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Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs.

Marquard AM, Eklund AC, Joshi T, Krzystanek M, Favero F, Wang ZC, Richardson AL, Silver DP, Szallasi Z, Birkbak NJ - Biomark Res (2015)

Bottom Line: They measure telomeric allelic imbalance (named NtAI), large scale transition (named LST), and loss of heterozygosity (named HRD-LOH), and it is suggested that these signatures may act as biomarkers for the state of DNA repair deficiency in a given cancer.We explored the pan-cancer distribution of scores of the three signatures utilizing a panel of 5371 tumors representing 15 cancer types from The Cancer Genome Atlas, and found a good correlation between scores of the three signatures (Spearman's ρ 0.73-0.87).In addition we found that cancer types ordinarily receiving platinum as standard of care have higher median scores of all three signatures.

View Article: PubMed Central - PubMed

Affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 8, 2800 Lyngby, Denmark.

ABSTRACT

Background: Ovarian and triple-negative breast cancers with BRCA1 or BRCA2 loss are highly sensitive to treatment with PARP inhibitors and platinum-based cytotoxic agents and show an accumulation of genomic scars in the form of gross DNA copy number aberrations. Cancers without BRCA1 or BRCA2 loss but with accumulation of similar genomic scars also show increased sensitivity to platinum-based chemotherapy. Therefore, reliable biomarkers to identify DNA repair-deficient cancers prior to treatment may be useful for directing patients to platinum chemotherapy and possibly PARP inhibitors. Recently, three SNP array-based signatures of chromosomal instability were published that each quantitate a distinct type of genomic scar considered likely to be caused by improper DNA repair. They measure telomeric allelic imbalance (named NtAI), large scale transition (named LST), and loss of heterozygosity (named HRD-LOH), and it is suggested that these signatures may act as biomarkers for the state of DNA repair deficiency in a given cancer.

Results: We explored the pan-cancer distribution of scores of the three signatures utilizing a panel of 5371 tumors representing 15 cancer types from The Cancer Genome Atlas, and found a good correlation between scores of the three signatures (Spearman's ρ 0.73-0.87). In addition we found that cancer types ordinarily receiving platinum as standard of care have higher median scores of all three signatures. Interestingly, we also found that smaller subpopulations of high-scoring tumors exist in most cancer types, including those for which platinum chemotherapy is not standard therapy.

Conclusions: Within several cancer types that are not ordinarily treated with platinum chemotherapy, we identified tumors with high levels of the three genomic biomarkers. These tumors represent identifiable subtypes of patients which may be strong candidates for clinical trials with PARP inhibitors or platinum-based chemotherapeutic regimens.

No MeSH data available.


Related in: MedlinePlus

Overview of the type of genomic scars measured by each HR signature. Dark and light grey are used to indicate paternal and maternal chromosomes. A: Number of telomeric allelic imbalances (NtAI) counts the number of subtelomeric regions with allelic imbalance, that start beyond the centromere and extend to the telomere. B: Large-scale state transitions (LST) counts the number of chromosomal breaks between adjacent regions of at least 10 Mb. C: Homologous recombination deficiency score (HRD-LOH) measures the number of regions with LOH which are larger than 15 Mb, but shorter than the whole chromosome.
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Fig1: Overview of the type of genomic scars measured by each HR signature. Dark and light grey are used to indicate paternal and maternal chromosomes. A: Number of telomeric allelic imbalances (NtAI) counts the number of subtelomeric regions with allelic imbalance, that start beyond the centromere and extend to the telomere. B: Large-scale state transitions (LST) counts the number of chromosomal breaks between adjacent regions of at least 10 Mb. C: Homologous recombination deficiency score (HRD-LOH) measures the number of regions with LOH which are larger than 15 Mb, but shorter than the whole chromosome.

Mentions: Three signatures, each measuring a specific type of genomic scar in SNP array data, were published in 2012 by three groups, including ours. The Number of telomeric Allelic Imbalances (NtAI), published by us, was based on a type of genomic scar accumulation which could predict response to platinum-based chemotherapy in triple negative breast cancer (TNBC, expressing neither estrogen, progesterone, nor HER2 receptors) and high grade serous ovarian cancer [8]. Large Scale Transition (LST), published by Popova et al., was based on a type of genomic scar which was associated with loss of BRCA1 or BRCA2 in TNBC [13]. The Homologous Recombination Deficiency score (HRD-LOHa), published by Abkevich et al., was based on a type of genomic scar that was enriched in high grade serous ovarian cancer patients with loss of BRCA1 or BRCA2 [14]. The genomic scars measured by each signature are defined differently, although it is possible for a scar to be included in more than one signature (Figure 1). All three signatures are based on the assumption that summary measures of a defined type of genomic scar is proportional to the number of times an established cancer experienced error-prone DNA repair of a given type, which resulted in the measured genomic scar.Figure 1


Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs.

Marquard AM, Eklund AC, Joshi T, Krzystanek M, Favero F, Wang ZC, Richardson AL, Silver DP, Szallasi Z, Birkbak NJ - Biomark Res (2015)

Overview of the type of genomic scars measured by each HR signature. Dark and light grey are used to indicate paternal and maternal chromosomes. A: Number of telomeric allelic imbalances (NtAI) counts the number of subtelomeric regions with allelic imbalance, that start beyond the centromere and extend to the telomere. B: Large-scale state transitions (LST) counts the number of chromosomal breaks between adjacent regions of at least 10 Mb. C: Homologous recombination deficiency score (HRD-LOH) measures the number of regions with LOH which are larger than 15 Mb, but shorter than the whole chromosome.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4443545&req=5

Fig1: Overview of the type of genomic scars measured by each HR signature. Dark and light grey are used to indicate paternal and maternal chromosomes. A: Number of telomeric allelic imbalances (NtAI) counts the number of subtelomeric regions with allelic imbalance, that start beyond the centromere and extend to the telomere. B: Large-scale state transitions (LST) counts the number of chromosomal breaks between adjacent regions of at least 10 Mb. C: Homologous recombination deficiency score (HRD-LOH) measures the number of regions with LOH which are larger than 15 Mb, but shorter than the whole chromosome.
Mentions: Three signatures, each measuring a specific type of genomic scar in SNP array data, were published in 2012 by three groups, including ours. The Number of telomeric Allelic Imbalances (NtAI), published by us, was based on a type of genomic scar accumulation which could predict response to platinum-based chemotherapy in triple negative breast cancer (TNBC, expressing neither estrogen, progesterone, nor HER2 receptors) and high grade serous ovarian cancer [8]. Large Scale Transition (LST), published by Popova et al., was based on a type of genomic scar which was associated with loss of BRCA1 or BRCA2 in TNBC [13]. The Homologous Recombination Deficiency score (HRD-LOHa), published by Abkevich et al., was based on a type of genomic scar that was enriched in high grade serous ovarian cancer patients with loss of BRCA1 or BRCA2 [14]. The genomic scars measured by each signature are defined differently, although it is possible for a scar to be included in more than one signature (Figure 1). All three signatures are based on the assumption that summary measures of a defined type of genomic scar is proportional to the number of times an established cancer experienced error-prone DNA repair of a given type, which resulted in the measured genomic scar.Figure 1

Bottom Line: They measure telomeric allelic imbalance (named NtAI), large scale transition (named LST), and loss of heterozygosity (named HRD-LOH), and it is suggested that these signatures may act as biomarkers for the state of DNA repair deficiency in a given cancer.We explored the pan-cancer distribution of scores of the three signatures utilizing a panel of 5371 tumors representing 15 cancer types from The Cancer Genome Atlas, and found a good correlation between scores of the three signatures (Spearman's ρ 0.73-0.87).In addition we found that cancer types ordinarily receiving platinum as standard of care have higher median scores of all three signatures.

View Article: PubMed Central - PubMed

Affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 8, 2800 Lyngby, Denmark.

ABSTRACT

Background: Ovarian and triple-negative breast cancers with BRCA1 or BRCA2 loss are highly sensitive to treatment with PARP inhibitors and platinum-based cytotoxic agents and show an accumulation of genomic scars in the form of gross DNA copy number aberrations. Cancers without BRCA1 or BRCA2 loss but with accumulation of similar genomic scars also show increased sensitivity to platinum-based chemotherapy. Therefore, reliable biomarkers to identify DNA repair-deficient cancers prior to treatment may be useful for directing patients to platinum chemotherapy and possibly PARP inhibitors. Recently, three SNP array-based signatures of chromosomal instability were published that each quantitate a distinct type of genomic scar considered likely to be caused by improper DNA repair. They measure telomeric allelic imbalance (named NtAI), large scale transition (named LST), and loss of heterozygosity (named HRD-LOH), and it is suggested that these signatures may act as biomarkers for the state of DNA repair deficiency in a given cancer.

Results: We explored the pan-cancer distribution of scores of the three signatures utilizing a panel of 5371 tumors representing 15 cancer types from The Cancer Genome Atlas, and found a good correlation between scores of the three signatures (Spearman's ρ 0.73-0.87). In addition we found that cancer types ordinarily receiving platinum as standard of care have higher median scores of all three signatures. Interestingly, we also found that smaller subpopulations of high-scoring tumors exist in most cancer types, including those for which platinum chemotherapy is not standard therapy.

Conclusions: Within several cancer types that are not ordinarily treated with platinum chemotherapy, we identified tumors with high levels of the three genomic biomarkers. These tumors represent identifiable subtypes of patients which may be strong candidates for clinical trials with PARP inhibitors or platinum-based chemotherapeutic regimens.

No MeSH data available.


Related in: MedlinePlus