Detecting the mutational signature of homologous recombination deficiency in clinical samples

Gulhan, D.; Lee, Jake June-Koo; Melloni, Giorgio; Cortés-Ciriano, Isidro; Park, Peter J.

doi:10.1038/s41588-019-0390-2

Cited by 243 publications

(228 citation statements)

References 39 publications

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“…Furthermore, none of the tumors were polymerase epsilon (POLE)-mutated or mismatch repair deficient (MMRD); both are DNA repair defects known to associate with excellent response to immune checkpoint blockade 9,10 . Using a recently developed computational tool called SigMA (Signature Multivariate Analysis), which is capable of determining mutational signatures even when tumor mutational burden is low 11 we were able to test for the presence of a specific mutational signature, which has been shown to be associated with HRD, called signature 3 12 . Using SigMA on the OncoPanel sequencing data, we identified the presence of signature 3 in 51% (20/39) of the patients, thereafter denoted as Sig3 positive.…”

Section: Resultsmentioning

confidence: 99%

“…All remaining mutations were used for the mutational signature calls with SigMA, including mutations that do not have a consequence such as synonymous and intronic mutations. Mutational signatures were called using SigMA 11 . For this study, SigMA was optimized for OncoPanel using simulations generated specifically for its library using whole genome sequenced ovarian cancer datasets 11 .…”

Section: Methodsmentioning

confidence: 99%

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Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer

et al. 2020

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Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Singlecell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer

et al. 2020

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“…Previous methods to identify these tumors focused on the HR defects that result from a BRCA1/2 mutation and a high HR deficiency score (HRD-score). For both a significantly better response to platinum-based chemotherapy was observed [20][21][22][23][24]. In addition to genetic analysis, it is also possible to characterize HR-deficient tumors functionally.…”

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confidence: 99%

Prevention of DNA Replication Stress by CHK1 Leads to Chemoresistance Despite a DNA Repair Defect in Homologous Recombination in Breast Cancer

Meyer

Becker

Classen

et al. 2020

Cells

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Chromosomal instability not only has a negative effect on survival in triple-negative breast cancer, but also on the well treatable subgroup of luminal A tumors. This suggests a general mechanism independent of subtypes. Increased chromosomal instability (CIN) in triple-negative breast cancer (TNBC) is attributed to a defect in the DNA repair pathway homologous recombination. Homologous recombination (HR) prevents genomic instability by repair and protection of replication. It is unclear whether genetic alterations actually lead to a repair defect or whether superior signaling pathways are of greater importance. Previous studies focused exclusively on the repair function of HR. Here, we show that the regulation of HR by the intra-S-phase damage response at the replication is of overriding importance. A damage response activated by Ataxia telangiectasia and Rad3 related-checkpoint kinase 1 (ATR-CHK1) can prevent replication stress and leads to resistance formation. CHK1 thus has a preferred role over HR in preventing replication stress in TNBC. The signaling cascade ATR-CHK1 can compensate for a double-strand break repair error and lead to resistance of HR-deficient tumors. Established methods for the identification of HR-deficient tumors for Poly(ADP-Ribose)-Polymerase 1 (PARP1) inhibitor therapies should be extended to include analysis of candidates for intra-S phase damage response.

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“…CHORD-signature achieved similarly to CHORD (Supplementary figure 8), which can be explained by the reliance on similar features (Supplementary figure 7), namely microhomology deletions and SV signature 3 (SV3; analogous to 1-100kb duplications). COSMIC signature 3 (proposed as a sensitive marker for HRD in recent studies [16][17][18] ) is actually a less important feature for predicting HRD than microhomology deletions in both models, indicating that microhomology deletions serves as a better (univariate) marker of HRD compared to COSMIC signature 3, which may hamper HRD detection in tumors with already prominent endogenous signature 3 contribution. We conclude that accurate detection of HRD does not require mutational signatures, thereby simplifying HRD calling and avoiding the complications associated with the fitting step required for computing signature contributions in individual samples (for which there is currently no consensus approach) 19 .…”

Section: Performance Of Chordmentioning

confidence: 93%

Pan-cancer landscape of homologous recombination deficiency

Nguyen

Martens

Hoeck

et al. 2020

Preprint

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Homologous recombination deficiency (HRD) results in impaired double strand break repair and is a frequent driver of tumorigenesis. Here, we used a machine learning approach to develop a sensitive pan-cancer Classifier of HOmologous Recombination Deficiency (CHORD). CHORD employs genomewide genomic footprints of somatic mutations characteristic for HRD and that discriminates BRCA1and BRCA2-subtypes. Analysis of a metastatic pan-cancer cohort of 3,504 patients revealed HRD to occur at a frequency of 6% with highest rates for ovarian cancer (30%), comparable frequencies for breast, pancreatic and prostate cancer (12-13%) and incidental cases in other cancer types. Ovarian and breast cancer were equally driven by BRCA1-and BRCA2-type HRD, whereas for prostate, pancreatic and urinary tract cancers BRCA2-type HRD was predominant. Biallelic inactivation of BRCA1, BRCA2, RAD51C and PALB2 were found as the most common genetic causes of HRD (60% of all CHORD-HRD cases), with RAD51C and PALB2 inactivation resulting in BRCA2-type HRD. Loss of heterozygosity (LOH) was found to be the main inactivating mechanism in ovarian, breast and pancreatic cancer, whereas for prostate cancer deep deletions (primarily of BRCA2) are also a major cause. From the remaining 40% of CHORD-HRD patients, 35% had a monoallelic mutation in one of the HRD associated genes, suggesting that the second allele could be inactivated by epigenetic or regulatory mechanisms. For only 5% of CHORD-HRD patients, no mutations were identified that could explain the HRD phenotype. Taken together, our results demonstrate that broad genomics-based HRD testing is valuable for cancer diagnostics and could be used for patient stratification towards treatment with e.g. poly ADP-ribose polymerase inhibitors (PARPi).

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Detecting the mutational signature of homologous recombination deficiency in clinical samples

Cited by 243 publications

References 39 publications

Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer

Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer

Prevention of DNA Replication Stress by CHK1 Leads to Chemoresistance Despite a DNA Repair Defect in Homologous Recombination in Breast Cancer

Pan-cancer landscape of homologous recombination deficiency

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