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Pan-Cancer Study Uncovers TP53 Mutation Consequences, Related Prognostic Expression Signature

NEW YORK – A team from the US, France, and Sweden has started untangling the cancer genome in the context of TP53 mutations, integrating genomic data for tens of thousands of tumors to assess TP53 interactions in a pan-cancer setting.

As they reported online today in Cell Reports, the researchers used exome sequencing, gene expression, microRNA expression, protein expression, and DNA copy number data from the Cancer Genome Atlas (TCGA) project to look at the pathway changes associated with TP53 mutations in dozens of cancer types. Based on tumor profiles for more than 10,200 cancer patients, they teased out the genomic consequences of mutating TP53, while narrowing in on a TP53 mutation-related expression signature showing ties to overall survival in 11 of the cancer types.

More broadly, "the large-scale multi-data platform approach pioneered by [the] TCGA effort has provided an unparalleled opportunity to better understand structural mechanisms of p53 pathway inactivation and the resulting effect on the genetics and biology of many of the cancers examined," first and corresponding author Lawrence Donehower, a researcher affiliated with Baylor College of Medicine's Human Genome Sequencing Center and its molecular virology and microbiology department, and his colleagues wrote.

They noted that the current findings "may facilitate the development of diagnostic and therapeutic tools based on a more robust knowledge of the p53 signaling pathway in cancer."

For their analysis, the researchers studied exome sequencing profiles for 10,225 tumors, spanning 32 cancer types, which had been assessed for TCGA. Together with RNA sequencing, copy number, and other data, they were able to compare multiple genomic features in the 3,786 tumors with TP53 mutations to those in the remaining, TP53 mutation-free tumors.

The TP53 mutations tended to be most common in ovarian and uterine carcinosarcoma, the team reported. The vast majority of tumors with TP53 mutations — more than 90 percent — had loss-of-function changes affecting both copies of the tumor suppressor and transcriptional regulatory gene. In around 10 percent of tumors, each TP53 allele was impacted by a distinct alteration.

With the data on hand, though, the researchers were able to get a look at not only the distribution of TP53 mutations across cancer types and the mutation-prone sites in the gene, but also the interplay between TP53 mutations and other tumor genome features, ranging from genomic stability to gene and protein expression.

"TP53 mutations are associated with enhanced chromosomal instability, including increased amplification of oncogenes and deep deletion of tumor suppressor genes," the authors reported. "Tumors with TP53 mutations differ from their non-mutated counterparts in RNA, miRNA, and protein expression patterns, with mutant TP53 tumors displaying enhanced expression of cell cycle progression genes and proteins."

Among other thing, the data also made it possible for the investigators to look at the potential relationships between TP53 mutations and patient outcomes in various cancer types. There, they found that a particular signature — enhanced expression of four genes related to TP53 mutation — coincided with poorer patient outcomes for 11 of the cancer types marked by TP53 mutation.

"We found that 11 of 24 cancer types with high p53 signatures resulted in significantly poorer overall survival relative to their low-signature counterparts," the authors wrote, noting that "the mutant TP53 signature was distinctly better at predicting poorer outcomes than TP53 mutation status" in eight of the 11 cancer types.