Molecular profiling of driver events in metastatic uveal melanoma

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

doi:10.1038/s41467-020-15606-0

Molecular profiling of driver events in metastatic uveal melanoma

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

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Abstract

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.

Original language	English
Article number	1894
Pages (from-to)	1894
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15606-0
Publication status	Published - 1 Dec 2020
Externally published	Yes

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Karlsson, J., Nilsson, L. M., Mitra, S., Alsén, S., Shelke, G. V., Sah, V. R., Forsberg, E. M. V., Stierner, U., All-Eriksson, C., Einarsdottir, B., Jespersen, H., Ny, L., Lindnér, P., Larsson, E., Olofsson Bagge, R., & Nilsson, J. A. (2020). Molecular profiling of driver events in metastatic uveal melanoma. Nature Communications, 11(1), 1894. Article 1894. https://doi.org/10.1038/s41467-020-15606-0

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title = "Molecular profiling of driver events in metastatic uveal melanoma",

abstract = "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.",

keywords = "Animals, Cyclin-Dependent Kinase Inhibitor p16/genetics, Female, Gene Dosage, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Lymphocytes, Lymphocytes, Tumor-Infiltrating/pathology, Melanoma/genetics, Mice, Mutation, Neoplasms, Second Primary/genetics, Prognosis, Sequence Analysis, DNA, Transcriptome, Tumor Suppressor Proteins/genetics, Ubiquitin Thiolesterase/genetics, Uveal Neoplasms/genetics",

author = "Joakim Karlsson and Nilsson, {Lisa M} and Suman Mitra and Samuel Als{\'e}n and Shelke, {Ganesh Vilas} and Sah, {Vasu R} and Forsberg, {Elin M V} and Ulrika Stierner and Charlotta All-Eriksson and Berglind Einarsdottir and Henrik Jespersen and Lars Ny and Per Lindn{\'e}r and Erik Larsson and {Olofsson Bagge}, Roger and Nilsson, {Jonas A}",

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doi = "10.1038/s41467-020-15606-0",

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Karlsson, J, Nilsson, LM, Mitra, S, Alsén, S, Shelke, GV, Sah, VR, Forsberg, EMV, Stierner, U, All-Eriksson, C, Einarsdottir, B, Jespersen, H, Ny, L, Lindnér, P, Larsson, E, Olofsson Bagge, R & Nilsson, JA 2020, 'Molecular profiling of driver events in metastatic uveal melanoma', Nature Communications, vol. 11, no. 1, 1894, pp. 1894. https://doi.org/10.1038/s41467-020-15606-0

TY - JOUR

T1 - Molecular profiling of driver events in metastatic uveal melanoma

AU - Karlsson, Joakim

AU - Nilsson, Lisa M

AU - Mitra, Suman

AU - Alsén, Samuel

AU - Shelke, Ganesh Vilas

AU - Sah, Vasu R

AU - Forsberg, Elin M V

AU - Stierner, Ulrika

AU - All-Eriksson, Charlotta

AU - Einarsdottir, Berglind

AU - Jespersen, Henrik

AU - Ny, Lars

AU - Lindnér, Per

AU - Larsson, Erik

AU - Olofsson Bagge, Roger

AU - Nilsson, Jonas A

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

KW - Animals

KW - Cyclin-Dependent Kinase Inhibitor p16/genetics

KW - Female

KW - Gene Dosage

KW - Gene Expression Regulation, Neoplastic

KW - Gene Knockdown Techniques

KW - Humans

KW - Lymphocytes

KW - Lymphocytes, Tumor-Infiltrating/pathology

KW - Melanoma/genetics

KW - Mice

KW - Mutation

KW - Neoplasms, Second Primary/genetics

KW - Prognosis

KW - Sequence Analysis, DNA

KW - Transcriptome

KW - Tumor Suppressor Proteins/genetics

KW - Ubiquitin Thiolesterase/genetics

KW - Uveal Neoplasms/genetics

U2 - 10.1038/s41467-020-15606-0

DO - 10.1038/s41467-020-15606-0

M3 - Article

C2 - 32313009

SN - 2041-1723

VL - 11

SP - 1894

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1894

ER -

Molecular profiling of driver events in metastatic uveal melanoma

Abstract

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