ClinVar Genomic variation as it relates to human health

Ara et al. (1990) reported that the pro72-to-arg (P72R) change in p53 is caused by polymorphism rather than mutation. Olschwang et al. (1991) assessed the frequency of the pro72-to-arg (P72R) polymorphism and, from its frequency in colon cancer patients and control subjects, concluded that there was no strong association with colon cancer. In both the cancer group and the control group, the frequencies of the pro72 and arg72 alleles were about 31 and 69%, respectively. The E6 oncoprotein derived from tumor-associated human papillomaviruses (HPVs) binds to and induces degradation of p53. Storey et al. (1998) investigated the effect of the P72R polymorphism on susceptibility of p53 to E6-mediated degradation and found that the arg72 form of p53 was significantly more susceptible than the pro72 form. Moreover, allelic analysis of patients with HPV-associated tumors revealed a striking overrepresentation of homozygous arg72 p53 compared with the normal population, indicating that individuals homozygous for arg72 are about 7 times more susceptible to HPV-associated tumorigenesis than heterozygotes. Using immunoprecipitation followed by SDS-PAGE, Thomas et al. (1999) found that the arg72 and pro72 p53 variants did not differ in their ability to bind DNA in a sequence-specific manner. They concluded that arg72 and pro72 are conformationally indistinguishable and that both can be considered wildtype. However, Thomas et al. (1999) noted that p53(pro) was a stronger inducer of transcription than p53(arg), whereas p53(arg) induced apoptosis faster and was a more potent suppressor of transformation than p53(pro). Marin et al. (2000) found that some tumor-derived p53 mutants bound and inactivated p73 (601990). The binding of such mutants was influenced by whether TP53 codon 72 encoded arginine or proline. The ability of p53 to bind p73, neutralize p73-induced apoptosis, and transform cells in cooperation with EJ-Ras (see 190020) was enhanced when codon 72 encoded arg. Marin et al. (2000) found that the arg-containing allele was preferentially mutated and retained in squamous cell tumors arising in arg/pro germline heterozygotes. They concluded that inactivation of p53 family members may contribute to the biologic properties of a subset of p53 mutants, and that a polymorphic residue within p53 affects mutant behavior. Laryngeal papillomatosis is caused by human papillomavirus and is associated with malignant transformation in 3 to 7% of cases. Aaltonen et al. (2001) found no difference in the prevalence of the P72R polymorphism between a group of patients with laryngeal papillomas and a control group. The pro72-to-arg polymorphism occurs in the proline-rich domain of p53, which is necessary for the protein to fully induce apoptosis. Dumont et al. (2003) found that in cell lines containing inducible versions of alleles encoding the pro72 and arg72 variants, and in cells with endogenous p53, the arg72 variant induced apoptosis markedly better than the pro72 variant. They suggested that at least 1 source of this enhanced apoptotic potential is the greater ability of the arg72 variant to localize to mitochondria; this localization was accompanied by release of cytochrome c into the cytosol. In 92 Caucasian MLH1 (120436) or MSH2 (609309) mutation carriers, including 47 with colorectal cancer, Jones et al. (2004) analyzed the p53 codon 72 genotype and found that arg/pro heterozygotes were 1.94 times more likely to get colorectal cancer during any age interval and developed it 13 years earlier than arg/arg homozygotes. The number of pro/pro homozygotes was too small to provide meaningful results. Kruger et al. (2005) studied the p53 genotype of 167 unrelated patients with hereditary nonpolyposis colon cancer (HNPCC; see 120435) with germline mutations in either MSH2 or MLH1 and found that the median age of onset was 41 years for arg/arg, 36 years for arg/pro, and 32 years for pro/pro individuals (p less than 0.0001). There was no difference in age of onset in 126 patients with microsatellite stable colorectal cancers. Kruger et al. (2005) concluded that in a mismatch repair-deficient background, p53 codon 72 genotypes are associated with the age of onset of colorectal carcinoma in a dose-dependent manner. Bougeard et al. (2006) studied the effect of the MDM2 SNP309 polymorphism (164785.0001) and the arg72-to-pro polymorphism of the p53 gene on cancer risk in 61 French carriers of the p53 germline mutation. The mean age of tumor onset in p53 codon 72 polymorphism arg allele carriers (21.8 years) was different from that of pro/pro patients (34.4 years, p less than 0.05). Bougeard et al. (2006) also observed a cumulative effect of both polymorphisms because the mean ages of tumor onset in carriers of MDM2 G and p53 arg alleles (16.9 years) and those with the MDM2 T/T and p53 pro/pro genotypes (43 years) were clearly different (p less than 0.02). The results confirmed the impact of the MDM2 SNP309 G allele on the age of tumor onset in germline p53 mutation carriers, and suggested that this effect may be amplified by the p53 arg72 allele. IASPP (607463) is among the most evolutionarily conserved inhibitors of p53, whereas ASPP1 (606455) and ASPP2 (602143) are activators of p53. Bergamaschi et al. (2006) showed that, in addition to the DNA-binding domain, the ASPP family members also bound to the proline-rich region of p53 containing the codon 72 polymorphism. Furthermore, the ASPP family members, particularly IASPP, bound to and regulated the activity of p53 pro72 more efficiently than that of p53 arg72. Orsted et al. (2007) stated that arg72 increases the ability of p53 to locate to mitochondria and induce cell death, whereas pro72 exhibits lower apoptotic potential but increases cellular arrest in G1 of the cell cycle. In a study of 9,219 Danish individuals, they found that overall 12-year survival was increased in p53 arg/pro heterozygotes by 3% (P of 0.003) and in pro/pro homozygotes by 6% (P of 0.002) compared with arg/arg homozygotes, corresponding to an increase in median survival of 3 years for pro/pro versus arg/arg homozygotes. Pro/pro homozygotes also showed increased survival after development of cancer, or even after development of other life-threatening diseases, compared with arg/arg homozygotes. The arg72-to-pro change was not associated with decreased risk of cancer. Among 254 patients with glioblastoma multiforme (see 137800), El Hallani et al. (2009) found an association between the pro72 allele and earlier age at onset. The pro/pro genotype was present in 20.6% of patients with onset before age 45 years, compared to in 6.5% of those with onset after age 45 years (p = 0.002) and 5.9% among 238 controls (p = 0.001). The findings were confirmed in an additional cohort of 29 patients. The variant did not have any impact on overall patient survival. Analysis of tumor DNA from 73 cases showed an association between the pro allele and a higher rate of somatic TP53 mutations. In a study of 863 individuals with European grandparents from an unselected New Zealand birth cohort, Hancox et al. (2009) analyzed lung function (FEV1 and FEV1/FVC) between ages 18 and 32 in relation to cumulative history of cigarette smoking and the rs1042522 SNP, and found that the G allele was associated with smoking-related accelerated rate of decline in lung function (see 608852) (FEV1, p = 0.020; FEV1/FVC, p = 0.037). (less)

The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)