p53 codon 72 alleles influence the response to anticancer drugs in cells from aged people by regulating the cell cycle inhibitor p21WAF1.

A common polymorphism at codon 72 in p53 gene leads to an arginine to proline aminoacidic substitution which affects in an age-dependent manner the susceptibility of cells to undergo apoptosis after oxidative stress. Here we report that dermal fibroblasts from Proline allele carriers (Pro+) display a higher expression of p21WAF1 gene, in both basal conditions and after treatment with doxorubicin or camptothecin. This phenomenon is accompanied by a lower susceptibility of Pro+ cells to undergo apoptosis, a lower capability to over cross G1-S transition and an increased propensity to express markers of cell senescence, with respect to fibroblasts from Arginine homozygotes (Pro-). All these phenomena are particularly evident in cells from centenarians. We conclude that the functional difference between the two p53 codon 72 alleles exerts a broad impact on the capability of cell from aged people to respond to stressors such as cytotoxic drugs.

The G/C915 polymorphism of transforming growth factor beta1 is associated with human longevity: a study in Italian centenarians.

Sequence variations in a variety of pro- or anti-inflammatory cytokine genes have been found to influence successful aging and longevity. Because of the role played by the transforming growth factor beta1 (TGF-beta1) cytokine in inflammation and regulation of immune responses, the variability of the TGF-beta1 gene may affect longevity by playing a role in inflamm-aging. Two polymorphisms, G/A -800 and C/T -509, located in the 5' region, and two missense polymorphisms, T/C 869 and G/C 915 which change (Leu > Pro)10 and (Arg > Pro)25, respectively, located in the signal peptide, were analysed in 419 subjects from Northern and Central Italy, including 172 centenarians and 247 younger controls. In addition, the effects of the TGF-beta1 genetic variability on plasma levels of the biologically active form (naturally processed) of this cytokine were studied in 143 randomly selected subjects, including 73 centenarians. Significant differences were found at the +915 site as far as the C allele and GC genotype were concerned, both of them being lower in centenarians than in young controls (P=0.034 and 0.028, respectively), but none of the other tested genetic variants was significantly different between centenarians and controls. Moreover, a particular haplotype combination (G -800/C -509/C 869/C 915) was notably lower in centenarians than in younger individuals (P=0.007). Finally, active TGF-beta1 plasma levels were significantly increased in the elderly group, but no relationship with TGF-beta1 genotypes was observed. These results suggest that, at least in this population, the variability of the TGF-beta1 gene influences longevity and that the age-related increase in plasma levels of active TGF-beta1 seems not to be genetically regulated.

Retention of the p53 codon 72 arginine allele is associated with a reduction of disease-free and overall survival in arginine/proline heterozygous breast cancer patients.

PURPOSE: The arginine to proline substitution at codon 72 represents a common aminoacidic polymorphism of the p53 protein. Recent data suggest that p53 codon 72 may modulate the response to cancer therapy. The aim of this study was to test the hypothesis that the p53 codon 72 genotype, evaluated in the tumor tissue and in the disease-free lymph node, is related to differences in disease-free and overall survival among breast cancer-affected patients. EXPERIMENTAL DESIGN: We assessed the p53 codon 72 genotype in DNA from disease-free lymph nodes and neoplastic tissues obtained from 67 women affected by breast cancer who underwent surgical resection at the Bologna Breast Cancer Surgical Unit from 1993 to 1995. RESULTS: We found that the retention of the p53 codon 72 arginine allele in the tumor tissue of proline/arginine heterozygous breast cancer patients is associated with statistically significant reduced disease-free and overall survivals. CONCLUSIONS: Our findings suggest that the genotyping for p53 codon 72 locus in both the tumor tissue and in the lymph node of breast cancer patients could contribute to identify a subset of arginine/proline heterozygous patients who have a reduced survival that is associated with the specific retention of the arginine allele in the tumor tissue.

p53 codon 72 genotype affects apoptosis by cytosine arabinoside in blood leukocytes.

A wide difference in the susceptibility to undergo in vitro apoptosis exists among individuals, and this fact has potential implications in predicting the in vivo response to apoptotic agents, such as those employed in chemotherapy. In this report, we addressed the question whether the natural variability at p53 locus (the proline-arginine substitution at codon 72) affects the capacity of peripheral-blood mononuclear cells from healthy subjects to undergo in vitro apoptosis in response to the cytotoxic drug cytosine arabinoside. We found that cells from subjects carrying the arginine/arginine genotype undergo in vitro apoptosis at a higher extent in comparison to those from arginine/proline subjects. This finding suggests that naturally occurring genetic variability at p53 gene explains part of the inter-individual difference in the in vitro susceptibility to a chemotherapeutic drug, thus resulting as an eligible predictor marker of in vivo response to chemotherapy and its adverse effects.