Oncogene-like addiction to aneuploidy in human cancers

Abstract

Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harboring this alteration. Mechanistically, gaining chromosome 1q increases the expression of MDM4 and suppresses TP53 signaling, and we show that TP53 mutations are mutually-exclusive with 1q aneuploidy in human cancers. Thus, specific aneuploidies play essential roles in tumorigenesis, raising the possibility that targeting these "aneuploidy addictions" could represent a novel approach for cancer treatment.

Chromosome 8p engineering reveals increased metastatic potential targetable by patient-specific synthetic lethality in liver cancer

“…With the advent of precision therapeutics and promising concepts aiming to allow drugging of virtually any protein ( 54 , 55 ), powerful models to connect tumor-specific alterations with potential synthetic lethal targets are promising. Large-scale chromosomal deletions are highly prevalent throughout many human cancers and can be routinely detected in cancer diagnostics, but only recently models to study them in detail have been described ( 56 , 57 ). Our model permitted in-detail characterization of tumor biology in chr8p-deleted tumors leading to a better understanding of the mechanisms driving increased tumor progression and metastasis.…”

An elevated rate of whole-genome duplication events in cancers from Black patients

“…We found that WGD-positive tumors were more likely to have spread to regional or distant lymph nodes, which may warrant additional surveillance and interventions among Black patients. More broadly, chromosomal alterations are strongly associated with patient outcome, and analyzing tumor karyotypes as part of a standard pathological workup may improve our ability to preemptively detect aggressive disease 44,[67][68][69][70][71] . Additionally, recent research has demonstrated that WGD-positive cancer cells harbor unique genetic vulnerabilities.…”

Explainable deep learning on 7500 whole genomes elucidates cancer-specific patterns of chromosomal instability

“…The gain of chromosome 1q has been mechanistically linked to increased expression of MDM4 and suppression of TP53 signalling. Notably, TP53 mutations are mutually exclusive with 1q aneuploidy in human cancers, suggesting specific aneuploidies play essential roles in breast cancer tumorigenesis [61]. Furthermore, deletion of chromosome arm 11q has been observed in breast tumours.…”

“…Furthermore, deletion of chromosome arm 11q has been observed in breast tumours. While tumours with 11q deletion do not exhibit a more aggressive phenotype or genotype distinguishing them from those without this deletion, its association with relapse in patients with lymph node-negative breast cancer who did not receive anthracycline-based chemotherapy presents a novel avenue for cancer treatment [61].…”