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. 2006 Nov 27:4:50.
doi: 10.1186/1479-5876-4-50.

A gene expression signature associated with survival in metastatic melanoma

Susanna Mandruzzato  1 , Andrea Callegaro, Gianluca Turcatel, Samuela Francescato, Maria C Montesco, Vanna Chiarion-Sileni, Simone Mocellin, Carlo R Rossi, Silvio Bicciato, Ena Wang, Francesco M Marincola, Paola Zanovello
Affiliations

A gene expression signature associated with survival in metastatic melanoma

Susanna Mandruzzato et al. J Transl Med. .

Abstract

Background: Current clinical and histopathological criteria used to define the prognosis of melanoma patients are inadequate for accurate prediction of clinical outcome. We investigated whether genome screening by means of high-throughput gene microarray might provide clinically useful information on patient survival.

Methods: Forty-three tumor tissues from 38 patients with stage III and stage IV melanoma were profiled with a 17,500 element cDNA microarray. Expression data were analyzed using significance analysis of microarrays (SAM) to identify genes associated with patient survival, and supervised principal components (SPC) to determine survival prediction.

Results: SAM analysis revealed a set of 80 probes, corresponding to 70 genes, associated with survival, i.e. 45 probes characterizing longer and 35 shorter survival times, respectively. These transcripts were included in a survival prediction model designed using SPC and cross-validation which allowed identifying 30 predicting probes out of the 80 associated with survival.

Conclusion: The longer-survival group of genes included those expressed in immune cells, both innate and acquired, confirming the interplay between immunological mechanisms and the natural history of melanoma. Genes linked to immune cells were totally lacking in the poor-survival group, which was instead associated with a number of genes related to highly proliferative and invasive tumor cells.

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Figures

Figure 1
Figure 1
Supervised hierarchical representation of the 80 probes selected by SAM and related to survival probability. In blue the 80 probes selected by SAM and in black the 30 transcripts used to build the SPC survival predictor. Samples are labeled according to survival probability curves of Figure 2 (solid and dotted line for shorter and longer survival, respectively) and Martingale residuals of the null model are reported for each specimen. The Martingale residuals represent the difference between the observed and expected number of events for each individual. Thus, large negative residuals indicate that the observed number of deaths is less than the expected number of deaths, i.e. the individual lived longer than expected. Large positive residuals (closed to 1) indicate that the observed number of deaths is greater than the expected number of deaths, i.e. the individual's survival time was shorter than expected.
Figure 2
Figure 2
Survival probability of the 43 samples. A) Prediction was based on the v^1 MathType@MTEF@5@5@+=feaafiart1ev1aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacH8akY=wiFfYdH8Gipec8Eeeu0xXdbba9frFj0=OqFfea0dXdd9vqai=hGuQ8kuc9pgc9s8qqaq=dirpe0xb9q8qiLsFr0=vr0=vr0dc8meaabaqaciaacaGaaeqabaqabeGadaaakeaacuWG2bGDgaqcamaaBaaaleaacqaIXaqmaeqaaaaa@2F4D@ model using 30 transcripts with θ = 1.7 (v^130 MathType@MTEF@5@5@+=feaafiart1ev1aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacH8akY=wiFfYdH8Gipec8Eeeu0xXdbba9frFj0=OqFfea0dXdd9vqai=hGuQ8kuc9pgc9s8qqaq=dirpe0xb9q8qiLsFr0=vr0=vr0dc8meaabaqaciaacaGaaeqabaqabeGadaaakeaacuWG2bGDgaqcamaaDaaaleaacqaIXaqmaeaacqaIZaWmcqaIWaamaaaaaa@3130@). Dotted and solid curves represent samples with v^130 MathType@MTEF@5@5@+=feaafiart1ev1aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacH8akY=wiFfYdH8Gipec8Eeeu0xXdbba9frFj0=OqFfea0dXdd9vqai=hGuQ8kuc9pgc9s8qqaq=dirpe0xb9q8qiLsFr0=vr0=vr0dc8meaabaqaciaacaGaaeqabaqabeGadaaakeaacuWG2bGDgaqcamaaDaaaleaacqaIXaqmaeaacqaIZaWmcqaIWaamaaaaaa@3130@ higher and lower than median v^1 MathType@MTEF@5@5@+=feaafiart1ev1aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacH8akY=wiFfYdH8Gipec8Eeeu0xXdbba9frFj0=OqFfea0dXdd9vqai=hGuQ8kuc9pgc9s8qqaq=dirpe0xb9q8qiLsFr0=vr0=vr0dc8meaabaqaciaacaGaaeqabaqabeGadaaakeaacuWG2bGDgaqcamaaBaaaleaacqaIXaqmaeqaaaaa@2F4D@, respectively. Log-rank-p-value= 0.000127. B) The curves represent the predicted survival for patients obtained using different values of v1 (estimated using the first 1500 genes), i.e., the 10th (0.044), 25th (0.215), 50th (0.280), 75th (0.428), and 90th (0.563) percentiles of v1.
Figure 3
Figure 3
Immunohistochemical analysis. Representative sections of a melanoma biopsy immunostained with anti-HLA-DR (left panel, 20×), and anti-IL4R mAbs (right panel, 20×).
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