Journal Article

Molecular profiling of driver events in metastatic uveal melanoma

Nilsson, Lisa M., Lindnér, Per, Sah, Vasu R., Einarsdottir, Berglind, Alsén, Samuel, Karlsson, Joakim, Jespersen, Henrik, Larsson, Erik, Olofsson Bagge, Roger, Forsberg, Elin M. V., Mitra, Suman, Shelke, Ganesh Vilas, Stierner, Ulrika, All-Eriksson, Charlotta, Ny, Lars, Nilsson, Jonas A.

2020

Overview

Metastatic uveal melanoma is less well understood than its primary counterpart, has a distinct biology compared to skin melanoma, and lacks effective treatments. Here we genomically profile metastatic tumors and infiltrating lymphocytes. BAP1 alterations are overrepresented and found in 29/32 of cases. Reintroducing a functional BAP1 allele into a deficient patient-derived cell line, reveals a broad shift towards a transcriptomic subtype previously associated with better prognosis of the primary disease. One outlier tumor has a high mutational burden associated with UV-damage. CDKN2A deletions also occur, which are rarely present in primaries. A focused knockdown screen is used to investigate overexpressed genes associated withcopy number gains. Tumor-infiltrating lymphocytes are in several cases found tumor-reactive, but expression of the immune checkpoint receptors TIM-3 , TIGIT and LAG3 is also abundant. This study represents the largest whole-genome analysis of uveal melanoma to date, and presents an updated view of the metastatic disease. The genetics of uveal melanoma has mainly been studied in primary tumours. In this study, the authors perform whole genome sequencing as well as immune cell profiling of biopsy samples obtained from metastatic uveal melanoma patients, providing an updated genomic landscape of these advanced lesions.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/23 / 38/89 / 45 / 45/91 / 631/67 / 631/67/322 / 631/67/580 / 631/67/68 / 631/67/69 / 96 / 96/31 / allele / animal cell / animal experiment / animal model / animal tissue / Animals / Biopsy / BRCA1 associated ring domain protein 1 / Cancer and Oncology / Cancer och onkologi / CD39 antigen / cell / controlled study / cryopreservation / cyclin dependent kinase inhibitor 2A / Cyclin-Dependent Kinase Inhibitor p16 - genetics / DNA sequencing / down regulation / Female / flow cytometry / Gene Dosage / gene expression / Gene Expression Regulation, Neoplastic / gene knockdown / Gene Knockdown Techniques / gene mutation / Gene sequencing / genetic analysis / Genetics / genome / Genomes / Genomics / genotyping technique / hepatitis A virus cellular receptor 2 / HLA typing / human / human tissue / Humanities and Social Sciences / Humans / Immune checkpoint / Immune system / immunohistochemistry / liquid chromatography-mass spectrometry / Lymphocytes / Lymphocytes, Tumor-Infiltrating - pathology / Melanoma / Melanoma - genetics / Melanoma - immunology / Melanoma - metabolism / Melanoma - pathology / Metastases / Metastasis / metastatic uvea melanoma / Mice / molecular fingerprinting / mouse / multidisciplinary / Mutation / Neoplasms, Second Primary - genetics / Neoplasms, Second Primary - immunology / Neoplasms, Second Primary - metabolism / Neoplasms, Second Primary - pathology / nonhuman / Outliers (statistics) / Prognosis / programmed death 1 receptor / protein expression / protein protein interaction / proteomics / real time reverse transcription polymerase chain reaction / Science / Science (multidisciplinary) / Sequence Analysis, DNA / single cell RNA seq / skin / Skin cancer / Transcriptome / transcriptomics / tumor / tumor associated leukocyte / tumor biopsy / Tumor Suppressor Proteins - genetics / Tumor-infiltrating lymphocytes / Tumors / Ubiquitin Thiolesterase - genetics / upregulation / Uveal Neoplasms - genetics / Uveal Neoplasms - immunology / Uveal Neoplasms - metabolism / Uveal Neoplasms - pathology / Whole genome sequencing