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Association of homozygous variants of STING1 with outcome in human cervical cancer

DNA‐sensing receptor Cyclic GMP–AMP Synthase (cGAS) and its downstream signaling effector STimulator of INterferon Genes (STING) have gained significant interest in the field of tumor immunology, as a dysfunctional cGAS‐STING pathway is associated with poor prognosis and worse response to immunother...

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Autores principales: Lubbers, Joyce M., Koopman, Bart, de Klerk‐Sluis, Jessica M., van Rooij, Nienke, Plat, Annechien, Pijper, Harry, Koopman, Timco, van Hemel, Bettien M., Hollema, Harry, Wisman, Bea, Nijman, Hans W., de Bruyn, Marco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780010/
https://www.ncbi.nlm.nih.gov/pubmed/33040406
http://dx.doi.org/10.1111/cas.14680
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author Lubbers, Joyce M.
Koopman, Bart
de Klerk‐Sluis, Jessica M.
van Rooij, Nienke
Plat, Annechien
Pijper, Harry
Koopman, Timco
van Hemel, Bettien M.
Hollema, Harry
Wisman, Bea
Nijman, Hans W.
de Bruyn, Marco
author_facet Lubbers, Joyce M.
Koopman, Bart
de Klerk‐Sluis, Jessica M.
van Rooij, Nienke
Plat, Annechien
Pijper, Harry
Koopman, Timco
van Hemel, Bettien M.
Hollema, Harry
Wisman, Bea
Nijman, Hans W.
de Bruyn, Marco
author_sort Lubbers, Joyce M.
collection PubMed
description DNA‐sensing receptor Cyclic GMP–AMP Synthase (cGAS) and its downstream signaling effector STimulator of INterferon Genes (STING) have gained significant interest in the field of tumor immunology, as a dysfunctional cGAS‐STING pathway is associated with poor prognosis and worse response to immunotherapy. However, studies so far have not taken into account the polymorphic nature of the STING‐encoding STING1 gene. We hypothesized that the presence of allelic variance in STING1 would cause variation between individuals as to their susceptibility to cancer development, cancer progression, and potential response to (immuno)therapy. To start to address this, we defined the genetic landscapes of STING1 in cervical scrapings and investigated their corresponding clinical characteristics across a unique cohort of cervical cancer patients and compared them with independent control cohorts. Although we did not observe an enrichment of particular STING1 allelic variants in cervical cancer patients, we did find that the occurrence of homozygous variants HAQ/HAQ and R232H/R232H of STING1 were associated with both younger age of diagnosis and higher recurrence rate. These findings were accompanied by worse survival, despite comparable mRNA and protein levels of STING and numbers of infiltrated CD8(+) T cells. Our findings suggest that patients with HAQ/HAQ and R232H/R232H genotypes may have a dysfunctional cGAS‐STING pathway that fails to promote efficient anticancer immunity. Interestingly, the occurrence of these genotypes coincided with homozygous presence of the V48V variant, which was found to be individually associated with worse outcome. Therefore, we propose V48V to be further evaluated as a novel prognostic marker for cervical cancer.
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spelling pubmed-77800102021-01-08 Association of homozygous variants of STING1 with outcome in human cervical cancer Lubbers, Joyce M. Koopman, Bart de Klerk‐Sluis, Jessica M. van Rooij, Nienke Plat, Annechien Pijper, Harry Koopman, Timco van Hemel, Bettien M. Hollema, Harry Wisman, Bea Nijman, Hans W. de Bruyn, Marco Cancer Sci Basic and Clinical Immunology DNA‐sensing receptor Cyclic GMP–AMP Synthase (cGAS) and its downstream signaling effector STimulator of INterferon Genes (STING) have gained significant interest in the field of tumor immunology, as a dysfunctional cGAS‐STING pathway is associated with poor prognosis and worse response to immunotherapy. However, studies so far have not taken into account the polymorphic nature of the STING‐encoding STING1 gene. We hypothesized that the presence of allelic variance in STING1 would cause variation between individuals as to their susceptibility to cancer development, cancer progression, and potential response to (immuno)therapy. To start to address this, we defined the genetic landscapes of STING1 in cervical scrapings and investigated their corresponding clinical characteristics across a unique cohort of cervical cancer patients and compared them with independent control cohorts. Although we did not observe an enrichment of particular STING1 allelic variants in cervical cancer patients, we did find that the occurrence of homozygous variants HAQ/HAQ and R232H/R232H of STING1 were associated with both younger age of diagnosis and higher recurrence rate. These findings were accompanied by worse survival, despite comparable mRNA and protein levels of STING and numbers of infiltrated CD8(+) T cells. Our findings suggest that patients with HAQ/HAQ and R232H/R232H genotypes may have a dysfunctional cGAS‐STING pathway that fails to promote efficient anticancer immunity. Interestingly, the occurrence of these genotypes coincided with homozygous presence of the V48V variant, which was found to be individually associated with worse outcome. Therefore, we propose V48V to be further evaluated as a novel prognostic marker for cervical cancer. John Wiley and Sons Inc. 2020-11-20 2021-01 /pmc/articles/PMC7780010/ /pubmed/33040406 http://dx.doi.org/10.1111/cas.14680 Text en © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Basic and Clinical Immunology
Lubbers, Joyce M.
Koopman, Bart
de Klerk‐Sluis, Jessica M.
van Rooij, Nienke
Plat, Annechien
Pijper, Harry
Koopman, Timco
van Hemel, Bettien M.
Hollema, Harry
Wisman, Bea
Nijman, Hans W.
de Bruyn, Marco
Association of homozygous variants of STING1 with outcome in human cervical cancer
title Association of homozygous variants of STING1 with outcome in human cervical cancer
title_full Association of homozygous variants of STING1 with outcome in human cervical cancer
title_fullStr Association of homozygous variants of STING1 with outcome in human cervical cancer
title_full_unstemmed Association of homozygous variants of STING1 with outcome in human cervical cancer
title_short Association of homozygous variants of STING1 with outcome in human cervical cancer
title_sort association of homozygous variants of sting1 with outcome in human cervical cancer
topic Basic and Clinical Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780010/
https://www.ncbi.nlm.nih.gov/pubmed/33040406
http://dx.doi.org/10.1111/cas.14680
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