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  • Dissection of immune gene networks in primary melanoma tumors critical for antitumor surveillance of patients with stage II-III resectable disease.

Dissection of immune gene networks in primary melanoma tumors critical for antitumor surveillance of patients with stage II-III resectable disease.

The Journal of investigative dermatology (2014-02-14)
Shanthi Sivendran, Rui Chang, Lisa Pham, Robert G Phelps, Sara T Harcharik, Lawrence D Hall, Sebastian G Bernardo, Marina M Moskalenko, Meera Sivendran, Yichun Fu, Ellen H de Moll, Michael Pan, Jee Young Moon, Sonali Arora, Ariella Cohain, Analisa DiFeo, Tammie C Ferringer, Mikhail Tismenetsky, Cindy L Tsui, Philip A Friedlander, Michael K Parides, Jacques Banchereau, Damien Chaussabel, Mark G Lebwohl, Jedd D Wolchok, Nina Bhardwaj, Steven J Burakoff, William K Oh, Karolina Palucka, Miriam Merad, Eric E Schadt, Yvonne M Saenger
PMID24522433
ABSTRACT

Patients with resected stage II-III cutaneous melanomas remain at high risk for metastasis and death. Biomarker development has been limited by the challenge of isolating high-quality RNA for transcriptome-wide profiling from formalin-fixed and paraffin-embedded (FFPE) primary tumor specimens. Using NanoString technology, RNA from 40 stage II-III FFPE primary melanomas was analyzed and a 53-immune-gene panel predictive of non-progression (area under the curve (AUC)=0.920) was defined. The signature predicted disease-specific survival (DSS P<0.001) and recurrence-free survival (RFS P<0.001). CD2, the most differentially expressed gene in the training set, also predicted non-progression (P<0.001). Using publicly available microarray data from 46 primary human melanomas (GSE15605), a coexpression module enriched for the 53-gene panel was then identified using unbiased methods. A Bayesian network of signaling pathways based on this data identified driver genes. Finally, the proposed 53-gene panel was confirmed in an independent test population of 48 patients (AUC=0.787). The gene signature was an independent predictor of non-progression (P<0.001), RFS (P<0.001), and DSS (P=0.024) in the test population. The identified driver genes are potential therapeutic targets, and the 53-gene panel should be tested for clinical application using a larger data set annotated on the basis of prospectively gathered data.