Chromosome 3p deletion leads to extensive genomic alterations in diverse cancers and confers synthetic lethality in uveal melanoma

Abstract

Chromosome 3p (chr3p) is frequently deleted in multiple cancers, indicating the presence of shared tumor suppressors. Analysis of genomic alterations in 33 different cancer types implicates the deletion or deleterious mutations of SET-domain-containing 2 (SETD2) at chr3p21 in significantly facilitating the formation of isochromosomes, consisting of two identical mirror-imaged arms, thereby promoting genomic instability conducive to large-scale chromosomal rearrangements and rapid cancer genome evolution. Fracturing of dicentric isochromosomes during cell division is pervasive and follows the dynamic fragmentation pattern of solids under impulse. Across cancers, isochromosomes form most frequently on chr8 to amplify the MYC-containing q-arm and chr17 to delete the TP53-containing p-arm. In the most aggressive uveal melanoma (UVM) subtype, chr3 deletion also includes MITF, a critical melanocyte differentiation and survival factor, and co-occurs with chr8q amplification. We demonstrate that MITF is a master transcriptional regulator of GNAQ/GNA11, mutated in 90% of UVM patients, and the associated synthetic-lethal genes identified by recent CRISPR screening studies. MITF maintains MAPK and calcium homeostasis in UVM, and its deletion is thus accidental, creating an early crisis during oncogenesis. We further show that MITF, MYC, and GNAQ/GNA11 form coupled regulatory feedback loops in the melanocyte lineage, and MITF deletion in UVM creates acute dependency on MYC-mediated rescue via chr8q amplification, often as a consequence of isochromosome formation. The discovered feedback loops predict both overall and relapse-free patient survival within the most aggressive UVM subtype, explain sensitivity to therapeutic gene perturbations, and inform effective combinatorial therapies.