p53 amyloid pathology with cancer grades and p53 mutations

Abstract p53 mutation and amyloid formation are implicated with cancer pathogenesis, but the direct demonstration of the link between p53 amyloid load and cancer progression is lacking. Using multi-disciplinary techniques and a cohort of 59 tumor tissues (53 from Indian cancer patients and six normal tissues) of oral and stomach cancer types, we showed that p53 amyloid load and cancer grades are highly correlated. Further, next-generation sequencing (NGS) data suggest that not only mutant p53 (e.g., SNVs, deletions, and insertions) but wild-type p53 also formed amyloids either in the nucleus (50%) and/or in the cytoplasm in most cancer tissues. Interestingly, in all these cancer tissues, p53 displays a loss of DNA binding and transcriptional activities, which is highly aggravated with the amyloid load and cancer grades. The p53 amyloids also sequester higher amounts of p63/p73 isoforms in higher-grade of tumor tissues. The data suggest p53 misfolding/aggregation and subsequent amyloid formation lead to loss and gain of p53 tumorigenic function, aggravation of which might determine the cancers grades.