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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

Comparison of signature scores to other measures of genome instability. Spearman correlation coefficients between each of the three HR signatures (NtAI, LST and HRD-LOH) and each of three alternative genomic signatures (wGII, FLOH and Nmut, see text for details).
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Fig5: Comparison of signature scores to other measures of genome instability. Spearman correlation coefficients between each of the three HR signatures (NtAI, LST and HRD-LOH) and each of three alternative genomic signatures (wGII, FLOH and Nmut, see text for details).

Mentions: As NtAI, LST and HRD-LOH can be considered a type of genomic instability score, we next compared the signature scores to three other previously published measures of chromosomal instability: the weighted genome integrity index (wGII) [18], the frequency of LOH (FLOH) [19], and the total number of mutations per sample (Nmut) [20], Figure 5. We observed that both NtAI and LST scores showed a good correlation with wGII (median ρ = 0.75 and 0.64, respectively), whereas HRD-LOH was lower, with a median ρ = 0.49. Correlation to FLOH was lower for both NtAI and LST (median ρ = 0.53 & ρ = 0.39), but HRD-LOH was considerably higher with median ρ = 0.76. This is not surprising, since HRD-LOH is measuring a type of LOH. The correlation to Nmut was much lower for all three signatures, with ρ = 0.11, 0.16 and 0.16 for NtAI, LST and HRD-LOH, respectively. This suggests that a simple measure of mutation counts is not a good surrogate for genomic scars as defined by either method, but that more general measures of chromosomal instability such as wGII and FLOH are correlated to these genomic scar-based approaches.Figure 5


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)

Comparison of signature scores to other measures of genome instability. Spearman correlation coefficients between each of the three HR signatures (NtAI, LST and HRD-LOH) and each of three alternative genomic signatures (wGII, FLOH and Nmut, see text for details).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: Comparison of signature scores to other measures of genome instability. Spearman correlation coefficients between each of the three HR signatures (NtAI, LST and HRD-LOH) and each of three alternative genomic signatures (wGII, FLOH and Nmut, see text for details).
Mentions: As NtAI, LST and HRD-LOH can be considered a type of genomic instability score, we next compared the signature scores to three other previously published measures of chromosomal instability: the weighted genome integrity index (wGII) [18], the frequency of LOH (FLOH) [19], and the total number of mutations per sample (Nmut) [20], Figure 5. We observed that both NtAI and LST scores showed a good correlation with wGII (median ρ = 0.75 and 0.64, respectively), whereas HRD-LOH was lower, with a median ρ = 0.49. Correlation to FLOH was lower for both NtAI and LST (median ρ = 0.53 & ρ = 0.39), but HRD-LOH was considerably higher with median ρ = 0.76. This is not surprising, since HRD-LOH is measuring a type of LOH. The correlation to Nmut was much lower for all three signatures, with ρ = 0.11, 0.16 and 0.16 for NtAI, LST and HRD-LOH, respectively. This suggests that a simple measure of mutation counts is not a good surrogate for genomic scars as defined by either method, but that more general measures of chromosomal instability such as wGII and FLOH are correlated to these genomic scar-based approaches.Figure 5

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