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Clin Cancer Res. 2019 Sep 15;25(18):5513-5524. doi: 10.1158/1078-0432.CCR-19-1215. Epub 2019 Jun 21.

Evolutionary Routes in Metastatic Uveal Melanomas Depend on MBD4 Alterations.

Author information

1
Institut Curie, PSL Research University, INSERM U830, Paris, France.
2
Institut Curie, PSL Research University, Department of Medical Oncology, Paris, France.
3
Institut Curie, PSL Research University, Translational Research Department, Paris, France.
4
Institut Curie, PSL Research University, Institut Curie Genomics of Excellence (ICGex) Platform, Paris, France.
5
Institut Curie, PSL Research University, Biological Resource Center, Paris France.
6
Somatic Genetic Unit, Department of Genetics, Institut Curie, PSL Research University, Paris, France.
7
Leiden University Medical Center, Leiden, the Netherlands.
8
Department of Biopathology, Institut Curie, PSL Research University, Paris, France.
9
Faculty of Medicine, University of Paris Descartes, Paris, France.
10
Department of Medical Imaging, Institut Curie, PSL Research University, Paris, France.
11
Department of Radiation Oncology, Institut Curie, PSL Research University, Paris, France.
12
Department of Pathology, Quinze-Vingts National Ophthalmology Hospital, Paris, France.
13
Department of Ophthalmology IV, Quinze-Vingts National Ophthalmology Hospital, Paris, France.
14
Department of Ocular Oncology, Institut Curie, PSL Research University, Paris, France.
15
Department of Surgical Oncology, Institut Curie, PSL Research University, Institut Curie, Paris, France.
16
Institut Curie, PSL Research University, INSERM U830, Paris, France. marc-henri.stern@curie.fr.
17
Department of Genetics, Institut Curie, PSL Research University, Paris, France.
#
Contributed equally

Abstract

PURPOSE:

Uveal melanomas (UM) are genetically simple tumors carrying few copy number alterations (CNA) and a low mutation burden, except in rare MBD4-deficient, hypermutated cases. The genomics of uveal melanoma metastatic progression has not been described. We assessed the genetic heterogeneity of primary and metastatic MBD4-proficient and -deficient uveal melanomas.Experimental Design: We prospectively collected 75 metastatic and 16 primary samples from 25 consecutive uveal melanoma patients, and performed whole-exome sequencing.

RESULTS:

MBD4-proficient uveal melanomas contained stable genomes at the nucleotide level, acquiring few new single nucleotide variants (SNVs; 16 vs. 13 in metastases and primary tumors, respectively), and no new driver mutation. Five CNAs were recurrently acquired in metastases (losses of 1p, 6q, gains of 1q, 8q, and isodisomy 3). In contrast, MBD4-deficient uveal melanomas carried more than 266 SNVs per sample, with high genetic heterogeneity and TP53, SMARCA4, and GNAS new driver mutations. SNVs in MBD4-deficient contexts were exploited to unveil the timeline of oncogenic events, revealing that metastatic clones arose early after tumor onset. Surprisingly, metastases were not enriched in monosomy 3, a previously defined metastatic risk genomic feature. Monosomy 3 was associated with shorter metastatic-free interval compared with disomy 3 rather than higher rate of relapse.

CONCLUSIONS:

MBD4-proficient uveal melanomas are stable at the nucleotide level, without new actionable alterations when metastatic. In contrast, MBD4 deficiency is associated with high genetic heterogeneity and acquisition of new driver mutations. Monosomy 3 is associated with time to relapse rather than rate of relapse, thus opening avenues for a new genetic prognostic classification of uveal melanomas.

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