Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents
Abstract Background Homologous recombination (HR) repair deficiency arising from defects in BRCA1 or BRCA2 is associated with characteristic patterns of somatic mutations. In this genetic study, we ask whether inactivating mutations in further genes of the HR pathway or the DNA damage checkpoint als...
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doaj-8760977339c040bda5b2a0d40c2805082020-11-25T04:07:52ZengBMCGenome Biology1474-760X2019-11-0120111310.1186/s13059-019-1867-0Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agentsÁdám Póti0Hella Gyergyák1Eszter Németh2Orsolya Rusz3Szilárd Tóth4Csenger Kovácsházi5Dan Chen6Bernadett Szikriszt7Sándor Spisák8Shunichi Takeda9Gergely Szakács10Zoltan Szallasi11Andrea L. Richardson12Dávid Szüts13Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Radiation Genetics, Kyoto University Medical SchoolInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesComputational Health Informatics Program (CHIP), Boston Children’s HospitalJohns Hopkins University School of MedicineInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of SciencesAbstract Background Homologous recombination (HR) repair deficiency arising from defects in BRCA1 or BRCA2 is associated with characteristic patterns of somatic mutations. In this genetic study, we ask whether inactivating mutations in further genes of the HR pathway or the DNA damage checkpoint also give rise to somatic mutation patterns that can be used for treatment prediction. Results Using whole genome sequencing of an isogenic knockout cell line panel, we find a universal HR deficiency-specific base substitution signature that is similar to COSMIC signature 3. In contrast, we detect different deletion phenotypes corresponding to specific HR mutants. The inactivation of BRCA2 or PALB2 leads to larger deletions, typically with microhomology, when compared to the disruption of BRCA1, RAD51 paralogs, or RAD54. Comparison with the deletion spectrum of Cas9 cut sites suggests that most spontaneously arising genomic deletions are not the consequence of double-strand breaks. Surprisingly, the inactivation of checkpoint kinases ATM and CHK2 has no mutagenic consequences. Analysis of tumor exomes with biallelic inactivating mutations in the investigated genes confirms the validity of the cell line models. We present a comprehensive analysis of sensitivity of the investigated mutants to 13 therapeutic agents for the purpose of correlating genomic mutagenic phenotypes with drug sensitivity. Conclusion Our results suggest that no single genomic mutational class shows perfect correlation with sensitivity to common treatments, but the contribution of COSMIC signature 3 to base substitutions, or a combined measure of different features, may be reasonably good at predicting platinum and PARP inhibitor sensitivity.http://link.springer.com/article/10.1186/s13059-019-1867-0Mutation signatureBRCA1BRCA2RAD51CPALB2RAD52 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ádám Póti Hella Gyergyák Eszter Németh Orsolya Rusz Szilárd Tóth Csenger Kovácsházi Dan Chen Bernadett Szikriszt Sándor Spisák Shunichi Takeda Gergely Szakács Zoltan Szallasi Andrea L. Richardson Dávid Szüts |
spellingShingle |
Ádám Póti Hella Gyergyák Eszter Németh Orsolya Rusz Szilárd Tóth Csenger Kovácsházi Dan Chen Bernadett Szikriszt Sándor Spisák Shunichi Takeda Gergely Szakács Zoltan Szallasi Andrea L. Richardson Dávid Szüts Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents Genome Biology Mutation signature BRCA1 BRCA2 RAD51C PALB2 RAD52 |
author_facet |
Ádám Póti Hella Gyergyák Eszter Németh Orsolya Rusz Szilárd Tóth Csenger Kovácsházi Dan Chen Bernadett Szikriszt Sándor Spisák Shunichi Takeda Gergely Szakács Zoltan Szallasi Andrea L. Richardson Dávid Szüts |
author_sort |
Ádám Póti |
title |
Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents |
title_short |
Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents |
title_full |
Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents |
title_fullStr |
Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents |
title_full_unstemmed |
Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents |
title_sort |
correlation of homologous recombination deficiency induced mutational signatures with sensitivity to parp inhibitors and cytotoxic agents |
publisher |
BMC |
series |
Genome Biology |
issn |
1474-760X |
publishDate |
2019-11-01 |
description |
Abstract Background Homologous recombination (HR) repair deficiency arising from defects in BRCA1 or BRCA2 is associated with characteristic patterns of somatic mutations. In this genetic study, we ask whether inactivating mutations in further genes of the HR pathway or the DNA damage checkpoint also give rise to somatic mutation patterns that can be used for treatment prediction. Results Using whole genome sequencing of an isogenic knockout cell line panel, we find a universal HR deficiency-specific base substitution signature that is similar to COSMIC signature 3. In contrast, we detect different deletion phenotypes corresponding to specific HR mutants. The inactivation of BRCA2 or PALB2 leads to larger deletions, typically with microhomology, when compared to the disruption of BRCA1, RAD51 paralogs, or RAD54. Comparison with the deletion spectrum of Cas9 cut sites suggests that most spontaneously arising genomic deletions are not the consequence of double-strand breaks. Surprisingly, the inactivation of checkpoint kinases ATM and CHK2 has no mutagenic consequences. Analysis of tumor exomes with biallelic inactivating mutations in the investigated genes confirms the validity of the cell line models. We present a comprehensive analysis of sensitivity of the investigated mutants to 13 therapeutic agents for the purpose of correlating genomic mutagenic phenotypes with drug sensitivity. Conclusion Our results suggest that no single genomic mutational class shows perfect correlation with sensitivity to common treatments, but the contribution of COSMIC signature 3 to base substitutions, or a combined measure of different features, may be reasonably good at predicting platinum and PARP inhibitor sensitivity. |
topic |
Mutation signature BRCA1 BRCA2 RAD51C PALB2 RAD52 |
url |
http://link.springer.com/article/10.1186/s13059-019-1867-0 |
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