Human Molecular Genetics, 2000, Vol. 9, No. 2 283-287
© 2000 Oxford University Press
Involvement of PTEN mutations in the genetic pathways of colorectal cancerogenesis
Dipartimento di Medicina Interna e Medicina Pubblica, Sezione di Genetica Medica, Policlinico, Piazza Giulio Cesare, 70124 Bari, Italy, 1Genetica Medica and 2Divisione di Chirurgia, IRCCS ‘De Bellis’, 70013 Castellana, Italy
Received 17 September 1999; Revised and Accepted 17 November 1999.
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ABSTRACT |
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So far, somatic mutations of the PTEN gene have been found in several different neoplasms but not in colorectal tumours. As exons 7 and 8 of the PTEN coding sequence contain an (A)6 repeat and mononucleotide repeat sequences are targets for mutations in tumours with microsatellite instability (MI), we screened a panel of sporadic colorectal tumours exhibiting MI to test whether PTEN gene repeats are frequently mutated in MI+ colorectal cancers. Of 32 cases studied, seven mutations were found in six (18.75%) patients, as a PTEN biallelic frameshift mutation was observed in one case, with consequent loss of function of the gene. Loss of heterozygosity, evaluated in the remaining five cases using the microsatellite marker D10S541, was detected in two of three informative samples. To further address the role of the PTEN gene in MI+ colorectal cancer, in the six patients with mutated PTEN, we analysed the mononucleotide repeats of six other genes: BAX, hMSH3, hMSH6, TGFbRII, IGFIIR and APC. In two of these six patients, mutations of the TGFbRII gene only were present, indicating that PTEN may have a role in the mutator pathway of colorectal tumorigenesis. Overall, these results indicate that PTEN mutations are selected for during tumorigenesis in MI+ colorectal tumours. The mutation of both PTEN alleles and evidence that the PTEN protein is expressed in normal colon suggest that loss of function of this gene could play a direct role in tumorigenesis.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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PTEN is a candidate tumour suppressor gene that has recently been isolated and localized at chromosomal band 10q23 (1–3). This gene has three different names: PTEN (phosphatase and tensin homologue deleted on chromosome ten) (1), MMAC1 (mutated in multiple advanced cancers 1) (2) and TEP1 (TGF-ß-regulated and epithelial cell-enriched phosphatase 1) (3), and codes for the 403 amino acid protein with tyrosine phosphatase activity. It contains a region of homology to tensin and auxillin, cytoskeletal proteins that interact with adhesion molecules. Germ-line mutations of PTEN are responsible for Cowden syndrome (4), also known as multiple hamartoma syndrome, and Bannayan–Zonana syndrome (5) whose features include lipoma and haemangiomas. Somatic mutations of the gene have been found in prostate, endometrial, breast and brain tumours but seem to be a relatively rare event in colorectal cancer (6–9).
As exon 7 and 8 PTEN sequences contain an (A)6 repeat and mononucleotide repeat sequences are frequent targets for mutations in endometrial tumours with microsatellite instability (MI+) (6,10), we decided to screen a panel of sporadic colorectal tumours exhibiting genetic instability, to test whether these repeats in the PTEN gene are mutational targets in MI+ colorectal cancer.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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A total of 32 MI+ tumours were analysed. The PCR products of exons 7 and 8 of PTEN were sequenced and seven frameshift mutations in the (A)6 tracts were found in six samples, as in one case (T186) the same tumour showed two different mutations, in exon 7 and in exon 8, respectively. RT–PCR analysis of the tumour mRNA of this patient showed that of eight plasmids three contained an (A)5 tract in exon 7 and a wild-type mononucleotide repeat in exon 8 and five contained a wild-type (A)6 tract in exon 7 and a frameshift mutation in the (A)6 tract of exon 8. In addition to the A deletion in the (A)6 tract of exon 8, one of these plasmids contained a missense mutation (N310Q), also in exon 8 (Fig. 1).
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The frameshift mutations observed in the six tumour samples were either a 1 bp deletion in the (A)6 repeat of exon 7 or a 1 bp deletion in the (A)6 repeat of exon 8 (Fig. 2) and both created a premature stop, at codon 275 of exon 7 and codon 343 of exon 8, respectively. A summary of the mutational analysis of the two PTEN exons is shown in Table 1.
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To assess the role of PTEN gene mutations in colorectal cancer, we first examined the presence of the PTEN mRNA in normal colonic mucosa. To increase the sensitivity of our analysis of RNA expression, we performed RT–PCR assays using the primer pair reported by Wang et al. (11) to avoid the amplification of a PTEN pseudogene. As predicted, a 671 bp product was obtained from normal colonic mucosa and from normal prostate tissue used as control (data not shown).
Because mRNA expression of tumour suppressor genes does not necessarily reflect protein expression, we aimed to assess the presence of the PTEN protein in normal colonic mucosa using a goat polyclonal antibody raised against the N-terminus of human PTEN protein. A band migrating at 55 kDa was detected in the western blot of whole cell extracts (Fig. 3) prepared from normal colonic cells, as well as in extracts of normal prostate tissue recently demonstrated to contain the PTEN protein (11–12). All together, these results indicate that the PTEN gene is expressed in normal colonic mucosa.
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We then decided to investigate the role of PTEN mutations in the ‘mutator pathway’ of tumorigenesis in MI+ colorectal cancer, searching for the presence of instability in genes whose mutations contribute to uncontrolled growth and progression to malignancy. The region comprising mononucleotide repeats of BAX, hMSH3, hMSH6, TGFbRII, IGFIIR and APC genes was characterized in tumours and corresponding normal tissues from these six patients. Table 1 shows the results of the analysis. BAX frameshift mutations were detected in patients T186, T212 and T388 (Fig. 1); patients T180 and T186 showed mutations in both the hMSH3 and hMSH6 genes (Fig. 1). Mutations of the TGFbRII gene were present in all of the six patients analyzed in the region of the poly(A) sequence whereas the GT repeat region was normal in all of them; mutations of IGFIIR and APC genes were not detected in any of the patients.
Because MLH1 and MSH2 gene mutations are the most frequent cause of DNA instability in colorectal tumours, we screened the entire coding sequence of these two genes for mutations in the three carriers of PTEN mutations whose tumour DNA was available. In patient T180 one A deletion was found at nucleotide 77 in the first exon of MLH1; no mutations were identified in the MLH1 and in the MSH2 gene of the other two patients.
The pathology reports for these six patients with PTEN mutations did not show any characteristic features. Patient T186, a female, had a stage II moderately differentiated adenocarcinoma of the caecum; patients T212, T381, T388 and T400 had a stage II poorly differentiated adenocarcinoma of the proximal colon; patient T180 had two synchronous stage II moderately differentiated adenocarcinomas of the rectum. The latter patient had been surgically treated for an adenocarcinoma of the caecum 20 years previously.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Several lines of evidence suggest that functional inactivation of PTEN is required in the pathogenesis of tumours of various histological origins. Although frequently occurring in glioblastoma, prostate and endometrium sporadic cancers, PTEN gene mutations seem to be a relatively rare event in colorectal cancer. Since there are two sites containing an (A)6 repeat in the PTEN coding sequence and mononucleotide repeat sequences constitute frequent targets for mutations in tumours with microsatellite instability (MI+), we analysed a panel of colorectal tumours exhibiting MI for frameshift mutations to assess whether mutational inactivation of PTEN contributes to colorectal tumorigenesis.
Seven mutations of the PTEN gene, all of which consisted of the deletion of 1 bp in the (A)6 tract of exon 7 or of exon 8 resulting in a stop codon and subsequent premature termination, were found in 6 of 32 (18.75%) cases studied. Cancers with mutated PTEN did not show a striking clinical phenotype.
In one of the six patients, T186, a PTEN biallelic frameshift mutation was observed, i.e. a deletion in the (A)6 tract of exon 7 in one allele and a deletion in the (A)6 tract of exon 8 in the other allele, with consequent loss of function of the gene. We did not have enough DNA or fresh tissue available from the other five patients to perform a mutation search in the coding sequence of the PTEN gene to detect the mutation of the second allele, according to Knudson’s two hits theory. We therefore screened DNA isolated from paraffin blocks for loss of heterozygosity (LOH), using the linked microsatellite marker D10S541. Three samples were informative and two of these, T180 and T388, showed LOH.
To gain a better understanding of the role of PTEN gene function in colonic cells, we checked the expression of the PTEN gene at both RNA and protein level. Our data demonstrate that the PTEN protein is present in normal colonic cells.
Then, to address the role of PTEN mutations in the mutator pathway of colorectal tumorigenesis, the six patients with alterations of the PTEN gene were analysed for the presence of frameshift mutations in the mononucleotide repeats of six other genes: TGFbRII, hMSH3, hMSH6, BAX, IGFIIR and APC, whose mutations contribute to progression towards malignancy in colorectal cancer. Interestingly, in patients T381 and T400 mutations of the TGFbRII gene only were present, indicating that PTEN probably plays a role in the mutator pathway of colorectal tumorigenesis.
In Cowden and Bannayan syndrome patients (13–14), exons 7 and 8, believed to encode potential tyrosine kinase phosphorylation sites of the PTEN protein, are the second hot spot for mutations. However, it should be noted that the great majority of germ-line mutations responsible for these two hereditary syndromes occur in different sites on exons 7 and 8 from those of the poly(A) repeats, reflecting different mutational mechanisms. Cowden syndrome is characterized by intestinal hamartomatous polyps but no studies to date have succeeded in demonstrating their progression to colorectal carcinoma. Interestingly, colon cancer has been described in Pten+/– chimeric mice (15).
Mutations of the PTEN gene in colorectal cancers had not been observed in previous reports (6–9). However, all of these studies analysed unselected patients. Because MI has been observed in 12–15% of sporadic colorectal cancers and mutations of the PTEN gene in 18% of MI+ colorectal tumours, when analysing unselected colorectal tumours PTEN alterations would be expected in ~2.7% of cases. Therefore, a negative result is likely unless the sample studied is big enough.
Overall, our results indicate that PTEN mutations are selected for during tumorigenesis in MI+ colorectal tumours; in addition, the evidence that the PTEN protein is expressed in colonic cells, as well as the presence of mutations in both alleles of the PTEN gene, provide support to the idea that loss of function of the gene plays a direct role in tumorigenesis.
Although the mechanisms through which PTEN mutations contribute to cancer are not yet entirely clear, several studies emphasize the importance of PTEN in normal cell homeostasis. PTEN possesses lipid phosphatase activity and a tyrosine phosphatase domain, the latter being responsible for a decrease in fibronectin-mediated focal adhesion kinase phosphorylation (16). Thus, PTEN may act as a regulator of cell surface interactions with the extracellular matrix through its protein phosphatase activity and as a controller of cell growth through its lipid phosphatase activity, which could, in turn, downregulate protein kinase B (PKB)/serine/threonine kinase encoded by the akt proto-oncogene (AKT) (17). It has recently (18) been shown that PTEN-deficient cells exhibit a reduced ability to trigger apoptosis when they receive a death signal, accompanied by constitutively increased levels of PKB/AKT phosphorylation. Changes in the phosphorylation level of this latter protein are crucial in regulating cell survival by conferring resistance to PTEN-induced apoptosis. On the basis of these data it seems reasonable to speculate that PTEN mutations are not simply bystander events but play an active role in promoting abnormal growth of colorectal cells.
The data presented here aim to contribute to elucidating the function of the PTEN gene and its role in the so-called mutator pathway of tumorigenesis.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Tumour samples
A total of 32 MI+ but otherwise unselected colorectal tumours, paired with adjacent normal tissues, were analysed. All the tumour tissue samples were obtained at the surgery and freshly frozen. Gross cryostat dissection was limited to areas consisting mainly of neoplastic cells. Germ-line DNA was available either from peripheral blood or normal adjacent colon tissue from each patient.
High molecular weight genomic DNA was extracted from frozen tissues or blood according to the standard methods. MI was assessed using five polymorphic markers: BAT25, BAT26, D2S123, D5S346 and D18S858. MI was considered present when two or more of the five markers showed instability.
Mutational analysis of PTEN
Mutations of PTEN at repetitive sequences within its coding region were identified using a PCR-based assay. The 229 bp region encompassing the PTEN poly(A)6 repeat beginning at nucleotide 795 of exon 7 and the 200 bp region encompassing the poly(A)6 repeat beginning at position 963 of exon 8 were amplified using the primers reported by Risinger et al. (10). PCR was carried out for 30 cycles, each cycle consisting of denaturation for 20 s at 95°C, annealing for 20 s at 48°C, and extension for 30 s at 72°C. Mutations were searched by single-strand conformation polymorphism (SSCP) analysis; after electrophoresis the gel bands were visualized by the silver staining method; bands with mobility alterations were gel- and column-purified and directly sequenced using the ABI Ready Reaction Dye Terminator Cycle Sequencing kit according to the manufacturer’s instructions (Perkin Elmer, Norwalk, CT) and the 377 ABI Prism Sequencer. All the tumours with variant SSCP bands were sequenced in forward and reverse orientations. All mutations were confirmed by duplicate sequencing of a newly amplified product. Determination of the presence of the mutation in the same or different alleles was addressed by PCR amplification of the PTEN mRNA using the following primers: 5'-ATCCTCAGTTTGTGGTCT-3' and 5'-GGAGAAAAGTATCGGTTGGC-3'. The PCR products, corresponding to the 382 bp region encompassing the poly(A)6 repeats of exon 7 and exon 8, were cloned into plasmid vectors (TOPO-TA cloning kit; Invitrogen, Groningen, The Netherlands) and several clones sequenced as before.
LOH analysis
Total genomic DNA purified from paraffin-embedded sections was screened for LOH using the polymorphic marker D10S541 flanking the PTEN locus.
Analysis of BAX, hMSH3, hMSH6, TGFbRII, IGFIIR and APC mononucleotide repeats
The presence of frameshift mutations in the following genes: BAX, hMSH3, hMSH6, TGFbRII, IGFIIR and APC, containing mononucleotide repeats was studied. The 94 bp region encompassing the BAX(G)8 tract at nucleotides 114–121, the 92 bp region of IGFIIR containing poly(G)8 at nucleotides 4089–4096, the poly(C)8 and poly(A)8 repeats at codons 1116–1118, respectively, of the hMSH6 gene and at codons 381–383 of hMSH3, and the (A)10 microsatellite sequence at nucleotides 709–718 of TGFbRII were characterized using the primers and the PCR conditions as described by Yamamoto et al. (19). The PCR products were characterized by electrophoresis on denaturing 6% polyacrylamide sequencing gels and by SSCP, followed by sequencing of bands with mobility alterations.
In addition, the (A)7 tract at the nucleotide 6573 and the two (A)6 repeats at nucleotides 5370 and 5385, respectively, of the APC gene were analysed. The amplification was performed using the primers for the fragments L and P of exon 15 (20). The PCR products were then sequenced.
Mutational analysis of MSH1 and MLH2 genes
The promoter regions and each exon of MLH1 and MSH2 genes from genomic DNA were individually amplified and subsequently sequenced directly.
Western blot analysis
Specimens of normal colonic mucosa and prostate tissue were diced into very small pieces and homogenized with a dounce homogenizer. The cells were lysed in a solution containing 0.5% Nonidet P40, 50 mM Tris–HCl pH 8, 110 mM NaCl, 0.5% Triton X-100 and proteinase inhibitors, 2 mM PMSF, 0.5 µg/ml leupeptin. Lysates consisting of 150 µg of protein were separated by SDS–PAGE (10%) and transferred to Immobilon P membranes (Millipore, Bedford, MA). The membranes were then probed with antiPTEN(N-19) polyclonal antibody (Santa Cruz Biotechnology, Santa Cruz, CA) at 1:700 dilution according to the manufacturer’s protocol. After overnight incubation, detection was performed using alkaline phosphatase-conjugated secondary antibody visualized by incubation in NBT/BCIP developing solutions.
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ACKNOWLEDGEMENTS |
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We thank Dr Alessandro Stella for helpful discussion and Mary V.C. Pragnell for careful linguistic text revision. This work was partially supported by MURST (ex 40%) and AIRC. The experiments performed here complied with the current laws in Italy.
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FOOTNOTES |
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+ These authors contributed equally to this work
§ To whom correspondence should be addressed. Tel: +39 0805478270; Fax: +39 0805478269; Email: guanti@medgene.uniba.it
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REFERENCES |
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