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Genome Biol. 2019 Nov 14;20(1):240. doi: 10.1186/s13059-019-1867-0.

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

Author information

1
Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudosok krt 2, Budapest, H-1117, Hungary.
2
Department of Oncotherapy, University of Szeged, Szeged, Hungary.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
4
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
5
Department of Radiation Genetics, Kyoto University Medical School, Kyoto, 606-8501, Japan.
6
Institute of Cancer Research, Medical University Vienna, Vienna, Austria.
7
Computational Health Informatics Program (CHIP), Boston Children's Hospital, Boston, MA, USA.
8
Harvard Medical School, Boston, MA, USA.
9
Danish Cancer Society Research Center, Copenhagen, Denmark.
10
SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
11
Johns Hopkins University School of Medicine, Baltimore, MD, USA. aricha58@jhu.edu.
12
Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudosok krt 2, Budapest, H-1117, Hungary. szuts.david@ttk.mta.hu.

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.

KEYWORDS:

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

PMID:
31727117
PMCID:
PMC6857305
DOI:
10.1186/s13059-019-1867-0
[Indexed for MEDLINE]
Free PMC Article

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