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The survey that showed p53 is the most commonly altered gene in human cancer and that the pattern of its mutations differs by cancer type and by cause, such as tobacco smoke in lung cancer and a dietary toxin in liver cancer.
Hollstein, Sidransky, Vogelstein and Harris compiled the p53 mutations reported across human tumours and showed that they occurred in a wide range of cancers, clustered in the evolutionarily conserved regions of the gene, and mostly changed single amino acids rather than truncating the protein. The spectrum of mutations varied by tumour type and exposure: G to T changes typical of tobacco carcinogens in lung cancer and a specific codon 249 change in liver cancers from regions with aflatoxin exposure. The paper established p53 mutation as a molecular record of carcinogen exposure.
This paper is why TP53 status is reported in almost every tumour genome and why mutational signatures can point to causes. Its idea that mutation patterns record exposures grew into the mutational signature field, and TP53 mutation remains a marker of shorter survival and a drug target still being pursued.
This paper is the reason TP53 status, MDM2 amplification and CDKN2A loss are read together in tumour genomes. It frames the current drug development around MDM2 inhibitors and mutant p53 reactivators as attempts to restore a network rather than a single protein.
This review fixed the picture of p53 as the guardian of the genome that every textbook uses. It explains why TP53-mutant cancers are aggressive and hard to treat, why MDM2 inhibitors are being developed to reactivate wild-type p53, and why germline TP53 testing matters in families.
Shares Levine 1997: p53, the cellular gatekeeper for growth and division, Tumour suppressor gene, Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center, Colorectal cancer.
Shares Vogelstein, Lane and Levine 2000: surfing the p53 network, TP53.
Shares Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center, Colorectal cancer.
Shares Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center, TP53, Colorectal cancer.
Shares Vogelstein, Lane and Levine 2000: surfing the p53 network, TP53, Non-small-cell lung cancer.
Shares Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Vogelstein, Lane and Levine 2000: surfing the p53 network, TP53.