Aneuploidy as a driver of human cancer.

Aneuploidy, an abnormal chromosome composition, is a major contributor to cancer development and progression and an important determinant of cancer therapeutic responses and clinical outcomes. Despite being recognized as a hallmark of human cancer, the exact role of aneuploidy as a 'driver' of cancer is still largely unknown. Identifying the specific genetic elements that underlie the recurrence of common aneuploidies remains a major challenge of cancer genetics. In this Review, we discuss recurrent aneuploidies and their function as drivers of tumor development. We then delve into the context-dependent identification and functional characterization of the driver genes underlying driver aneuploidies and examine emerging strategies to uncover these driver genes using cancer genomics data and cancer models. Lastly, we explore opportunities for targeting driver aneuploidies in cancer by leveraging the functional consequences of these common genetic alterations.

A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements.

Chromosomal instability (CIN) generates micronuclei-aberrant extranuclear structures that catalyze the acquisition of complex chromosomal rearrangements present in cancer. Micronuclei are characterized by persistent DNA damage and catastrophic nuclear envelope collapse, which exposes DNA to the cytoplasm. We found that the autophagic receptor p62/SQSTM1 modulates micronuclear stability, influencing chromosome fragmentation and rearrangements. Mechanistically, proximity of micronuclei to mitochondria led to oxidation-driven homo-oligomerization of p62, limiting endosomal sorting complex required for transport (ESCRT)-dependent micronuclear envelope repair by triggering autophagic degradation. We also found that p62 levels correlate with increased chromothripsis across human cancer cell lines and with increased CIN in colorectal tumors. Thus, p62 acts as a regulator of micronuclei and may serve as a prognostic marker for tumors with high CIN.

Increased RNA and protein degradation is required for counteracting transcriptional burden and proteotoxic stress in human aneuploid cells.

Aneuploidy results in a stoichiometric imbalance of protein complexes that jeopardizes cellular fitness. Aneuploid cells thus need to compensate for the imbalanced DNA levels by regulating their RNA and protein levels, but the underlying molecular mechanisms remain unknown. Here, we dissected multiple diploid vs. aneuploid cell models. We found that aneuploid cells cope with transcriptional burden by increasing several RNA degradation pathways, and are consequently more sensitive to the perturbation of RNA degradation. At the protein level, aneuploid cells mitigate proteotoxic stress by reducing protein translation and increasing protein degradation, rendering them more sensitive to proteasome inhibition. These findings were recapitulated across hundreds of human cancer cell lines and primary tumors, and aneuploidy levels were significantly associated with the response of multiple myeloma patients to proteasome inhibitors. Aneuploid cells are therefore preferentially dependent on several key nodes along the gene expression process, creating clinically-actionable vulnerabilities in aneuploid cells.