Homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration
Abstract 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 Perso...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-03-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-023-00368-x |
| _version_ | 1797429498262585344 |
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| author | Erica S. Tsang Veronika Csizmok Laura M. Williamson Erin Pleasance James T. Topham Joanna M. Karasinska Emma Titmuss Intan Schrader Stephen Yip Basile Tessier-Cloutier Karen Mungall Tony Ng Sophie Sun Howard J. Lim Jonathan M. Loree Janessa Laskin Marco A. Marra Steven J. M. Jones David F. Schaeffer Daniel J. Renouf |
| author_facet | Erica S. Tsang Veronika Csizmok Laura M. Williamson Erin Pleasance James T. Topham Joanna M. Karasinska Emma Titmuss Intan Schrader Stephen Yip Basile Tessier-Cloutier Karen Mungall Tony Ng Sophie Sun Howard J. Lim Jonathan M. Loree Janessa Laskin Marco A. Marra Steven J. M. Jones David F. Schaeffer Daniel J. Renouf |
| author_sort | Erica S. Tsang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-09T09:14:00Z |
| format | Article |
| id | doaj.art-94cf2e36a62f41e6b8a8f4c6c8888bcf |
| institution | Directory Open Access Journal |
| issn | 2397-768X |
| language | English |
| last_indexed | 2024-03-09T09:14:00Z |
| publishDate | 2023-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj.art-94cf2e36a62f41e6b8a8f4c6c8888bcf2023-12-02T07:45:17ZengNature Portfolionpj Precision Oncology2397-768X2023-03-017111210.1038/s41698-023-00368-xHomologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy durationErica S. Tsang0Veronika Csizmok1Laura M. Williamson2Erin Pleasance3James T. Topham4Joanna M. Karasinska5Emma Titmuss6Intan Schrader7Stephen Yip8Basile Tessier-Cloutier9Karen Mungall10Tony Ng11Sophie Sun12Howard J. Lim13Jonathan M. Loree14Janessa Laskin15Marco A. Marra16Steven J. M. Jones17David F. Schaeffer18Daniel J. Renouf19Department of Medical Oncology, BC CancerCanada’s Michael Smith Genome Sciences Centre at BC CancerCanada’s Michael Smith Genome Sciences Centre at BC CancerCanada’s Michael Smith Genome Sciences Centre at BC CancerPancreas Centre BCPancreas Centre BCCanada’s Michael Smith Genome Sciences Centre at BC CancerCanada’s Michael Smith Genome Sciences Centre at BC CancerDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Pathology and Laboratory Medicine, University of British ColumbiaCanada’s Michael Smith Genome Sciences Centre at BC CancerDepartment of Pathology and Laboratory Medicine, University of British ColumbiaDepartment of Medical Oncology, BC CancerDepartment of Medical Oncology, BC CancerDepartment of Medical Oncology, BC CancerDepartment of Medical Oncology, BC CancerCanada’s Michael Smith Genome Sciences Centre at BC CancerCanada’s Michael Smith Genome Sciences Centre at BC CancerPancreas Centre BCDepartment of Medical Oncology, BC CancerAbstract 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.https://doi.org/10.1038/s41698-023-00368-x |
| spellingShingle | Erica S. Tsang Veronika Csizmok Laura M. Williamson Erin Pleasance James T. Topham Joanna M. Karasinska Emma Titmuss Intan Schrader Stephen Yip Basile Tessier-Cloutier Karen Mungall Tony Ng Sophie Sun Howard J. Lim Jonathan M. Loree Janessa Laskin Marco A. Marra Steven J. M. Jones David F. Schaeffer Daniel J. Renouf Homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration npj Precision Oncology |
| 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 |
| url | https://doi.org/10.1038/s41698-023-00368-x |
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