Identification of colorectal cancer patients with tumors carrying the TP53mutation on the codon 72 proline allele that benefited most from 5-fluorouracil (5-FU) based postoperative chemotherapy
- Ten-i Godai†1,
- Tetsuji Suda†2,
- Nobuhiro Sugano1,
- Kazuhito Tsuchida1,
- Manabu Shiozawa1,
- Hironobu Sekiguchi3,
- Akiko Sekiyama3,
- Mitsuyo Yoshihara2,
- Shoichi Matsukuma2,
- Yuji Sakuma2,
- Eiju Tsuchiya2,
- Yoichi Kameda4,
- Makoto Akaike1 and
- Yohei Miyagi2Email author
© Godai et al; licensee BioMed Central Ltd. 2009
Received: 1 June 2009
Accepted: 2 December 2009
Published: 2 December 2009
Although postoperative chemotherapy is widely accepted as the standard modality for Dukes' stage C or earlier stage colorectal cancer (CRC) patients, biomarkers to predict those who may benefit from the therapy have not been identified. Previous in vitro and clinical investigations reported that CRC patients with wild-type p53 gene (TP53)-tumors benefit from 5-fluorouracil (5-FU) based chemotherapy, while those with mutated TP53-tumors do not. However, these studies evaluated the mutation-status of TP53 by immunohistochemistry with or without single-strand conformation polymorphism, and the mutation frequency was different from study to study. In addition, the polymorphic status at p53 codon 72, which results in arginine or proline residues (R72P) and is thought to influence the function of the protein significantly, was not examined.
To evaluate the significance of the TP53 mutation as a molecular marker to predict the prognosis of CRC patients, especially those who received postoperative chemotherapy, we examined the mutation by direct sequencing from fresh CRC tumors and evaluated the R72P polymorphism of the mutated TP53 by a combined mutant allele- and polymorphic allele-specific polymerase chain reaction (PCR).
The TP53 mutation occurred in 147 (70%) of 211 Japanese CRC tumors. The mutation was observed in 93 (63%) tumors on the R72 allele and in 54 (37%) tumors on the P72 allele. Although the alterations to TP53 have no prognostic significance for CRC patients overall, we found that Dukes' stage C CRC patients who did not receive postoperative chemotherapy and carried the mutated TP53-R72 showed significantly longer survival times than those with the mutated TP53-P72 when evaluated by overall survival (p = 0.012).
Using a combined mutant allele- and polymorphic allele-specific PCR, we defined the codon 72 polymorphic status of the TP53 mutated allele in Japanese CRC patients. We raised a possibility that Dukes' stage C colorectal cancer patients with tumors carrying TP53 mutation, especially the P72 allele, benefited from 5-FU based postoperative chemotherapy.
The tumor suppressor, p53, has a central role in stress responses that induce cell cycle arrest, senescence, apoptosis or DNA repair, and preserve genomic stability [1–6]. Therefore, dysfunction of the p53 pathway is a hallmark of neoplasms. Approximately half of all human tumors carry an alteration of the gene, TP53 . Alterations of TP53 play a significant role in the progression of colorectal cancer (CRC) and may be a clinically useful molecular marker of prognosis or response to treatments such as chemotherapy, radiotherapy or combination of the two. TP53 is unique among tumor suppressor genes because its alteration not only results in loss-of-function of the product, but also generates a range of mutants demonstrating a gain-of-function phenotype. Li et al. and Blandino et al. reported that the expression of selected p53 mutants inhibited p53-independent apoptosis induced by the γ-irradiation and the anticancer reagents such as doxorubicin, cisplatin and etoposide [8, 9]. Thereafter, in the last 10 years, the gain-of-function p53 mutants have been under intensive investigation because understanding the precise molecular mechanisms may provide information for personalized management and create promising therapeutic targets to benefit a large number of cancer patients [10, 11].
More than 200 single nucleotide polymorphisms (SNPs) have been identified for TP53, 19 of which are exonic. Eleven of the exonic SNPs are non-synonymous resulting in an exchange of coding amino acid residues . One of these SNPs results in either arginine (R) or proline (P) residues at codon 72 (R72P, rs1042522). A decade ago, this SNP gained attention when Storey et al. reported that the wild-type p53 with an arginine residue at codon 72 (hereafter p53-R72) is efficiently degraded by the E6 protein of the oncogenic type human papilloma viruses (HPV) and that p53-R72 homozygotes are at risk for HPV-associated uterine cervical cancer . In contrast, later reports demonstrated that p53 with a proline residue at codon 72 (hereafter p53-P72) is associated with an increased risk in lung, esophagus, breast, urothelial and colorectal cancers [13–18]. However, other studies did not find any association with colorectal cancer [19, 20]. The significance of the polymorphism R72P in association with the risk of cancer development or outcomes of cancer patients remains inconclusive, possibly due to differences in ethnic groups, genetic heterogeneity, sample number, cancer types, and treatment modalities in the each investigated cancer and population.
TP53 mutation in combination with the codon 72 polymorphic status has been examined extensively. Selected p53 mutants have been shown to gain the ability to bind to p73, a homologue of p53, and to inactivate the apoptosis pathway mediated by p73. Interestingly, this gain-of-function mutation is influenced by the p53 codon 72 polymorphism, and the mutated p53-R72 bind p73 more efficiently than the mutated p53-P72 . As a result, the mutated p53-R72 show an enhanced dominant negative influence on the p73L/p73 pathway [22, 23] and a significantly decreased response to cytotoxic chemotherapeutic reagents . Although these in vitro-findings are partly supported by clinical investigations in several kinds of cancers [25–27], it is not yet addressed in CRC. Thus, in this study, we examined the polymorphism R72P of mutated TP53 in relation to the outcome of CRC patients who was received postoperative chemotherapy.
Patient population and tissue specimens
Histological and clinical features of colorectal cancer patients (n = 212)
Age (years +/- SD)
64.5 +/- 10.8
Primary tumor location
Dukes' stage, (%)
Histopathological grade, (%)
Nucleic acid preparation and cDNA synthesis
Genomic DNA was isolated from tumor tissues using the QIAamp DNA Mini Kit (Qiagen KK, Tokyo, Japan) according to the manufacture's instructions. RNA was extracted with the TRIZOL® Reagent (Invitrogen, Carlsbad, CA), following the manufacture's instructions. First-strand cDNA was synthesized with an oligo(dT)12-18 primer and the SuperScript® First-Strand Synthesis System for RT-PCR (Invitrogen).
Mutational analysis of TP53 was performed by direct sequencing. Briefly, a 1.64 kb fragment of TP53 (corresponding to exons 5-8) was amplified from genomic DNA extracted from each tumor by polymerase chain reaction (PCR). The PCR products were purified and directly sequenced using GenomeLab™ DTCS Quick Start Kit and the CEQ™ 2000XL DNA Analysis System (Beckman Coulter, Inc., Fullerton, CA). The obtained nucleotide sequences were compared with the TP53 reference sequence (GenBank accession number X54156). The primers used to amplify exons 5-8 of TP53 are available on request.
Determination of the TP53codon 72 polymorphic status of tumors
For the determination of polymorphism at codon 72 of TP53, an allele-specific PCR assay was used as described previously [12, 30] with minor modifications. The precise information for PCR conditions is provided in Additional file 1.
For the TP53 mutated tumors with arginine/proline heterogeneous polymorphic status at codon 72, a combined method of the polymorphic allele-specific  and the mutant allele-specific  PCR was performed to determine whether the TP53 mutation occurred on the arginine allele or on the proline allele. Briefly, the method was designed to place the polymorphic nucleotides at the 3'-end of the forward primers and the mutated sites at the 3'-end of the reverse primers. The nucleotide sequences of the two polymorphic allele specific primers were 5'-gaggctgctccccg-3' for the arginine allele and 5'-gaggctgctccccc-3' for the proline allele. The nucleotide sequences of the reverse primers, specific to each mutation site, are listed in Additional file 2. The precise information for PCR conditions is also provided in Additional file 1.
The relationship between the codon 72 polymorphic status of the mutated allele of TP53 and individual clinicopathological variables were assessed using chi-square tests. Overall survival curves were generated by Kaplan-Meier analysis, and the log rank test was used to compare between survival curves. Differences were considered significant when a P value < 0.05 was obtained. All the statistic analyses were performed by SPSS version 15 for Windows (SPSS Inc. Chicago, IL).
TP53codon 72 polymorphic status of the tumors
Genotype frequencies at codon 72 of TP53 in colorectal cancer patients (n = 211)
Cases, n (%)
Age (years +/- SD)
64.7 +/- 10.8
64.8 +/- 11.2
63.2 +/- 10.2
Size (cm), n (%)
p53 mutations, n (%)
Mutations by codon 72 status, n
Mutation on Arg
Mutation on Pro
Dukes' stage, n (%)
TP53mutations of the tumors
TP53 mutation occurred in 148 (70%) of the tumors. One patient with tumors heterozygous for the codon 72 polymorphism had two different TP53 mutations on each allele. Therefore, we removed this case and used 211 patients for the following analyses (Table 2). Individual mutations in detail and the codon 72 allelism are shown in Additional file 3, 4. Briefly, we found 107 missense (73%), 8 frameshift (5%), 9 splice (6%), 17 nonsense (12%), 2 missense+nonsense (1%) and 4 other mutations. Silent mutation was considered as wild-type in the present study for analyses. Eleven non-synonymous polymorphisms, including the codon 72 (R72P), are now recognized in TP53. We evaluated 5 polymorphic sites except for R72P located in exons 5-8, including V217 M, R267W, P278A, R290H and N311S , respectively. In the present study, all the examined sequences corresponding to the above polymorphic sites matched completely to the TP53 reference sequence used, and no exonic non-synonymous polymorphism other than R72P was observed.
TP53codon 72 status with or without mutations and patient outcome
TP53 mutation and allelism (n = 211)
Mutation on Arg
Mutation on Pro
Case, n (%)
Primary tumor location, n (%)
Site, n (%)
Histopathological grade, n (%)
Lymph node metastasis, n (%)
Dukes' stage, n (%)
Significance of the codon 72 status on the clinicopathological factors
The CRC specimens were stratified by the location (colon or rectum), the histological subclasses and the Dukes' stage (Table 2). The frequency of mutation that occurred on the TP53-R72 or -P72 was not statistically different in tumor location or histological subclass (Table 3).
The TP53 mutation rate showed a tendency to increase with the Dukes' stage progression to stage C. The TP53 mutation was 55% (23 out of 42) in Dukes' stage A patients and 84% (63 out of 75) in stage C patients, and this difference was statistically significant (p < 0.05, chi-square test; Table 3). However, frequency of the mutations that occurred on the TP53-R72 or -P72 and the Dukes' stage showed no significant relevance (p > 0.05, chi-square test). In addition, the overall survival of the patients was not different between the mutated alleles and the Dukes' stages (data not shown).
Significance of the codon 72 status of the mutated TP53on the patient outcome after postoperative chemotherapy
TP53 mutations showing effective p73 inhibition in vitroand the patient outcome
We tested whether patients with 18 TP53 mutated allelotypes  demonstrate a poor prognosis or resistance to postoperative chemotherapy. Twenty-seven patients (5 in Dukes' stage A, 6 in stage B, 11 in stage C, and 5 in stage D) had such tumors. However, there were no statistical differences of survival when compared with the others overall, in each Dukes' stage, in patients that received chemotherapy or in patients without chemotherapy (data not shown).
Although postoperative adjuvant therapy is accepted widely as the standard modality for stage III, Dukes' stage C or earlier stage CRC patients, Tang et al. reported that one-fourth of stage III patients and two-thirds of stage II patients received no such therapy . Those patients tended to be older and to have less advanced tumors when compared with those who received postoperative adjuvant therapy. Therefore, predicting the patients who benefit from postoperative adjuvant therapy is important to selectively recommend the therapy and to improve the prognosis.
Although alterations of TP53 appear to have little- or no-prognostic significance for CRC patients treated with surgery alone , several clinical studies have demonstrated that CRC patients with wild-type TP53-tumors gain a survival benefit from 5-FU based postoperative chemotherapy, but those with TP53-mutated tumors do not [35–37]. Westra et al. also showed the same results from stage III colon cancer patients . These studies were conducted in Australia, Europe and the United States. A large cohort, "the TP53-CRC-international collaborative study", which is a meta-analysis study analyzing more than 3,500 CRC patients from 17 countries, also demonstrated that Dukes' C tumors with wild-type TP53 showed a significantly better survival when treated with postoperative adjuvant chemotherapy . This extensive meta-analysis, however, involved 2 Japanese studies with 103 CRC patients, corresponding to only 2.9% of all cases evaluated, and the TP53 mutation frequency ranged widely from 31% to 84%. In the present study, we included Japanese CRC patients from a single institute, and observed TP53 mutation in 70% of colorectal cancers. The Dukes' stage C patients who received postoperative chemotherapy showed a better overall survival than those who did not. This is consistent with previous investigations. However, the patients that benefited from the 5-FU based postoperative chemotherapy were not the patients with tumors containing wild-type TP53, but those with tumors containing TP53 mutation. Although Bunz et al. demonstrated in vitro that the apoptosis-inducing effect of 5-FU was almost abrogated when they deleted TP53 in the wild-type TP53 carrying human colon cancer cell, HCT116 , this situation is quite different from the actual clinical setting in which p53 function was knocked out not by homozygous deletion, but by missense mutation. Actually, we found that 72% of the TP53 alterations were missense mutation, which may result in gain-of-function oncogenic properties. Our results suggest that the oncogenic property of mutated p53 is involved significantly in the malignant phenotype of these tumors, and that the 5-FU based postoperative chemotherapy is effective.
Longley et al. reported that 5-FU increased Fas protein expression in the wild-type TP53 colon cancer HCT116 cells, but not in the TP53-null cells or TP53-mutated colon cancer H630 cells . Our results showed that the tumors carrying the mutation on TP53-P72 benefited most from the 5-FU based postoperative chemotherapy seems contradictory to the results of those reports. However, it is unclear what TP53 mutation occurred in H630 and how the oncogenic property of p53 gain-of-function mutation in combination with R72P status influences the apoptosis system. Therefore, there may be unknown pathways of apoptosis that function preferentially in colorectal cancer cells with the mutated TP53-P72 in response to 5-FU based postoperative chemotherapy.
Predicting which patients will benefit from the postoperative adjuvant therapy is important to improve CRC prognosis, and the prediction may be different when different adjuvant therapies are performed. In the present study, we identified CRC patients with tumors carrying TP53 mutation, especially on the codon 72 proline allele, as those patients that benefited most from 5-FU based postoperative chemotherapy. This result seems to be contradictory to several previous clinical reports or in vitro studies, but, we evaluated TP53 mutation by direct sequencing on fresh tumor samples and the precise discrimination of polymorphic status of the codon 72 were different from previous studies. The ethnic background of the investigated population may also be responsible for the differences.
In the present study, we identified the codon 72 polymorphic status of the TP53 mutated allele in CRC patients. We found that Dukes' stage C CRC patients with the mutated TP53-R72 who did not receive postoperative chemotherapy showed significantly longer survival times than those with the mutated TP53-P72. Our results raised a possibility that Dukes' stage C CRC patients with tumors carrying TP53 mutation, especially the P72 allele, benefited most from 5-FU based postoperative chemotherapy, but we need to collect more CRC cases to form definite conclusions.
This research was supported by grants from Kanagawa Cancer Research Fund. We thank Mr. Yoshiyasu Nakamura and Ms. Yukiko Yamazaki for their technical assistance. We thank Dr. Naoyuki Okamoto for his assistance with the statistical analyses.
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