Tumour gene expression signature in primary melanoma predicts long-term outcomes

Manik Garg ,Georgina V Long ,Serigne Lo ,Julia Newton-Bishop ,Jérémie Nsengimana ,John F Thompson ,Christine Parkinson ,Mark R Middleton ,Pippa Corrie ,David J Adams ,Richard A Scolyer ,Felicity Newell ,Nikki Stefanos ,Alvis Brāzma ,Yibing Yan ,John Tadross ,Nuno A Fonseca ,D Timothy Bishop ,Martin Lauss ,James S Wilmott ,Matthew J Wongchenko ,Ismael A Vergara ,Dominique‐Laurent Couturier ,Göran Jönsson ,Sarah Mcdonald ,Roy Rabbie

doi:10.1038/s41467-021-21207-2

Abstract

Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR = 1.63, p = 5.24 × 10−5) and overall survival (HR = 1.61, p = 1.67 × 10−4), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (pAUROC = 7.03 × 10−4), or published prognostic signatures (pAUROC < 0.05). The signature score negatively correlated with measures of immune cell infiltration (ρ = −0.75, p < 2.2 × 10−16), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.

Highlights

Adjuvant systemic therapies are routinely used following resection of stage III melanoma, accurate prognostic information is needed to better stratify patients
Principal component analysis (PCA) showed that primary Cutaneous melanoma (CM) (n = 204) and melanoma spread to local lymph nodes (LNs; n = 175) clustered separately, suggesting an impact of the microenvironment on tumour gene expression (Supplementary Fig. S2; see “Methods” section “Visualization of inherent distribution of samples”)
We decided to treat these as separate datasets, focussing our analyses on the primary melanoma samples followed by a validation of our results in the regional LN metastases from this dataset

Summary

Introduction

Adjuvant systemic therapies are routinely used following resection of stage III melanoma, accurate prognostic information is needed to better stratify patients. We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR = 1.63, p = 5.24 × 10−5) and overall survival (HR = 1.61, p = 1.67 × 10−4), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. Patients with resected AJCC stage III melanoma are eligible for adjuvant immune checkpoint inhibitors, as well as BRAF-targeted therapies, based on randomised trials confirming a reduction in the risk of relapse and improved overall survival (OS)[4,5,6,7]. A further recent unsupervised clustering analysis based on 677 primary melanoma transcriptomes (generated using the Illumina DASL array platform) embedded within a population-controlled cohort study from the Leeds Melanoma Cohort (LMC) identified a six-class 150 gene prognostic signature ( referred to as LMC_150)[16]

Methods

Results

Conclusion