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 ( Re storing D isomy in A neuploid cells using C RISPR T argeting), 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 p53 signaling, and we show that TP53 mutations are mutually-exclusive with 1q aneuploidy in human cancers. Thus, tumor cells can be dependent on specific aneuploidies, raising the possibility that these “aneuploidy addictions” could be targeted as a therapeutic strategy.

Cytogenetic resource enables mechanistic resolution of changing trends in human pluripotent stem cell aberrations linked to feeder-free culture

“…We ranked the expressed genes based on their essentiality to the pluripotent state 18 ( Figure 4B ). Notably, one of the top three most essential genes within this region is MDM4 , a known regulator of TP53 19 and a putative driver gene in the pathology of multiple types of cancers 20,21 . RNA-seq analysis of H7 and H9 v1q versus wild-type sublines further revealed differential expression of the p53 pathway in the v1q hPSCs ( Figure 4C ).…”

“…Nonetheless, it is important to note that additional genes present in the amplified region of chromosome 1q could also play a role in the behaviour of variant cells. Intriguingly, chromosome 1q is amplified in many cancers 19 and MDM4 was recently proposed as a driver of recurrent chromosome 1q gains in breast cancer through increased expression of MDM4 and reduced TP53 signalling 21 . These parallels between variant hPSCs and cancer reinforce concerns regarding their safety for regenerative medicine.…”

Gain of 1q confers an MDM4-driven growth advantage to undifferentiated and differentiating hESC while altering their differentiation capacity

“…Finally, MDM4 has recently been shown to also be the driver of the addiction of cancers to chromosome 1q gains to support their malignant growth 59 . The similarities between the genetic abnormalities found in cancers and hPSC have been already noted in the past 60–62 .…”

“…The similarities between the genetic abnormalities found in cancers and hPSC have been already noted in the past 60–62 . Gains of 20q11.21, one of the most common acquired abnormalities in hPSC 9 , appear in over 80% of pancreatic and colorectal carcinomas 63,64 and gains of 1q appears in over half of the cases of hepatocellular carcinoma 65 and have been recently identified as the first copy number alterations occurring in breast cancer and melanoma evolution 59 . These parallels, together with the high incidence of the gain of 1q in culture, the fact that the variant cells can take over also during differentiation and that the gain of 1q impacts the final cell product, stress the importance of factoring in the genetic integrity of the cells not only in a clinical setting, but also in a research context to ensure reliable and reproducible science 66,68 .…”

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.…”