p53 Polymorphisms: Cancer Implications

NATIVE EDIT TEST --- Catherine Whibley; Paul D. P. Pharoah; Monica Hollstein

Pediatr Health. 2009;15(4):119-128.

Abstract

The normal functioning of p53² is a potent barrier^[2] to cancer. Tumour-associated mutations² in TP53, typically single nucleotide substitutions in the coding sequence, are a hallmark of most human cancers and cause dramatic defects in p53 function. By contrast, only a small fraction, if any, of the >200 naturally occurring sequence variations (single nucleotide polymorphisms, SNPs) of TP53 in human populations are expected to cause measurable perturbation of p53 function. Polymorphisms in the TP53 locus that might have cancer-related phenotypical manifestations are the subject of this Review. Polymorphic variants of other genes in the p53 pathway, such as MDM2, which might have biological consequences either individually or in combination with p53 variants are also discussed.

Introduction

The tumour suppressor p53 is a key player in stress responses that preserve genomic stability, responding to a variety of insults including DNA damage, hypoxia, metabolic stress and oncogene activation.^[1,2] The most well-documented mechanism by which p53 exercises its protective roles is as a transcription factor. By binding to specific response elements in DNA, p53 modulates the transcription of genes that govern the major defences against tumour growth, which include cell cycle arrest, apoptosis, maintenance of genetic integrity, inhibition of angiogenesis and cellular senescence.^[3] p53 also interacts with numerous cellular proteins, including several that control programmed cell death, and these molecular interactions might contribute to the inhibitory role of p53 in tumorigenesis.^{[4,5,6,7,8,9]}

Malfunction of the p53 pathway is an almost universal hallmark of human tumours.^[1,2] Somatic mutation of TP53 that results in the absence or dysfunction of p53 is one of the most common mechanisms by which the p53 pathway is damaged during tumorigenesis. The direct loss of properly functioning p53 is also associated with an unfavourable prognosis in some types of cancer.^[10] In this Review, three distinct sets of sequence alterations at the TP53 locus will be referred to: tumour-associated mutations, germline Li�Fraumeni mutations and germline p53 polymorphisms.

The tumour-associated mutations in sporadic cancers arise in somatic cells, both spontaneously and as a consequence of DNA damage. The mutations selected for in tumorigenesis are usually single base substitutions that result in amino acid substitutions in the DNA-binding domain (DBD) of p53 (missense mutations). Typically, the mutant tumour-associated p53 proteins have lost most or all of the normal p53 functions. Although mutation in TP53 is a frequent mechanism by which p53 function is lost in tumorigenesis, in some types of cancer other routes prevail, such as gene amplification of key negative regulators of p53, MDM2 and MDM4 .

Germline TP53 mutations are found in individuals with Li�Fraumeni syndrome, which confers an increased risk of developing various cancers, including sarcomas, breast and brain cancers, and adrenocortical tumours, at an early age of onset.^[11] As is the case for somatic tumour-associated mutations, Li�Fraumeni mutations are most often missense base substitutions in the DBD, and encode defective proteins.

Germline TP53 polymorphisms are the subject of this Review. Unlike mutations associated with Li�Fraumeni syndrome or somatic tumour-associated mutations, most polymorphisms are expected to be phenotypically silent, with an occasional variant that might affect cancer risk by compromising the normal activities of p53, although the effects of these variants are probably more subtle than those of p53 mutations associated with cancer or Li�Fraumeni syndrome. To avoid confusion, single nucleotide polymorphisms (SNPs) are not usually referred to as mutations, which is a term generally reserved for p53 sequence changes that arise during tumorigenesis or are found in patients with Li�Fraumeni syndrome.

TP53 is unique among tumour suppressor genes because so many different missense mutations can occur within it that generate a range of mutant p53 proteins with varying levels of residual activity. These diverse tumour-associated mutations have been compiled in databases, together with details of the frequency of the mutations and a summary of molecular studies that have characterized the activities of each mutant (the IARC TP53 mutation database, the p53 Knowledgebase, the TP53 Web Site and the Database of germline p53 mutations). Depending on the mutation, different elements of normal p53-mediated responses can be lost and some mutants can gain new non-wild-type functions. The oncogenic properties of gain-of-function mutant p53 proteins are currently under intensive investigation because an in-depth understanding of the molecular mechanisms might ultimately have translational benefits in the clinic.^[12] There is evidence to suggest that gain-of-function mutants can interact with other transcription factors, such as nuclear transcription factor Y (NF-Y) or p73, to transcriptionally activate or repress a unique subset of genes, leading to disruption of cell cycle regulation and apoptosis.^[13] Mutant p53 interactions with multiprotein complexes that are involved in recombination and DNA double-strand break repair might also contribute to the deregulation of homologous recombination, interchromosomal translocations and aneuploidy, which are observed in neoplastic cells that express gain-of-function p53 mutants.^[14,15,16]

A major lesson from the human tumour-associated p53 mutation databases is that TP53 is unusually vulnerable to a large range of single nucleotide alterations that compromise the function of the wild-type protein and can even confer new oncogenic activities. This raises the possibility that at least some of the germline polymorphisms of TP53 in healthy populations might also impinge on p53 function. This is despite the fact that only a small fraction of the many polymorphic sequence variations at gene loci in the human genome (most of which are intronic) are likely to have any cancer-associated phenotypical manifestations. Features that suggest a potential phenotypical consequence include polymorphisms in the coding sequence that alter amino acid sequence, or variants that affect expression levels; for example, polymorphisms in promoters, splice sites, untranslated regions (UTRs) or protein-binding elements. Unlike the high-penetrance germline mutations that underlie syndromes such as Li�Fraumeni and ataxia�telangiectasia (discussed later), polymorphisms are generally expected to have more modest effects, such as causing an earlier age of disease onset or leading to a small increase in the risk of cancer. This presents methodological challenges for establishing and verifying the biological effects of polymorphisms. Identifying polymorphisms that have a small effect on cancer risk requires a multidisciplinary approach, including molecular studies and population-based research using high-throughput sequencing and high-resolution SNP mapping.

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Table 1. Additional Roles for the p53 Tumour Suppressor
Physiological roles of p53	Examples of proposed mechanisms	Refs
Reproduction	Transcription of LIF is controlled by p53, with enhancement by the p53-R72 variantLevels of LIF affect implantation success	^[65,66]
Prolonged organismal life span	p53 controls stem cell self-renewalIn carriers of the p53-P72 variant, apoptosis can be attenuated, with a reduced age-associated attrition of stem cell populations	^{[85,161,162,163]}
Antioxidant functions	Transcriptional activation of genes encoding enzymes that reduce the cellular levels of reactive oxygen species, including GPX1, SOD2 and sestrins	^[164]
Autophagy	Transcriptional activation of DRAM, a lysosomal membrane protein required for autophagyInhibition of mTOR, a negative regulator of autophagy	^[165,166]
Glucose metabolism	Transcriptional activation of TIGAR, which blocks glycolysis and directs the pathway to the pentose phosphate shunt	^[167,168]
Mitochondrial respiration	Transcriptional activation of SOCS2, a cytokine-induced negative regulator of cytokine signalling	^[169]
Embryonic stem cell pools	Suppression of NANOG by p53 causes embryonic stem cell differentiation	^[170]

DRAM, damage-regulated autophagy mediator; GPX1, glutathione peroxidase 1; IGF1R, insulin-like growth factor 1 receptor; LIF, leukaemia-inhibitory factor; SOCS2, suppressor of cytokine signalling 2; SOD2, superoxide dismutase [Mn], mitochondrial; TIGAR, TP53-induced glycolysis and apoptosis regulator.

Table 2. Polymorphisms in p53 Pathway Genes
Gene	Relation to p53	Cellular function	Polymorphisms potentially associated with cancer	Disease association	Potential or associated functional change	Refs
TP53	Encodes p53	Tumour suppressor: induces cell cycle arrest and apoptosis and senescence in response to stress	R72PP47SIntron 3 16 bp insertion	p53 often mutated in cancer Germline TP53 mutations in Li�Fraumeni syndrome Knockout mice are susceptible to tumours	See text	^[1,2,3]
MDM2	Regulator of p53 protein Induced by p53	Core control of p53 levels, activity and localization within the cell	SNP309 (promoter region)	Homozygous knockout in mice is embryonic lethal, but can be rescued by simultaneous knockout of Trp53	Enhanced SP1 binding site (G variant) increases transcription by ER Higher MDM2 levels suppress p53, reducing tumour suppression	^[113]
CDKN1A	Induced by p53	Regulator of cell cycle progression	S31RR84Q	Knockout mice develop normally, but develop tumours early	Reduced G1 arrest in response to DNA damage, which could alter responses to therapy	^{[131,141,142]}
ATM	Phosphorylates (and activates) p53 in response to DNA damage	Recognizes DNA damage and activates p53 and DNA damage response pathways	D1853N	Homozygous mutant ATM results in AT, which confers a 100-fold increased cancer risk	Decreased activation of p53	^[122,171]
BAX	Induced by p53 Interacts with other apoptotic proteins at the mitochondria	Forms a heterodimer with BCL-2 , activating MOMP and the mitochondrial apoptotic pathway	g>a (125 bp upstream of start site)	Lower levels of BAX in multiple tumour types predict poor response to chemotherapy		^[148,172]
TP53I3	Induced by p53	Oxidoreductase-like protein involved in apoptosis	Promoter microsatellite		Increased induction by p53 with increased microsatellite length improves apoptotic response	^[145]
AKT1	Activates MDM2, which inhibits p53	A Ser�Thr kinase induced by growth factors that inhibits apoptosis by activating MDM2	The haplotype (five SNPs in AKT1) in Caucasian populations results in higher levels of AKT1 than in African populations	Some polymorphisms are associated with schizophrenia Knockout mice are smaller (Akt1^-/- )	Lower levels of AKT1 sensitize cells to apoptotic signals	^[173,174]
TP73	Induces p53 Induced by p53 Physically interacts with p53	p53-like protein, shares many p53 functions, including induction of apoptosis and cell cycle arrest	Two linked SNPs in the non-coding region of exon 2		In combination with MDM2 SNP309 increases cancer risk	^[175,176]
NQO1	Stabilizes p53 by an MDM2-independent mechanism	Protects against oxidative stress and carcinogenesis	P187S	NQO1 variant associated with susceptibility to various cancers Altered expression in many tumours and Alzheimer's disease	P187S causes loss of NQO1 activity, and its tumour- suppressive and antioxidative effects, affecting cancer risk and response to therapy	^{[108,177,178]}

AT, ataxia�telangiectasia; ATM, ataxia�telangiectasia mutated; bp, base pair; CDKN1A, cyclin-dependent kinase inhibitor 1; ER, oestrogen receptor; MOMP, mitochondrial outer membrane permeabilization; NQO1, NADPH dehydrogenase quinone 1; SNP, single nucleotide polymorphism; TP53I3, tumour protein p53 inducible protein 3.

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