Evolutionary Routes in Metastatic Uveal Melanomas Depend on MBD4 Alterations

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.

Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study

“…BRAF, NRAS and KIT were analyzed and reportedly wildtype as expected in 30, 22, and 20 patients, respectively. Mutations and inactivations of MBD4 which were previously linked to a hypermutator profile with high sensitivity to PD-1 inhibition were not investigated in any case [18,19].…”

Metastatic uveal melanoma managed with best supportive care

“…Limitations of our study include, in addition to the retrospective data collection, lack of genetic prognosticators and lack of a universal definition of BSC [12]. To improve understanding of the natural course of metastatic UM, we encourage collaboration to enrol patients who receive BSC in order to collect their WF stage and additional prognostic factors, especially genetic ones [31][32][33]. We strongly advocate using a validated system, such as the WF stage, for evidence-based, stage-specific reporting of outcomes.…”

Effects of plaque brachytherapy and proton beam radiotherapy on prognostic testing: a comparison of uveal melanoma genotyped by microsatellite analysis

“…Although, MSA is a highly successful genotyping technique at our centre for UM samples yielding a small amount of DNA, next-generation sequencing (NGS) panels are increasingly being used for this type of analysis. This comprises broader pan cancer panels, 37 38 whole exome sequencing 39 and targeted NGS panels, 40 including a bespoke NGS UM panel quite advanced in its development at our own centre, 41 based on The Cancer Genome Atlas mutational data, 42 which also successfully obtains reliable genotyping data in previously irradiated tumours.…”