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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Manik Garg
  • Dominique Laurent Couturier
  • Jérémie Nsengimana
  • Nuno A. Fonseca
  • Matthew Wongchenko
  • Yibing Yan
  • Julia Newton-Bishop
  • Christine Parkinson
  • Mark R. Middleton
  • D. Timothy Bishop
  • Sarah McDonald
  • Nikki Stefanos
  • John Tadross
  • Ismael A. Vergara
  • Serigne Lo
  • Felicity Newell
  • James S. Wilmott
  • John F. Thompson
  • Georgina V. Long
  • Richard A. Scolyer
  • Pippa Corrie
  • David J. Adams
  • Alvis Brazma
  • Roy Rabbie
Organisations
External organisations
  • European Bioinformatics Institute
  • University of Cambridge
  • University of Newcastle upon Tyne
  • University of Porto
  • Genentech, Inc
  • Cambridge University Hospitals NHS Foundation Trust
  • University of Oxford
  • University of Sydney
  • Imam Abdulrahman Bin Faisal University
  • QIMR Berghofer Medical Research Institute
  • Royal Prince Alfred Hospital
  • Wellcome Trust Sanger Institute
  • University of Leeds
  • Royal North Shore Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Cancer and Oncology
Original languageEnglish
Article number1137
JournalNature Communications
Volume12
Issue number1
Publication statusPublished - 2021
Publication categoryResearch
Peer-reviewedYes