© The Author 2006. Published by Oxford University Press.
BRIEF COMMUNICATION |
Association Between MDM2–SNP309 and Age at Colorectal Cancer Diagnosis According to p53 Mutation Status
Affilations of authors: IST-Genova (CM, MM) c/o Azienda Ospedaliera di Padova and Istituto Oncologico Veneto, Padova, Italy (MB, GE, RB); Clinical Trials and Biostatistical Unit, Istituto Oncologico Veneto, Padova, Italy (GLDS); Department of Oncology and Surgical Sciences, University of Padova, Padova, Italy (MCS, MQ, CB, SA, EDA, DN, AA)
Correspondence to: Chiara Menin, PhD, Dipartimento di Scienze Oncologiche e Chirurgiche, Sezione di Oncologia, via Gattamelata 64, 35128 Padova, Italy (e-mail: chiara.menin{at}unipd.it).
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ABSTRACT |
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 TopNotes Abstract References |
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A single-nucleotide polymorphism (SNP) in the promoter of the MDM2 gene, SNP309 (a T
G change), was recently implicated in the early onset of cancer in individuals with Li-Fraumeni syndrome and of sporadic soft-tissue sarcoma. SNP309 induces an increase in the level of Mdm2 protein, which causes attenuation of the p53 pathway. To investigate the effect of this polymorphism in colorectal cancer pathogenesis, we genotyped 153 colorectal cancer patients who were randomly selected from among 330 consecutive patients stratified according to p53 mutation status and age at diagnosis, for alleles of MDM2–SNP309. Among the 77 patients with p53 wild-type tumors, the median age at colorectal cancer diagnosis was 71.5 years for patients with the T/T genotype and 61.0 years for patients with SNP309 (T/G or G/G genotype) (estimated difference between medians [Hodges–Lehmann method] = 8.0 years, 95% confidence interval = 1.0 to 16.0 years; P = .03 [two-sided Wilcoxon rank sum test]). Our data indicate that MDM2–SNP309 is a modifier of the age at colorectal cancer onset for patients whose tumors have a wild-type p53 gene.
Genetic factors play a key role in the predisposition to colorectal cancer as well as in the initiation and progression of the disease. High-penetrance mutations in several genes (i.e., APC, DNA mismatch repair genes, LKB1, and SMAD4) confer predispositions to familial cases of colorectal cancer (i.e., familial adenomatous polyposis, Lynch syndromes, hamartomatous polyposis), which account for less than 5% of all colorectal cancer cases (1). However, low-penetrance variants of these and other genes, such as common alleles at single-nucleotide polymorphisms (SNPs) (1,2), account for much of the predisposition resulting in sporadic cases of colorectal cancer and are probably responsible for much of the uncharacterized influence of inherited genetic changes on the development of colorectal cancer.
Genes implicated in low-penetrance genetic susceptibility to colorectal cancer are usually investigated on the basis of their biologic plausibility. For example, candidate low-penetrance variants have been identified in genes that encode carcinogen metabolism enzymes, methylation enzymes, DNA repair proteins, microenvironmental modifiers, oncogenes, and tumor suppressor genes (2,3). Approximately 50% of colorectal cancers have alterations in the gene that encodes the tumor suppressor p53, which regulates the cellular stress response pathway that has been shown to be critical for maintenance of genomic integrity. Therefore, genetic variants that interfere with the p53–cellular stress response pathway might function as modifiers of individual colorectal cancer risk. The intracellular level of p53 is regulated through an autoregulatory feedback loop in which p53 induces transcription of MDM2, a gene that encodes a ubiquitin protein ligase that regulates the stability of p53 by targeting it for proteasomal degradation. Therefore, overexpression of the MDM2 gene should be oncogenic. Indeed, a recent study has shown that a SNP in the MDM2 gene promoter, SNP309 (a TG change at nucleotide 309 in the first intron), increases the affinity of the promoter for the transcriptional activator Sp1, resulting in higher levels of MDM2 mRNA and Mdm2 protein and a subsequent attenuation of the p53 pathway (4). Accordingly, human cancer cell lines homozygous (G/G) for SNP309 and wild-type p53 (i.e., Manca, CCF-STTG1, and A875 cells) showed a drug-induced DNA damage response similar to that of cells that were wild type (T/T) for SNP309 and mutant for the p53 gene (Saos 2 cells). These data led the authors to hypothesize that MDM2–SNP309 could modify cancer incidence as well as the timing of cancer onset. In the same study (4), it was reported that in families afflicted with the cancer predisposition disorder Li-Fraumeni syndrome, which is characterized by a germline p53 mutation, members who were either heterozygous or homozygous for the G allele of MDM2–SNP309 were diagnosed with tumors 9–10 years earlier than those who were homozygous for the wild-type allele (T) of SNP309. These authors also observed an earlier age at tumor diagnosis (i.e., earlier by approximately 12 years) among a group of patients with unknown p53 status who developed sporadic adult soft-tissue sarcoma.
To further explore the relevance of these findings, we tested the hypothesis that MDM2–SNP309 acts as a low-penetrance gene for colorectal cancer susceptibility among the general population. We randomly selected 153 Italian white colorectal cancer patients from among 330 consecutive patients with histologically confirmed colon or rectal adenocarcinoma who were stratified according to p53 mutation status (negative or positive) and age quartiles and who had been treated at Surgical Section of our department between 1991 and 1998. All patients provided written informed consent to genetic studies, which were approved by the ethical committee of the Oncology Centre of the Veneto Region in Padova, Italy. To verify the hypothesis that patients bearing MDM2–SNP309 may develop colorectal cancer 10 years earlier than patients with the wild-type allele, we analyzed 153 patients because we determined that a sample size of 76 patients for each group of p53 status would give us an 85% power to detect a 10-year difference in colorectal cancer diagnosis, using the Wilcoxon rank-sum test, with two-sided statistical significance set at .05. To obtain a representative sample with respect to age groups, we stratified our cohort for age quartiles and p53 status randomly selecting 19 patients in each stratum. The average and median ages of the 153 colorectal cancer patients at diagnosis were 63.8 years (standard deviation = 14.2 years) and 65.0 years (range = 24.0 to 92.0 years), respectively. Sixty-nine patients had tumors that were confined to the colon with no metastatic secondary tumor [American Joint Commission on Cancer (AJCC) stage I or II (5)], and 84 patients presented with lymph node or distant metastasis (AJCC stage III or IV). Twenty-two tumors were classified as grade 1, 110 as grade 2, 17 as grade 3, and four tumors were mucinous. For MDM2–SNP309 genotyping, tumor DNA was isolated by standard phenol–chloroform method from frozen tissues and amplified by a polymerase chain reaction (PCR) using primer pairs specific for the two alleles: primers F1 (5'-GGATTTCGGACGGCTCTC-3') and R1 (5'-TCCGGACCTCCCGCGCCGA-3') were used to amplify the 121-bp wild-type allele (T) and primers F2 (5'-GTTTTGTTGGACTGGGGCTA-3') and R2 (5'-ATCCGGACCTCCCGCGCCGC-3') were used to amplify the 168-bp mutant allele (G). Two independent PCR assays were performed for each allele by using 100 ng of genomic DNA, 15 pmol of each primer, 1 U of TaqGold polymerase (Applied Biosystems, Foster City, CA), 200 µM dNTP, 1.5 mM MgCl2, 10 mM Tris–HCl (pH 8.3), 50 mM KCl, and 5% dimethyl sulfoxide. The amplification protocol consisted of 35 cycles of 94 °C for 30 seconds, followed by 60 °C for 30 seconds and 72 °C for 30 seconds. The amplification products were resolved on a 3% NuSieve–agarose gel (BioWhittaker Molecular Applications, Rockland, ME) and stained with ethidium bromide. To establish the MDM2–SNP309 frequency in the general population, we also performed MDM2–SNP309 genotyping on blood samples from 92 healthy control subjects selected from among geographically matched white blood donors. In all 330 cases, we searched for mutations in exons 4–8 of the gene encoding p53 by subjecting DNA to PCR followed by single-strand conformational polymorphism detection of point mutations (PCR–SSCP analysis), as previously described (6); tumor samples that displayed a shifted electrophoretic pattern compared with the corresponding normal tissue from the same patient were subsequently analyzed by direct DNA sequencing (6).
The results of MDM2–SNP309 genotyping are summarized in Table 1. We observed no association between MDM2–SNP309 and colorectal cancer incidence. In fact, we found that the frequency of the T/G and G/G genotypes of SNP309 was similar in colorectal cancer patients and control subjects, regardless of p53 mutation status (P = .89; two-sided Fisher's exact test); moreover, we found no association between MDM2–SNP309 and histologic grade or tumor stage (data not shown).
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We next compared the age distribution at colorectal cancer diagnosis for patients who had the homozygous wild-type (T/T) genotype with that of patients who had either heterozygous (T/G) or homozygous (G/G) variant genotypes at SNP309 by using the Wilcoxon rank-sum test. We found no statistically significant association between SNP309 genotype and the median age at diagnosis when all 153 colorectal cancer patients were included in the analysis [median age at diagnosis was 69 years for patients with T/T genotype at SNP309 and 63 years for patients with T/G or G/G genotype at SNP309; estimated difference between medians by Hodges–Lehmann method (7) = 4.0 years; 95% confidence interval (CI) = 0 years to 9.0 years; P = .07 (two-sided Wilcoxon rank-sum test)]. When only the 77 colorectal cancer patients who had p53 wild-type tumors were included in the analysis, we found a statistically significant association between the age at colorectal cancer diagnosis and MDM2–SNP309. Among the patients with p53 wild-type tumors, the median age at colorectal cancer diagnosis was 71.5 years for patients with the T/T genotype at SNP309 and 61.0 years for patients with the T/G or G/G genotype at SNP309 (estimated difference between medians = 8.0 years, 95% CI = 1.0 years to 16.0 years; P = .03 [two-sided Wilcoxon rank-sum test]) (Fig. 1, A). By contrast, the age at colorectal cancer diagnosis among p53 mutation–positive patients was not associated with the SNP309 genotype (median age at diagnosis was 67 years for patients with T/T genotype at SNP309 and 65 years for patients with T/G or G/G genotype at SNP309; estimated difference between medians = 0 years; 95% CI = –5.0 to 7.0 years; P = .89 [two-sided Wilcoxon rank-sum test]) (Fig. 1, B).
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Our observations support the hypothesis that in tumors with p53 mutations, MDM2–SNP309 does not affect the timing of cancer onset because the mutant p53 itself is likely the crucial factor in carcinogenesis. On the other hand, in tumors with wild-type p53, the presence of the G allele of MDM2–SNP309 induces constitutive high levels of Mdm2 protein that blocks p53 transactivation functions early (4,8). Therefore, the onset of colorectal cancer might be accelerated in cells with MDM2–SNP309 (T/G heterozygous or G/G homozygous) and wild-type p53 gene. In fact, many studies have shown that overexpression of MDM2 is an important event in tumor progression [reviewed in Momand et al. (9)], and Abdel-Fattah et al. (10) have found that it is an early event during the adenoma–carcinoma sequence.
To examine whether MDM2–SNP309 had functional consequences with respect to level of p53 protein in the tumors, we subjected all 153 tumor samples to immunohistochemical staining with two different monoclonal antibodies against human p53, BP53-12-1 (1 : 500 dilution; BioGenex, San Ramon, CA) and polyclonal antibody 1801 (1 : 100 dilution; Oncogene Science, Uniondale, NY), as previously described (6). Samples showing more than 10% stained cells were scored as positive. Among the 45 colorectal cancer patients who had wild-type p53 and had the T/G or G/G genotype at MDM2–SNP309, 18 (40%) scored positive by immunohistochemistry for p53 protein (data not shown). It was recently reported that overexpression of endogenous MDM2 via the G allele at SNP309 may have resulted in the formation of an inactive complex between Mdm2 and p53 (11). This complex localizes at the chromatin level and stabilizes p53, which becomes detectable by immunohistochemistry. However, MDM2 overexpression also promotes the rapid degradation of p53 (12), which might explain the lack of p53 staining in tumors from the remaining 27 colorectal cancer patients within this group. Mdm2 has been reported to display both p53-dependent and p53-indepedent activities in connection with its tumorigenic properties (12). Indeed, the fact that Mdm2 interacts with other cellular proteins that are involved in cell cycle regulation (13) might partially explain the lack of association between MDM2 overexpression and stabilization of p53 in colorectal cancers (10,14,15). Additional studies that focus on the expression status of p53 and Mdm2, at both the gene and protein levels, as well as on the expression of other proteins targeted by the Mdm2 protein, are needed to determine the specific role played by SNP309-mediated MDM2 overexpression in colorectal cancer pathogenesis.
In conclusion, our results support the hypothesis that MDM2–SNP309 is a modifier of age at colorectal cancer onset, but only among patients with wild-type p53 tumors. This hypothesis is consistent with the data reported by Bond et al. (4), which demonstrated an association between early cancer onset and MDM2–SNP309 in Li-Fraumeni patients as well as in sporadic soft-tissue sarcomas. In fact, more than half of tumors that arise in Li-Fraumeni patients retain a wild-type p53 gene (16), which likely codes for functional p53 that is susceptible to the effect of an aberrant MDM2 expression due to SNP309 like the sporadic colorectal cancers with wild-type p53 reported in our study. On the other hand, most (75%–80%) of the colorectal cancers with a p53 mutation lose the other (wild type) allele (6), rendering them insensitive to MDM2–SNP309. Nevertheless, our study cannot exclude the possibility that MDM2–SNP309 is associated with age at tumor onset in patients with p53 mutated tumors that retain the wild-type p53 allele. The finding of an MDM2–SNP309 modifier effect on age of cancer onset reported by Bond et al. in sporadic soft-tissue sarcomas, regardless of p53 mutation status, might simply reflect the relatively low p53 mutation frequency in this type of tumor (9). We conclude that the effects of MDM2–SNP309 on the timing of tumor formation require functional p53 and that both genes contribute to the genetic variability that underlies the phenotypic difference seen in individual susceptibility to colorectal cancer.
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NOTES |
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Supported by grants from the Ministero della Ricerca Scientifica e Tecnologica (FIRB ‘01; PRIN ‘03), Associazione Italiana per la Ricerca sul Cancro (AIRC), Lega Italiana per la Lotta contro i Tumori (LILT), and Fondazione Cassa di Risparmio di Padova e Rovigo. The study sponsors did not contribute to the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.
M. Biscuola is a research fellow of the Istituto Oncologico Veneto, Padova, Italy.
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Manuscript received July 26, 2005; revised November 30, 2005; accepted December 8, 2005.
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