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2016 ; 6
(4
): a026302
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Genetic Modifiers of the p53 Pathway
#MMPMID27037420
Basu S
; Murphy ME
Cold Spring Harb Perspect Med
2016[Apr]; 6
(4
): a026302
PMID27037420
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The tumor suppressor gene TP53 is the most frequently mutated gene in human
cancer; this gene is subject to inactivation by mutation or deletion in >50% of
sporadic cancers. Genes that encode proteins that regulate p53 function, such as
MDM2, MDM4, and CDKN2A (p14(ARF)) are also frequently altered in tumors, and it
is generally believed that the p53 pathway is likely to be inactivated by
mutation in close to 100% of human tumors. Unlike most other cancer-relevant
signaling pathways, some of the genes in the p53 pathway contain functionally
significant single nucleotide polymorphisms (SNPs) that alter the amplitude of
signaling by this protein. These variants, thus, have the potential to impact
cancer risk, progression, and the efficacy of radiation and chemotherapy. In
addition, the p53 pathway plays a role in other biological processes, including
metabolism and reproductive fitness, so these variants have the potential to
modify other diseases as well. Here we have chosen five polymorphisms in three
genes in the p53 pathway for review, two in TP53, two in MDM2, and one in MDM4.
These five variants were selected based on the quality and reproducibility of
functional data associated with them, as well as the convincingness of
epidemiological data in support of their association with disease. We also
highlight two other polymorphisms that may affect p53 signaling, but for which
functional or association data are still forthcoming (KITLG and ANRIL). Finally,
we touch on three questions regarding genetic modifiers of the p53 pathway: Why
did these variants arise? Were they under selection pressure? And, is there
compelling evidence to support genotyping these variants to better predict
disease risk and prognosis?
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