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Independent replication of a melanoma subtype gene signature and evaluation of its prognostic value and biological correlates in a population cohort.

Nsengimana J, Laye J, Filia A, Walker C, Jewell R, Van den Oord JJ, Wolter P, Patel P, Sucker A, Schadendorf D, Jönsson GB, Bishop DT, Newton-Bishop J - Oncotarget (2015)

Bottom Line: Genomewide microarray gene expressions were profiled in 300 archived tumors (224 primaries, 76 secondaries).Specifically, molecular high-grade tumors were more frequent in patients with lower vitamin D levels whereas high immune tumors came from patients with predicted shorter telomeres.Our data confirm the utility of molecular biomarkers in melanoma prognostic estimation using tiny archived specimens and shed light on biological mechanisms likely to impact on cancer initiation and progression.

View Article: PubMed Central - PubMed

Affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.

ABSTRACT
Development and validation of robust molecular biomarkers has so far been limited in melanoma research. In this paper we used a large population-based cohort to replicate two published gene signatures for melanoma classification. We assessed the signatures prognostic value and explored their biological significance by correlating them with factors known to be associated with survival (vitamin D) or etiological routes (nevi, sun sensitivity and telomere length). Genomewide microarray gene expressions were profiled in 300 archived tumors (224 primaries, 76 secondaries). The two gene signatures classified up to 96% of our samples and showed strong correlation with melanoma specific survival (P=3 x 10(-4)), Breslow thickness (P=5 x 10(-10)), ulceration (P=9.x10-8) and mitotic rate (P=3 x 10(-7)), adding prognostic value over AJCC stage (adjusted hazard ratio 1.79, 95%CI 1.13-2.83), as previously reported. Furthermore, molecular subtypes were associated with season-adjusted serum vitamin D at diagnosis (P=0.04) and genetically predicted telomere length (P=0.03). Specifically, molecular high-grade tumors were more frequent in patients with lower vitamin D levels whereas high immune tumors came from patients with predicted shorter telomeres. Our data confirm the utility of molecular biomarkers in melanoma prognostic estimation using tiny archived specimens and shed light on biological mechanisms likely to impact on cancer initiation and progression.

No MeSH data available.


Related in: MedlinePlus

A. Full dataset classification using the 4-class signature and Kaplan-Meir survival curves using primary tumors from LMC (melanoma specific and relapse free survival)HI=high immune, NL=normal-like, PG=pigmentation, PRF=proliferative group. B. Full dataset classification using the 2-grade signature and Kaplan-Meir survival curves using primary tumors from LMC (melanoma specific and relapse free survival). Green = downregulation, red=upregulation.
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Figure 1: A. Full dataset classification using the 4-class signature and Kaplan-Meir survival curves using primary tumors from LMC (melanoma specific and relapse free survival)HI=high immune, NL=normal-like, PG=pigmentation, PRF=proliferative group. B. Full dataset classification using the 2-grade signature and Kaplan-Meir survival curves using primary tumors from LMC (melanoma specific and relapse free survival). Green = downregulation, red=upregulation.

Mentions: Figure 1A depicts the molecular classes identified as a heatmap. As reported previously [10, 11], genes such as MITF and TYR are highly expressed in the pigmentation class, KRT10 and KRT17 in the normal-like class, IRF8 and VCAM1 in high-immune tumors. Similarly, our data strongly suggested that patients with tumors that exhibit a particular molecular subtype have equally distinct survival profiles (Figure 1A). The patients with tumors classified in normal-like or high immune showed significantly better outcome than those classified as proliferative or pigmentation subtypes. Our data also demonstrated that only 2.7% of tumors classified as normal-like were metastatic compared to 54% of those classified as proliferative (Supplementary Table S3). There was no difference in survival patterns when the analysis was restricted to primary tumors from LMC, to all primaries from both datasets or all primaries and metastatic tumors combined (Figure 2). In addition, our data confirmed that the molecular subtypes are strongly correlated with AJCC stage (P=2.4 × 10−5) and 3 of its histological features: Breslow thickness (P= 2.4 × 10−9), microscopic ulceration (P=3.0 × 10−6) and mitotic rate (P=2.5 × 10−5) (Table 1). These results did not change when LMC and chemotherapy data were pooled (Supplementary Table S3).


Independent replication of a melanoma subtype gene signature and evaluation of its prognostic value and biological correlates in a population cohort.

Nsengimana J, Laye J, Filia A, Walker C, Jewell R, Van den Oord JJ, Wolter P, Patel P, Sucker A, Schadendorf D, Jönsson GB, Bishop DT, Newton-Bishop J - Oncotarget (2015)

A. Full dataset classification using the 4-class signature and Kaplan-Meir survival curves using primary tumors from LMC (melanoma specific and relapse free survival)HI=high immune, NL=normal-like, PG=pigmentation, PRF=proliferative group. B. Full dataset classification using the 2-grade signature and Kaplan-Meir survival curves using primary tumors from LMC (melanoma specific and relapse free survival). Green = downregulation, red=upregulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4484486&req=5

Figure 1: A. Full dataset classification using the 4-class signature and Kaplan-Meir survival curves using primary tumors from LMC (melanoma specific and relapse free survival)HI=high immune, NL=normal-like, PG=pigmentation, PRF=proliferative group. B. Full dataset classification using the 2-grade signature and Kaplan-Meir survival curves using primary tumors from LMC (melanoma specific and relapse free survival). Green = downregulation, red=upregulation.
Mentions: Figure 1A depicts the molecular classes identified as a heatmap. As reported previously [10, 11], genes such as MITF and TYR are highly expressed in the pigmentation class, KRT10 and KRT17 in the normal-like class, IRF8 and VCAM1 in high-immune tumors. Similarly, our data strongly suggested that patients with tumors that exhibit a particular molecular subtype have equally distinct survival profiles (Figure 1A). The patients with tumors classified in normal-like or high immune showed significantly better outcome than those classified as proliferative or pigmentation subtypes. Our data also demonstrated that only 2.7% of tumors classified as normal-like were metastatic compared to 54% of those classified as proliferative (Supplementary Table S3). There was no difference in survival patterns when the analysis was restricted to primary tumors from LMC, to all primaries from both datasets or all primaries and metastatic tumors combined (Figure 2). In addition, our data confirmed that the molecular subtypes are strongly correlated with AJCC stage (P=2.4 × 10−5) and 3 of its histological features: Breslow thickness (P= 2.4 × 10−9), microscopic ulceration (P=3.0 × 10−6) and mitotic rate (P=2.5 × 10−5) (Table 1). These results did not change when LMC and chemotherapy data were pooled (Supplementary Table S3).

Bottom Line: Genomewide microarray gene expressions were profiled in 300 archived tumors (224 primaries, 76 secondaries).Specifically, molecular high-grade tumors were more frequent in patients with lower vitamin D levels whereas high immune tumors came from patients with predicted shorter telomeres.Our data confirm the utility of molecular biomarkers in melanoma prognostic estimation using tiny archived specimens and shed light on biological mechanisms likely to impact on cancer initiation and progression.

View Article: PubMed Central - PubMed

Affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.

ABSTRACT
Development and validation of robust molecular biomarkers has so far been limited in melanoma research. In this paper we used a large population-based cohort to replicate two published gene signatures for melanoma classification. We assessed the signatures prognostic value and explored their biological significance by correlating them with factors known to be associated with survival (vitamin D) or etiological routes (nevi, sun sensitivity and telomere length). Genomewide microarray gene expressions were profiled in 300 archived tumors (224 primaries, 76 secondaries). The two gene signatures classified up to 96% of our samples and showed strong correlation with melanoma specific survival (P=3 x 10(-4)), Breslow thickness (P=5 x 10(-10)), ulceration (P=9.x10-8) and mitotic rate (P=3 x 10(-7)), adding prognostic value over AJCC stage (adjusted hazard ratio 1.79, 95%CI 1.13-2.83), as previously reported. Furthermore, molecular subtypes were associated with season-adjusted serum vitamin D at diagnosis (P=0.04) and genetically predicted telomere length (P=0.03). Specifically, molecular high-grade tumors were more frequent in patients with lower vitamin D levels whereas high immune tumors came from patients with predicted shorter telomeres. Our data confirm the utility of molecular biomarkers in melanoma prognostic estimation using tiny archived specimens and shed light on biological mechanisms likely to impact on cancer initiation and progression.

No MeSH data available.


Related in: MedlinePlus