p53 is a selective barrier to chromosome loss in cancer

Aneuploidy and TP53 mutations are among the most frequent genetic alterations in cancer. p53 inactivation is widely considered a key enabling event for aneuploidy emergence. However, whether p53 protects against specific types of aneuploidy, and whether this is universal across cancer types, remains unclear. By analyzing aneuploidy features across cancer types in the TCGA database, we show that p53 inactivation is neither sufficient nor necessary for cancer aneuploidy. While p53-deficient tumors show higher pan-cancer aneuploidy, within individual cancer types p53-proficient and -deficient tumors often have comparable aneuploidy levels, and p53-proficient cancers can be highly aneuploid. Instead, p53 deficiency is associated with a higher frequency of chromosome losses. Single-cell sequencing of non-transformed cells after induced chromosomal instability reveals preferential p53 pathway activation upon chromosome loss but not gain. Prolonged culture selectively enriches for monosomies when p53 is inactivated. p53 thus acts as a context-dependent safeguard against aneuploidy, particularly against chromosome losses.