signature=c71b8724ae3e5190efd1c258776e420e,Abstract 4652: Identification and validation of a novel n...

Abstract

Incidence of malignant melanoma is rapidly increasing - with a doubling rate of 10-20 years. Conventional histopathological and clinical staging (based on Breslow tumor thickness, lymph node status, and ulceration) is largely inadequate for predicting clinical outcome of malignant melanoma. On the other hand, molecular prognostic markers are not yet available. Here, we identified a nine-gene signature which is closely associated with overall survival of melanoma patients.

To identify prognostic genes we correlated gene expression profiles of 136 primary melanomas with patient overall survival using Cox regression analysis: Initially, a comparative analysis of 20 high-risk vs. 20 low-risk primary melanomas with a clinical follow-up of more than 20 years (training cohort) was performed using whole-genome DNA microarray analysis and yielded 92 prognostically relevant candidate genes. Technical and statistical validation using TaqMan Array real-time RT-PCR and correlation of gene expression with patient overall survival reduced candidate gene number to 11. Expression of these 11 genes was further analyzed in an extended group of 91 primary melanomas (study cohort), yielding a nine-gene signature with prognostic significance. This novel prognostic melanoma gene signature was successfully validated using an independent set of 45 primary melanomas (validation cohort).

A risk score, based on the expression of the nine genes of the signature (KRT9, SPINK7/ECG2, KBTBD10, DCD, HES6, COL6A6, PIP, SCGB1D2, SCGB2A2), or any subgroup thereof, predicted patient overall survival in the study cohort (p = 0.0004, hazard ratio 3.83), independently of conventional AJCC 2002 staging. When combining gene expression score and AJCC staging, approximately two thirds (29/45, 64%) of patients with AJCC intermediate prognosis (i.e. stages IIA, IIB, and IIIA) were reclassified into good prognosis, exhibiting a long-term overall survival probability of 95%. Misclassification rate of all patients classified into good prognosis (low-risk gene score combined with AJCC stages I IIA/B, or IIIA) was very low at 4.6% and 6.25% in the training and validation cohorts, respectively.

The prognostic value of this novel signature-based risk score is its ability to identify patients at low risk, not identified by AJCC staging. This re-classification may allow these patients to stay treatment-free while experiencing excellent long-term survival. The remaining patients are risk patients and are in need of adjuvant therapies.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4652.