Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number240
JournalGenome biology
Volume20
Issue number1
DOIs
Publication statusPublished - Nov 14 2019

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Homologous Recombination
homologous recombination
Cytotoxins
recombination
inhibitor
mutation
COSMIC
somatic mutation
genomics
Mutation
phenotype
inactivation
substitution
cell lines
Exome
Phenotype
Recombinational DNA Repair
Cell Line
mutants
airborne thematic mapper

Keywords

  • ATM
  • BRCA1
  • BRCA2
  • CHEK2
  • Microhomology deletion
  • Mutation signature
  • PALB2
  • PARP inhibitor
  • RAD51C
  • RAD52

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

Cite this

Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents. / Póti, Ádám; Gyergyák, Hella; Németh, Eszter; Rusz, Orsolya; Tóth, Szilárd; Kovácsházi, Csenger; Chen, Dan; Szikriszt, Bernadett; Spisák, Sándor; Takeda, Shunichi; Szakács, Gergely; Szallasi, Zoltan; Richardson, Andrea L.; Szüts, Dávid.

In: Genome biology, Vol. 20, No. 1, 240, 14.11.2019.

Research output: Contribution to journalArticle

Póti, Á, Gyergyák, H, Németh, E, Rusz, O, Tóth, S, Kovácsházi, C, Chen, D, Szikriszt, B, Spisák, S, Takeda, S, Szakács, G, Szallasi, Z, Richardson, AL & Szüts, D 2019, 'Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents', Genome biology, vol. 20, no. 1, 240. https://doi.org/10.1186/s13059-019-1867-0
Póti, Ádám ; Gyergyák, Hella ; Németh, Eszter ; Rusz, Orsolya ; Tóth, Szilárd ; Kovácsházi, Csenger ; Chen, Dan ; Szikriszt, Bernadett ; Spisák, Sándor ; Takeda, Shunichi ; Szakács, Gergely ; Szallasi, Zoltan ; Richardson, Andrea L. ; Szüts, Dávid. / Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents. In: Genome biology. 2019 ; Vol. 20, No. 1.
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AU - Rusz, Orsolya

AU - Tóth, Szilárd

AU - Kovácsházi, Csenger

AU - Chen, Dan

AU - Szikriszt, Bernadett

AU - Spisák, Sándor

AU - Takeda, Shunichi

AU - Szakács, Gergely

AU - Szallasi, Zoltan

AU - Richardson, Andrea L.

AU - Szüts, Dávid

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N2 - 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.

AB - 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.

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