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Homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration
There is emerging evidence about the predictive role of homologous recombination deficiency (HRD), but this is less defined in gastrointestinal (GI) and thoracic malignancies. We reviewed whole genome (WGS) and transcriptomic (RNA-Seq) data from advanced GI and thoracic cancers in the Personalized O...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10039042/ https://www.ncbi.nlm.nih.gov/pubmed/36964191 http://dx.doi.org/10.1038/s41698-023-00368-x |
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author | Tsang, Erica S. Csizmok, Veronika Williamson, Laura M. Pleasance, Erin Topham, James T. Karasinska, Joanna M. Titmuss, Emma Schrader, Intan Yip, Stephen Tessier-Cloutier, Basile Mungall, Karen Ng, Tony Sun, Sophie Lim, Howard J. Loree, Jonathan M. Laskin, Janessa Marra, Marco A. Jones, Steven J. M. Schaeffer, David F. Renouf, Daniel J. |
author_facet | Tsang, Erica S. Csizmok, Veronika Williamson, Laura M. Pleasance, Erin Topham, James T. Karasinska, Joanna M. Titmuss, Emma Schrader, Intan Yip, Stephen Tessier-Cloutier, Basile Mungall, Karen Ng, Tony Sun, Sophie Lim, Howard J. Loree, Jonathan M. Laskin, Janessa Marra, Marco A. Jones, Steven J. M. Schaeffer, David F. Renouf, Daniel J. |
author_sort | Tsang, Erica S. |
collection | PubMed |
description | There is emerging evidence about the predictive role of homologous recombination deficiency (HRD), but this is less defined in gastrointestinal (GI) and thoracic malignancies. We reviewed whole genome (WGS) and transcriptomic (RNA-Seq) data from advanced GI and thoracic cancers in the Personalized OncoGenomics trial (NCT02155621) to evaluate HRD scores and single base substitution (SBS)3, which is associated with BRCA1/2 mutations and potentially predictive of defective HRD. HRD scores were calculated by sum of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions scores. Regression analyses examined the association between HRD and time to progression on platinum (TTPp). We included 223 patients with GI (n = 154) or thoracic (n = 69) malignancies. TTPp was associated with SBS3 (p < 0.01) but not HRD score in patients with GI malignancies, whereas neither was associated with TTPp in thoracic malignancies. Tumors with gBRCA1/2 mutations and a somatic second alteration exhibited high SBS3 and HRD scores, but these signatures were also present in several tumors with germline but no somatic second alterations, suggesting silencing of the wild-type allele or BRCA1/2 haploinsufficiency. Biallelic inactivation of an HR gene, including loss of XRCC2 and BARD1, was identified in BRCA1/2 wild-type HRD tumors and these patients had prolonged response to platinum. Thoracic cases with high HRD score were associated with high RECQL5 expression (p ≤ 0.025), indicating another potential mechanism of HRD. SBS3 was more strongly associated with TTPp in patients with GI malignancies and may be complementary to using HRD and BRCA status in identifying patients who benefit from platinum therapy. |
format | Online Article Text |
id | pubmed-10039042 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-100390422023-03-26 Homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration Tsang, Erica S. Csizmok, Veronika Williamson, Laura M. Pleasance, Erin Topham, James T. Karasinska, Joanna M. Titmuss, Emma Schrader, Intan Yip, Stephen Tessier-Cloutier, Basile Mungall, Karen Ng, Tony Sun, Sophie Lim, Howard J. Loree, Jonathan M. Laskin, Janessa Marra, Marco A. Jones, Steven J. M. Schaeffer, David F. Renouf, Daniel J. NPJ Precis Oncol Article There is emerging evidence about the predictive role of homologous recombination deficiency (HRD), but this is less defined in gastrointestinal (GI) and thoracic malignancies. We reviewed whole genome (WGS) and transcriptomic (RNA-Seq) data from advanced GI and thoracic cancers in the Personalized OncoGenomics trial (NCT02155621) to evaluate HRD scores and single base substitution (SBS)3, which is associated with BRCA1/2 mutations and potentially predictive of defective HRD. HRD scores were calculated by sum of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions scores. Regression analyses examined the association between HRD and time to progression on platinum (TTPp). We included 223 patients with GI (n = 154) or thoracic (n = 69) malignancies. TTPp was associated with SBS3 (p < 0.01) but not HRD score in patients with GI malignancies, whereas neither was associated with TTPp in thoracic malignancies. Tumors with gBRCA1/2 mutations and a somatic second alteration exhibited high SBS3 and HRD scores, but these signatures were also present in several tumors with germline but no somatic second alterations, suggesting silencing of the wild-type allele or BRCA1/2 haploinsufficiency. Biallelic inactivation of an HR gene, including loss of XRCC2 and BARD1, was identified in BRCA1/2 wild-type HRD tumors and these patients had prolonged response to platinum. Thoracic cases with high HRD score were associated with high RECQL5 expression (p ≤ 0.025), indicating another potential mechanism of HRD. SBS3 was more strongly associated with TTPp in patients with GI malignancies and may be complementary to using HRD and BRCA status in identifying patients who benefit from platinum therapy. Nature Publishing Group UK 2023-03-24 /pmc/articles/PMC10039042/ /pubmed/36964191 http://dx.doi.org/10.1038/s41698-023-00368-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Tsang, Erica S. Csizmok, Veronika Williamson, Laura M. Pleasance, Erin Topham, James T. Karasinska, Joanna M. Titmuss, Emma Schrader, Intan Yip, Stephen Tessier-Cloutier, Basile Mungall, Karen Ng, Tony Sun, Sophie Lim, Howard J. Loree, Jonathan M. Laskin, Janessa Marra, Marco A. Jones, Steven J. M. Schaeffer, David F. Renouf, Daniel J. Homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration |
title | Homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration |
title_full | Homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration |
title_fullStr | Homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration |
title_full_unstemmed | Homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration |
title_short | Homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration |
title_sort | homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10039042/ https://www.ncbi.nlm.nih.gov/pubmed/36964191 http://dx.doi.org/10.1038/s41698-023-00368-x |
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