Chromosome 3p Deletion Leads to Extensive Genomic Alterations in Diverse Cancers and Confers Synthetic Lethality in Uveal Melanoma

TL;DR

Deleting part of chromosome 3p causes genomic instability in many cancers and creates a treatment target in uveal melanoma.

Contribution

The study reveals how chr3p deletion leads to isochromosomes and identifies MITF as a key driver in uveal melanoma with therapeutic implications.

Findings

SETD2 deletion or mutation on chr3p promotes isochromosome formation and genomic instability in diverse cancers.

MITF hemizygous deletion in uveal melanoma drives compensatory evolution and influences patient survival.

Combinatorial targeting of MITF and synthetic lethal genes may improve outcomes for uveal melanoma patients with chr3p deletion and 8q+ amplification.

Abstract

Isochromosomes are chromosomal aberrations consisting of two identical mirror-imaged arms and simultaneous deletion of the complementary arms. We show that SETD2 deleterious mutations or hemizygous deletion of chr3p containing the gene leads to isochromosomes in cancer patients. Dicentric isochromosomes, known to form a chromatin bridge between dividing cells, are prone to massive fragmentation, which can be modeled computationally. In uveal melanoma (UVM), chr3 deletion also includes MITF, but we show that MITF is a master regulator of key driver genes of UVM. We demonstrate how this accidental hemizygous deletion of MITF in UVM imposes a strong selection pressure on subsequent compensatory genome evolution, explains differences in patient survival, and provides therapeutic opportunities.

Background: Chromosome 3p (chr3p) is frequently deleted in multiple cancers, indicating the presence of shared tumor suppressors. In aggressive uveal melanomas (UVM), this deletion often co-occurs with chr8q amplification (8q+), suggesting strong selection pressure during UVM evolution. Methods: To understand the pattern of genomic alterations mediated by chr3p deletion, we have developed an algorithm for detecting isochromosomes in 10,632 TCGA cancer patients. We further perform integrative genomics analysis to investigate how chr3p deletion could affect subsequent cancer genome evolution and synthetic lethality in UVM. Results: 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, thereby promoting genomic instability conducive to rapid cancer genome evolution. Fracturing of dicentric isochromosomes during cell division is pervasive and follows the dynamic fragmentation pattern of solids under impulse. In the most aggressive UVM subtype, chr3 deletion includes MITF, a master regulator of melanocyte survival and differentiation, and co-occurs with 8q+. We demonstrate that MITF is a master transcriptional regulator of GNAQ/GNA11 and associated synthetic-lethal genes in UVM. MITF maintains MAPK and calcium homeostasis in UVM, and its hemizygous deletion is thus accidental, likely 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 8q+. 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. Conclusions: SETD2 deletion potentiates isochromosome formation across diverse cancers. Combinatorial targeting of MITF together with a previously identified synthetic lethal gene may benefit UVM patients harboring both chr3 deletion and 8q+.

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