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Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity
Cancer represents a broad spectrum of molecularly and morphologically diverse diseases. Individuals with the same clinical diagnosis can have tumors with drastically different molecular profiles and clinical response to treatment. It remains unclear when these differences arise during disease course...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055121/ https://www.ncbi.nlm.nih.gov/pubmed/36993286 http://dx.doi.org/10.1101/2023.03.15.532870 |
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author | Houlahan, Kathleen E. Khan, Aziz Greenwald, Noah F West, Robert B. Angelo, Michael Curtis, Christina |
author_facet | Houlahan, Kathleen E. Khan, Aziz Greenwald, Noah F West, Robert B. Angelo, Michael Curtis, Christina |
author_sort | Houlahan, Kathleen E. |
collection | PubMed |
description | Cancer represents a broad spectrum of molecularly and morphologically diverse diseases. Individuals with the same clinical diagnosis can have tumors with drastically different molecular profiles and clinical response to treatment. It remains unclear when these differences arise during disease course and why some tumors are addicted to one oncogenic pathway over another. Somatic genomic aberrations occur within the context of an individual’s germline genome, which can vary across millions of polymorphic sites. An open question is whether germline differences influence somatic tumor evolution. Interrogating 3,855 breast cancer lesions, spanning pre-invasive to metastatic disease, we demonstrate that germline variants in highly expressed and amplified genes influence somatic evolution by modulating immunoediting at early stages of tumor development. Specifically, we show that the burden of germline-derived epitopes in recurrently amplified genes selects against somatic gene amplification in breast cancer. For example, individuals with a high burden of germline-derived epitopes in ERBB2, encoding human epidermal growth factor receptor 2 (HER2), are significantly less likely to develop HER2-positive breast cancer compared to other subtypes. The same holds true for recurrent amplicons that define four subgroups of ER-positive breast cancers at high risk of distant relapse. High epitope burden in these recurrently amplified regions is associated with decreased likelihood of developing high risk ER-positive cancer. Tumors that overcome such immune-mediated negative selection are more aggressive and demonstrate an “immune cold” phenotype. These data show the germline genome plays a previously unappreciated role in dictating somatic evolution. Exploiting germline-mediated immunoediting may inform the development of biomarkers that refine risk stratification within breast cancer subtypes. |
format | Online Article Text |
id | pubmed-10055121 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-100551212023-03-30 Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity Houlahan, Kathleen E. Khan, Aziz Greenwald, Noah F West, Robert B. Angelo, Michael Curtis, Christina bioRxiv Article Cancer represents a broad spectrum of molecularly and morphologically diverse diseases. Individuals with the same clinical diagnosis can have tumors with drastically different molecular profiles and clinical response to treatment. It remains unclear when these differences arise during disease course and why some tumors are addicted to one oncogenic pathway over another. Somatic genomic aberrations occur within the context of an individual’s germline genome, which can vary across millions of polymorphic sites. An open question is whether germline differences influence somatic tumor evolution. Interrogating 3,855 breast cancer lesions, spanning pre-invasive to metastatic disease, we demonstrate that germline variants in highly expressed and amplified genes influence somatic evolution by modulating immunoediting at early stages of tumor development. Specifically, we show that the burden of germline-derived epitopes in recurrently amplified genes selects against somatic gene amplification in breast cancer. For example, individuals with a high burden of germline-derived epitopes in ERBB2, encoding human epidermal growth factor receptor 2 (HER2), are significantly less likely to develop HER2-positive breast cancer compared to other subtypes. The same holds true for recurrent amplicons that define four subgroups of ER-positive breast cancers at high risk of distant relapse. High epitope burden in these recurrently amplified regions is associated with decreased likelihood of developing high risk ER-positive cancer. Tumors that overcome such immune-mediated negative selection are more aggressive and demonstrate an “immune cold” phenotype. These data show the germline genome plays a previously unappreciated role in dictating somatic evolution. Exploiting germline-mediated immunoediting may inform the development of biomarkers that refine risk stratification within breast cancer subtypes. Cold Spring Harbor Laboratory 2023-03-16 /pmc/articles/PMC10055121/ /pubmed/36993286 http://dx.doi.org/10.1101/2023.03.15.532870 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Houlahan, Kathleen E. Khan, Aziz Greenwald, Noah F West, Robert B. Angelo, Michael Curtis, Christina Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity |
title | Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity |
title_full | Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity |
title_fullStr | Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity |
title_full_unstemmed | Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity |
title_short | Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity |
title_sort | germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055121/ https://www.ncbi.nlm.nih.gov/pubmed/36993286 http://dx.doi.org/10.1101/2023.03.15.532870 |
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