age at diagnosis was 62 years (range 26–91). Age was not associated with invasive disease-free survival or overall survival after adjuvant chemotherapy. Among the BRCA1-deficient cases (82/237), 90% were diagnosed before the age of 70 and were predominantly of the basal-like subtype. In the full TNBC cohort, reported associations of patient age with changes in Ki67 expression, PIK3CA mutations, and a luminal androgen receptor subtype were confirmed. Within DNA repair deficiency or gene expression defined molecular subgroups, age-related alterations in, e.g., overall gene expression, immune cell marker gene expression, genetic mutational and rearrangement signatures, amount of copy number alterations, and tumor mutational burden did, however, not appear distinct. Similar non-significant associations for genetic alterations with age were obtained for other breast cancer subgroups in public WGS data. Consistent with age-related immunosenescence, TIL counts decreased linearly with patient age across different genetic TNBC subtypes. CONCLUSIONS: Age-related alterations in TNBC, as well as breast cancer in general, need to be viewed in the context of underlying genomic phenotypes. Based on this notion, age at diagnosis alone does not appear to provide an additional layer of biological complexity above that of proposed genetic and transcriptional phenotypes of TNBC. Consequently, treatment decisions should be less influenced by age and more driven by tumor biology. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-021-01392-0. BioMed Central 2021-02-10 2021 /pmc/articles/PMC7874480/ /pubmed/33568222 http://dx.doi.org/10.1186/s13058-021-01392-0 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Aine, Mattias Boyaci, Ceren Hartman, Johan Häkkinen, Jari Mitra, Shamik Campos, Ana Bosch Nimeus, Emma Ehinger, Anna Vallon-Christersson, Johan Borg, Åke Staaf, Johan Molecular analyses of triple-negative breast cancer in the young and elderly |
title | Molecular analyses of triple-negative breast cancer in the young and elderly |
title_full | Molecular analyses of triple-negative breast cancer in the young and elderly |
title_fullStr | Molecular analyses of triple-negative breast cancer in the young and elderly |
title_full_unstemmed | Molecular analyses of triple-negative breast cancer in the young and elderly |
title_short | Molecular analyses of triple-negative breast cancer in the young and elderly |
title_sort | molecular analyses of triple-negative breast cancer in the young and elderly |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874480/ https://www.ncbi.nlm.nih.gov/pubmed/33568222 http://dx.doi.org/10.1186/s13058-021-01392-0 |
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