Evolutionary Routes in Metastatic Uveal Melanomas Depend on <i>MBD4</i> Alterations.

Abstract

Uveal melanomas (UM) are genetically simple tumors carrying few copy number alterations (CNA) and a low mutation burden, except in rare <i>MBD4</i>-deficient, hypermutated cases. The genomics of uveal melanoma metastatic progression has not been described. We assessed the genetic heterogeneity of primary and metastatic <i>MBD4</i>-proficient and -deficient uveal melanomas.<b>Experimental Design:</b> We prospectively collected 75 metastatic and 16 primary samples from 25 consecutive uveal melanoma patients, and performed whole-exome sequencing. <i>MBD4</i>-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, <i>MBD4</i>-deficient uveal melanomas carried more than 266 SNVs per sample, with high genetic heterogeneity and <i>TP53, SMARCA4</i>, and <i>GNAS</i> new driver mutations. SNVs in <i>MBD4</i>-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. <i>MBD4</i>-proficient uveal melanomas are stable at the nucleotide level, without new actionable alterations when metastatic. In contrast, <i>MBD4</i> 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.