This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mirabelli-Primdahl, L. Articles by Redston, M. Search for Related Content PubMed PubMed Citation Articles by Mirabelli-Primdahl, L. Articles by Redston, M.

ß-Catenin Mutations Are Specific for Colorectal Carcinomas with Microsatellite Instability but Occur in Endometrial Carcinomas Irrespective of Mutator Pathway¹

Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital [L. M-P., R. G., H. K., A. M., C. L., B. B., S. G., M. R.], Ontario Cancer Registry, Cancer Care Ontario [D. D., E. H.], and Departments of Surgery [R. G., S. G.], Public Health Sciences [E. H.], and Laboratory Medicine and Pathobiology [B. B., M. R.], University of Toronto, Toronto, Ontario, M5G 1X5 Canada

	ABSTRACT

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
Some colorectal tumors with wild-type adenomatous polyposis coli gene have activating mutations in ß-catenin (encoded by CTNNB1) that result in decreased phosphorylation by GSK-3ß and increased signaling through the Tcf/Lef transcription factors. To investigate the relationship between CTNNB1 mutations and underlying pathways of genomic instability, we examined 80 colorectal cancers stratified by the presence or absence of microsatellite instability (MSI). CTNNB1 mutations were identified in 13 (25%) of 53 cancers with high frequency MSI (MSI-H), including 12 point mutations at exon 3 phosphorylation sites (codons 41 and 45) and one deletion of the entire exon 3 degradation box. No CTNNB1 mutations were identified in 27 microsatellite stable or low frequency MSI (MSI-L) colorectal cancers (P < 0.01). In contrast, CTNNB1 mutations were identified in 3 of 9 (33%) MSI-H and 10 of 20 (50%) MSS/MSI-L endometrial carcinomas, suggesting a more generalized involvement in these tumors. Only six (46%) of the endometrial carcinoma CTNNB1 mutations occurred at residues directly phosphorylated by GSK-3ß, and only one of these was at either codon 41 or 45. All point mutations in MSI-H cancers were transitions, whereas 64% of those in MSS/MSI-L cancers were transversions (P < 0.01). The differences in the mutation profiles suggest that there may be molecular fingerprints of CTNNB1 mutations, determined by biological factors related to both tumor type and underlying pathways of genomic instability.

	Introduction

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
The Wnt signal transduction pathway was first implicated in mammalian tumorigenesis when the Drosophila gene, wingless, was shown to be the homologue of the mouse mammary oncogene, int-1 (later renamed Wnt-1; Refs. 1 and 2 ). The generalized importance of this pathway was realized when APC³ was found to regulate Wnt signaling by acting in a complex with GSK-3ß to control phosphorylation and degradation of ß-catenin (3, 4, 5) . Inactivating APC mutations occur in about 85% of colorectal carcinomas, resulting in ß-catenin stabilization and increased signaling through the Tcf/Lef transcription factors (6, 7, 8) . Recently, up to 50% of colorectal carcinomas without APC mutations were found to contain CTNNB1 mutations (9, 10, 11, 12) . These mutations alter APC-dependent exon 3 serine/threonine phosphorylation residues, leading to ß-catenin stabilization and activation of signaling (10 , 13) . Interestingly, about 50% of primary colorectal carcinomas with CTNNB1 mutations are MSI-H, suggesting that CTNNB1 mutations may be more common in the DNA MMR-deficient pathway of tumorigenesis (10 , 12 , 14 , 15) . CTNNB1 mutations are found in a number of other cancers, including about 13% of endometrial carcinomas; however, there has been no investigation of associations with underlying pathways of genomic instability (16, 17, 18, 19) . In the present study, we examined the relationship between CTNNB1 mutations and DNA MMR deficiency and found that CTNNB1 mutations were significantly more common in MSI-H colorectal carcinoma as compared to MSS/MSI-L colorectal carcinoma. Surprisingly, we found a high frequency of CTNNB1 mutations in endometrial carcinoma, regardless of the presence or absence of microsatellite instability. Comparison of these cancers suggests that CTNNB1 mutation profiles may reflect different underlying carcinogenic pathways.

	Materials and Methods

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
Tissue Samples.
Tumor samples were obtained from an ongoing, unlinked, population-based study of the frequency of MSI in human cancer. Ethics approval was obtained from The University of Toronto Human Ethics Committee prior to commencement of the study. Resected colorectal and endometrial carcinomas in patients <50 years of age were identified by The Ontario Cancer Registry, and paraffin blocks were retrieved from the treating hospitals. A blinded histopathological review was performed on all cases, and the results were entered into a coded database. For each case, normal and invasive carcinoma samples of at least 50% neoplastic cellularity were microdissected from two to three 10-µm unstained slides. Adjacent adenomas (colorectal carcinoma cases) or hyperplasias (endometrial carcinoma cases) were dissected separately when available. If cancers had more than one discreet morphological pattern, multiple tissue samples were also dissected separately. Genomic DNA was extracted as follows. Samples were incubated in 50–100 µl of lysis buffer [10 mM Tris-Cl (pH 8), 100 mM KCl, 2.5 mM MgCl₂, and 0.45% Tween 20] for 10 min at 95°C. Proteinase K (15–35 µl, 20 mg/ml) was added, and samples were incubated overnight at 65°C.

MSI Testing.
For the colorectal carcinomas, MSI was tested using the Bethesda Consensus Conference reference panel of 5 markers (BAT-25, BAT-26, D2S123, D5S346, and D17S250; Ref. 20 ), with conditions as described previously (21) . Colorectal carcinomas were classified as MSI-H if two or more loci displayed MSI, or as MSS, if no loci displayed MSI. If one locus had MSI, up to five additional loci were tested (BAT-40, BAT-RII, D18S58, D18S69, and D17S787); these reevaluated tumors were then classified as MSI-H if 40% of loci displayed MSI, or as MSI-L if 30% of loci displayed MSI (20) . For the endometrial carcinomas, MSI was tested using at least five markers from the Bethesda reference panel and the Bethesda alternative marker list (BAT-26, BAT-40, BAT RII, D2S123, D3S1611, D5S346, D17S787, D18S59, and D18S69). Definitions for MSS, MSI-L, and MSI-H were the same as for the colorectal carcinomas.

CTNNB1 Mutation Detection.
For the CTNNB1 mutation analysis, we selected cases from the ongoing population-based study, including all available MSI-H cancers, all MSI-L cancers, and a sampling of MSS cancers. In total, we studied 80 colorectal carcinomas, including 53 MSI-H cancers, 19 MSI-L cancers, and 8 MSS cancers, and 29 endometrial carcinomas, including 9 MSI-H cancers, 2 MSI-L cancers, and 18 MSS cancers. Exon 3 of CTNNB1 was amplified by PCR in five separate reactions using six primers as shown in Fig. 1A . The primer sequences were as follows: P1, 5'-AGTCACTGGCAGCAACAGTC-3'; P2, 5' -TCTTCCTCAGGATTGCCTT-3'; P3, 5' -GATTTGATGGAGTTGGACATGG-3'; P4, 5' -TGTTCTTGAGTGAAGGACTGAG-3'; P5, 5' -TACAACTGTTTTGAAAATCCAGCGTGGAC-3'; and P6, 5' -TCGAGTCATTGCATACTGTCC-3'. Using this approach, a small product including codons 30–48 (product P1-2) was amplified from all tumors for direct sequence analysis. Remaining PCR products were designed to screen for intragenic deletions beginning outside of the P1-2 primer, and including the ß-catenin regulatory region of exon 3 (codons 32–45). Fragments >250 bp are not reliably amplified from paraffin tissue; therefore, overlapping fragments were chosen to increase the likelihood of detecting deletions. Because the P5-4 and P5-6 PCR products are too large for successful amplification in the absence of an intragenic deletion, DNA extracted from peripheral blood lymphocytes was included as a separate control for PCR set-up. Although this approach would be expected to identify most of the deletions reported previously in CTNNB1 (11 , 12 , 19) , it is not possible to rule out deletions in the absence of a full-length PCR product spanning P5-6. Therefore, the results may be an underestimate of the actual CTNNB1 intragenic deletion frequency. For each PCR reaction, 2 µl of DNA was combined with 1 unit of Perkin-Elmer AmpliTaq DNA polymerase in a 15-µl PCR mixture, with PCR buffer, 1.5 mM MgCl₂, 0.13 mM deoxynucleotide triphosphates, and 0.4 µM of each primer. Samples were heat denatured at 94°C for 2 min, followed by 35 PCR cycles as follows: 94°C for 15 s, annealing temperature for 15 s, and 72°C for 20 s (in a DNA Engine, model PTC-200; MJ Research, Watertown, MA). The annealing temperatures were as follows: P1-2, 52°C; P3-4, 62°C; P5-4, 52°C; P3-6, 56°C; and P5-6, 46°C. To screen for intragenic deletions, PCR products (P3-4, P5-4, P3-6, and P5-6) were electrophoresed on 2% agarose gels and visualized by ethidium bromide staining. To detect nucleotide sequence alterations, the 98-bp P1-2 PCR product was electrophoresed on a 2% agarose gel, visualized by ethidium bromide staining, and excised from the gel, and DNA was purified using QIAquick Gel extraction kit (Qiagen, Mississauga, Ontario, Canada) as per the manufacturer’s instructions. Purified PCR products were sequenced using ThermoSequenase Radiolabeled Terminator Cycle Sequencing kit (Amersham, Cleveland, OH) as per the manufacturer’s instructions. Reactions were run on a 6% sequencing gel, dried onto filter paper, and exposed to Kodak Biomax film.

View larger version (33K): [in this window] [in a new window]   Fig. 1. Identification of CTNNB1 mutations. A, PCR strategy for CTNNB1 mutation detection. Primer pairs used to generate each of the five PCR products are as indicated. B, representative sequencing gel revealing point mutations in CTNNB1 exon 3. Colorectal carcinoma sample 54 (Lane 5) has an A to G substitution (S45P), and colorectal carcinoma sample 56 (Lane 6) has a G to A substitution (S45F). Sequencing reactions were run using the reverse primer P2. C, representative 2% agarose gel revealing intragenic deletion of CTNNB1 in PCR fragment P5-6. Carcinoma sample 128 (Lane 4, Del) has a 653-bp deletion. The deletion is not present in the adjacent adenoma sample (Lane 3). The full-length normal P5–6 PCR product is not successfully amplified from either of the paraffin DNA samples (Lanes 3 and 4). Lanes 1 and 6, 123-bp ladder; Lane 2, negative control; Lane 5 (Norm), full-length P5-6 PCR fragment from DNA extracted from peripheral blood lymphocytes.

	Results

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
Mutations in the CTNNB1 gene were identified in 13 (25%; 95% CI, 14–39%) of the MSI-H colorectal carcinomas and none (95% CI, 0–10%) of the MSS/MSI-L colorectal carcinomas (P < 0.01; Figs. 1B and 2 ; Table 1 ). All point mutations were amino acid substitutions at the threonine and serine residues at codons 41 and 45 (Fig. 2) . A single 653-bp intragenic deletion was identified (Fig. 1C) that joined nucleotide 27 of intron 2 to nucleotide 5 of intron 3, resulting in complete deletion of exon 3. CTNNB1 mutations predicting amino acid substitutions were identified in 3 (33%; 95% CI, 8–53%) of the MSI-H endometrial carcinomas and 10 (50%; 95% CI, 27–73%) of the MSS/MSI-L endometrial carcinomas (Fig. 2 ; Table 1 ). Only six of the endometrial carcinoma amino acid substitutions involved the serine and threonine residues at codons 33, 37, and 41 (Table 1) . The remaining seven substitutions were at codons 32 and 34, flanking the serine at codon 33 (Table 1) . No intragenic deletions were identified in the endometrial carcinomas. Silent nucleotide substitutions were also identified in two endometrial carcinomas (one MSI-H and one MSS; Table 1 ). These changes were not present in the normal tissues from these cases or in a separately dissected neoplastic sample, indicating that they were focal somatic alterations. All 16 of the nucleotide substitutions present in MSI-H cancers were transitions, whereas only 4 (36%) of the substitutions in MSS/MSI-L cancers were transitions (P < 0.01).

View larger version (16K): [in this window] [in a new window]   Fig. 2. Summary of mutations stratified by underlying genomic instability pathway (left panel). Upper half of figure, endometrial carcinomas; lower half of figure, colorectal carcinomas. Right panel, distribution of ß-catenin amino acid substitutions. Upper half, endometrial carcinomas; lower half, colorectal carcinoma mutations. ß-Catenin is given in one-letter amino acid codes; serine and threonine phosphorylation residues are indicated by codon number. Underlined letters, mutations found in MSS/MSI-L cancers. Silent mutations are italicized.

Comparison of pathological features (Table 2) revealed that MSI-H colorectal carcinomas with CTNNB1 mutations were more likely to be T4 tumors, right-sided, and of unusual histological subtypes. None of these trends were statistically significant. Irrespective of CTNNB1 mutation status, MSI-H colorectal carcinomas were more likely to be associated with right-sided location, marked tumor-infiltrating lymphocytes, marked Crohn’s-like lymphoid reactions, and nonmetastatic disease (Table 2) . Although mutations had no apparent associations with pathological features in the endometrial carcinomas, the number of cases was too small for a comprehensive analysis (data not shown).

	Discussion

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

Endometrial carcinoma is the second most common cancer in individuals with germ-line MMR gene mutations, suggesting that the molecular pathogenesis has similarities with colorectal carcinoma. In endometrial cancers, however, we found that CTNNB1 mutations were not specific to the MMR-deficient pathway. Furthermore, the high mutation frequency raises the possibility that activation of Wnt signaling may be universally important in a subset of these neoplasms. Although previous studies have found a low frequency of loss of heterozygosity at 5q21 in endometrial carcinomas, we are not aware of any rigorous searches to identify APC mutations (25 , 26) .

CTNNB1 mutations were reported previously in only 13% of endometrial carcinomas (16) . Most of our cancers were well to moderately differentiated endometrioid carcinomas, a subtype that had a higher CTNNB1 mutation frequency (18%) and a higher frequency of ß-catenin stabilization (46%) in the previous study (16) . Most CTNNB1 mutations reported in ovarian carcinomas are also found in endometrioid carcinomas, supporting a specific morphogenetic association (17) . Our cases were also selected for early age of onset, which could be associated with differences in tumor genetic profiles. Finally, the mutation frequencies could reflect differences in carcinogenic influences between Japan and North America. For instance, intragenic deletions of CTNNB1 were the predominant mutations reported in one series of Japanese colorectal cancers (11) .

The difference in the spectrum of missense mutations between colorectal and endometrial carcinomas was unexpected. All of the colorectal carcinoma amino acid substitutions were at known phosphorylation sites (codons 41 and 45), and three of the four mutations have been reported previously (10 , 12 , 13) . Although the final substitution, T41I, has not been described in colorectal carcinoma, it was present in one endometrial cancer (16) and in carcinogen-induced rodent tumors (27 , 28) . Several mutations at codons 41 and 45 have been shown to lead to ß-catenin stabilization (9 , 10 , 13 , 16 , 17) . In contrast, only 1 of 13 substitutions in the endometrial cancers (T41S; previously unreported) occurred at either codons 41 or 45. The remaining 12 substitutions occurred at codons 32, 33, 34, and 37 and included three novel mutations (D32H, S33C, and G34R). Although codons 32 and 34 are not known to be phosphorylated, mutations at these sites are observed frequently in human and carcinogen-induced rat tumors (16, 17, 18, 19 , 28 , 29) and may affect phosphorylation by altering recognition sequences or tertiary protein structure. Furthermore, these two residues are important for ß -catenin ubiquitination and proteasome-dependent degradation (30) .

It is possible that the DNA sequence surrounding codons 41 to 45 of CTNNB1 is specifically hypermutable in the setting of MMR deficiency. The predominance of transition mutations supports this possibility and parallels the mutation profile of some MMR-deficient cell lines (31) . Although codon 45 lies within a homocopolymer tract, which is known to be hypermutable (32) , the specific sequences that predispose to transitions in the setting of MMR are not known (33) . The presence of CTNNB1 mutations at codons 41 and 45 in small MSS colorectal adenomas (34) and the differences in the mutation profile of MSI-H endometrial cancers, however, suggest that sequence susceptibility is not the only factor. The presence of two silent CTNNB1 exon 3 alterations in the endometrial carcinomas also raises the possibility of a tissue-specific hypermutability or carcinogenic influence. An alternative explanation for the MSI pathway specificity of CTNNB1 mutations in colorectal cancer is that APC mutations and CTNNB1 mutations may not be biologically equivalent in tumorigenesis. Both genes may have functions outside of Wnt signaling that are important for clonal selection, and differences in the genetic targets of neoplastic progression between MSI-H and MSS colorectal cancers and between MSI-H colorectal and endometrial cancers are well established (6 , 23 , 35 , 36) . The recent finding that CTNNB1 mutations are frequent in small MSS adenomas suggests these neoplasms are less likely to progress and supports tumorigenic differences compared with APC inactivation (34) .

Adjacent adenomas contained the same CTNNB1 mutation as the invasive carcinomas in three of five cases. Although this is generally consistent with the hypothesized role of the APC pathway as a neoplasia gatekeeper (6) , at least two of the CTNNB1 mutations occurred during neoplastic progression from adenoma to carcinoma. In the endometrial carcinomas, we also found that two of the adjacent complex hyperplasias did not contain CTNNB1 mutations, suggesting that these alterations are not necessarily gatekeeper-type events. When multiple paired tumor samples were examined, however, the uniform presence of CTNNB1 mutations in both colorectal and endometrial cancers suggests that all have occurred during the early stages of malignant transformation. This contrasts findings in prostate cancer, where focal mutations suggest a late event during the advanced progression of subclones (18) .

If activating ß-catenin mutations are associated with specific biological attributes not present in tumors with APC inactivation, differences in the pathological features of these tumors might be expected. Although there was a tendency for MSI-H colorectal carcinomas with CTNNB1 mutations to be right-sided, higher stage, and of unusual histological subtypes, the number of cancers analyzed does not allow for definitive conclusions to be made. In comparison, many of the features known to be associated with MSI-H colorectal carcinomas (37) were uniformly present in tumors with and without CTNNB1 mutations. Although no associations between CTNNB1 mutations and pathological features of endometrial carcinomas were apparent, our series was very homogeneous in terms of the spectrum of grade, stage, and histological subtypes.

In summary, our findings confirm that CTNNB1 mutations are particularly common in MSI-H colorectal carcinomas. These mutations consist almost entirely of transitions at codons 41 and 45, revealing a relatively specific molecular fingerprint compared with CTNNB1 mutation profiles in other cancers. We also found that CTNNB1 mutations are very common in endometrial carcinomas; however, there is no association with the presence or absence of underlying microsatellite instability. Additional studies will be required to determine whether functional differences between ß -catenin activation and APC inactivation may explain some of these findings.

	ACKNOWLEDGMENTS

 
We thank Kazy Hay for assistance in acquiring paraffin blocks and Eugene Hsieh for assistance in analysis of data and preparation of the manuscript.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported in part by the National Cancer Institute of Canada (to E. H., B. B., S. G., and M. R.) with funds provided by the Canadian Cancer Society. R. G. is a Research Fellow of the National Cancer Institute of Canada with funds provided by the Terry Fox Run.

² To whom requests for reprints should be addressed, at Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Room 1073A, 600 University Avenue, Toronto, Ontario, M5G 1X5 Canada. E-mail: mredston{at}mtsinai.on.ca

³ The abbreviations used are: APC, adenomatous polyposis coli; MMR, mismatch repair; MSI, microsatellite instability; MSI-L, low frequency MSI; MSI-H, high frequency MSI; CI, confidence interval.

Received 3/17/99. Accepted 5/27/99.

	REFERENCES

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 

1. Nusse R., Varmus H. E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell, 31: 99-109, 1982.[Medline]
2. Rijsewijk F., Schuermann M., Wagenaar E., Parren P., Weigel D., Nusse R. The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell, 50: 649-657, 1987.[Medline]
3. Rubinfeld B., Souza B., Albert I., Muller O., Chamberlain S. H., Masiarz F. R., Munemitsu S., Polakis P. Association of the APC gene product with ß -catenin. Science (Washington DC), 262: 1731-1734, 1993.[Abstract/Free Full Text]
4. Su L. K., Vogelstein B., Kinzler K. W. Association of the APC tumor suppressor protein with catenins. Science (Washington DC), 262: 1734-1737, 1993.[Abstract/Free Full Text]
5. Rubinfeld B., Albert I., Porfiri E., Fiol C., Munemitsu S., Polakis P. Binding of GSK3ß to the APC-ß-catenin complex and regulation of complex assembly. Science (Washington DC), 272: 1023-1026, 1996.[Abstract]
6. Kinzler K. W., Vogelstein B. Lessons from hereditary colorectal cancer. Cell, 87: 159-170, 1996.[Medline]
7. Korinek V., Barker N., Morin P. J., van Wichen D., de Weger R., Kinzler K. W., Vogelstein B., Clevers H. Constitutive transcriptional activation by a ß-catenin-Tcf complex in APC-/- colon carcinoma. Science (Washington DC), 275: 1784-1787, 1997.[Abstract/Free Full Text]
8. Rubinfeld B., Albert I., Porfiri E., Munemitsu S., Polakis P. Loss of ß-catenin regulation by the APC tumor suppressor protein correlates with loss of structure due to common somatic mutations of the gene. Cancer Res., 57: 4624-4630, 1997.[Abstract/Free Full Text]
9. Ilyas M., Tomlinson I. P., Rowan A., Pignatelli M., Bodmer W. F. ß-Catenin mutations in cell lines established from human colorectal cancers. Proc. Natl. Acad. Sci. USA, 94: 10330-10334, 1997.[Abstract/Free Full Text]
10. Morin P. J., Sparks A. B., Korinek V., Barker N., Clevers H., Vogelstein B., Kinzler K. W. Activation of ß-catenin-Tcf signaling in colon cancer by mutations in ß-catenin or APC. Science (Washington DC), 275: 1787-1790, 1997.[Abstract/Free Full Text]
11. Iwao K., Nakamori S., Kameyama M., Imaoka S., Kinoshita M., Fukui T., Ishiguro S., Nakamura Y., Miyoshi Y. Activation of the ß-catenin gene by interstitial deletions involving exon 3 in primary colorectal carcinomas without adenomatous polyposis coli mutations. Cancer Res., 58: 1021-1026, 1998.[Abstract/Free Full Text]
12. Sparks A. B., Morin P. J., Vogelstein B., Kinzler K. W. Mutational analysis of the APC/ß-catenin/Tcf pathway in colorectal cancer. Cancer Res., 58: 1130-1134, 1998.[Abstract/Free Full Text]
13. Rubinfeld B., Robbins P., El-Gamil M., Albert I., Porfiri E., Polakis P. Stabilization of ß-catenin by genetic defects in melanoma cell lines. Science (Washington DC), 275: 1790-1792, 1997.[Abstract/Free Full Text]
14. Kitaeva M. N., Grogan L., Williams J. P., Dimond E., Nakahara K., Hausner P., DeNobile J. W., Soballe P. W., Kirsch I. R. Mutations in ß-catenin are uncommon in colorectal cancer occurring in occasional replication error-positive tumors. Cancer Res., 57: 4478-4481, 1997.[Abstract/Free Full Text]
15. Muller O., Nimmrich I., Finke U., Friedl W., Hoffmann I. A ß-catenin mutation in a sporadic colorectal tumor of the RER phenotype and absence of ß-catenin germline mutations in FAP patients. Genes Chromosomes Cancer, 22: 37-41, 1998.[Medline]
16. Fukuchi T., Sakamoto M., Tsuda H., Maruyama K., Nozawa S., Hirohashi S. ß-Catenin mutation in carcinoma of the uterine endometrium. Cancer Res., 58: 3526-3528, 1998.[Abstract/Free Full Text]
17. Palacios J., Gamallo C. Mutations in the ß-catenin gene (CTNNB1) in endometrioid ovarian carcinomas. Cancer Res., 58: 1344-1347, 1998.[Abstract/Free Full Text]
18. Voeller H. J., Truica C. I., Gelmann E. P. ß-Catenin mutations in human prostate cancer. Cancer Res., 58: 2520-2523, 1998.[Abstract/Free Full Text]
19. Koch A., Denkhaus D., Albrecht S., Leuschner I., von Schweinitz D., Pietsch T. Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the ß-catenin gene. Cancer Res., 59: 269-273, 1999.[Abstract/Free Full Text]
20. Boland C. R., Thibodeau S. N., Hamilton S. R., Sidransky D., Eshleman J. R., Burt R. W., Meltzer S. J., Rodriguez-Bigas M. A., Fodde R., Ranzani G. N., Srivastava S. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res., 58: 5248-5257, 1998.[Abstract/Free Full Text]
21. Bapat B. V., Madlensky L., Temple L. K. F., Hiruki T., Redston M., Baron D. L., Xia L., Marcus V. A., Soravia C., Mitri A., Shen W., Gryfe R., Berk T., Chodirker B. N., Cohen Z., Gallinger S. Family history characteristics, tumor microsatellite instability and germline MSH2 and MLH1 mutations in hereditary colorectal cancer. Hum. Genet., 104: 167-176, 1999.[Medline]
22. Heinen C. D., Richardson D., White R., Groden J. Microsatellite instability in colorectal adenocarcinoma cell lines that have full-length adenomatous polyposis coli protein. Cancer Res., 55: 4797-4799, 1995.[Abstract/Free Full Text]
23. Olschwang S., Hamelin R., Laurent-Puig P., Thuille B., De Rycke Y., Li Y. J., Muzeau F., Girodet J., Salmon R. J., Thomas G. Alternative genetic pathways in colorectal carcinogenesis. Proc. Natl. Acad. Sci. USA, 94: 12122-12127, 1997.[Abstract/Free Full Text]
24. Rimm D. L., Caca K., Hu G., Harrison F. B., Fearon E. R. Frequent nuclear/cytoplasmic localization of ß-catenin without exon 3 mutations in malignant melanoma. Am. J. Pathol., 154: 325-329, 1999.[Abstract/Free Full Text]
25. Jones M. H., Koi S., Fujimoto I., Hasumi K., Kato K., Nakamura Y. Allelotype of uterine cancer by analysis of RFLP and microsatellite polymorphisms: frequent loss of heterozygosity on chromosome arms 3p, 9q, 10q, and 17p. Genes Chromosomes Cancer, 9: 119-123, 1994.[Medline]
26. Berchuck A., Boyd J. Molecular basis of endometrial cancer. Cancer (Phila.), 76: 2034-2040, 1995.[Medline]
27. de La Coste A., Romagnolo B., Billuart P., Renard C. A., Buendia M. A., Soubrane O., Fabre M., Chelly J., Beldjord C., Kahn A., Perret C. Somatic mutations of the ß-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc. Natl. Acad. Sci. USA, 95: 8847-8851, 1998.[Abstract/Free Full Text]
28. Takahashi M., Fukuda K., Sugimura T., Wakabayashi K. ß-Catenin is frequently mutated and demonstrates altered cellular location in azoxymethane-induced rat colon tumors. Cancer Res., 58: 42-46, 1998.[Abstract/Free Full Text]
29. Dashwood R. H., Suzui M., Nakagama H., Sugimura T., Nagao M. High frequency of ß-catenin (ctnnb1) mutations in the colon tumors induced by two heterocyclic amines in the F344 rat. Cancer Res., 58: 1127-1129, 1998.[Abstract/Free Full Text]
30. Aberle H., Bauer A., Stappert J., Kispert A., Kemler R. ß-Catenin is a target for the ubiquitin-proteasome pathway. EMBO J., 16: 3797-3804, 1997.[Medline]
31. Malkhosyan S., McCarty A., Sawai H., Perucho M. Differences in the spectrum of spontaneous mutations in the hprt gene between tumor cells of the microsatellite mutator phenotype. Mutat. Res., 316: 249-259, 1996.[Medline]
32. Redston M. S., Caldas C., Seymour A. B., Hruban R. H., da Costa L., Yeo C. J., Kern S. E. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res., 54: 3025-3033, 1994.[Abstract/Free Full Text]
33. Greene C. N., Jinks-Robertson S. Frameshift intermediates in homopolymer runs are removed efficiently by yeast mismatch repair proteins. Mol. Cell. Biol., 17: 2844-2850, 1997.[Abstract]
34. Samowitz W. S., Powers M. D., Spirio L. N., Nollet F., van Roy F., Slattery M. L. ß-catenin mutations are more frequent in small colorectal adenomas than in larger adenomas and invasive carcinomas. Cancer Res., 59: 1442-1444, 1999.[Abstract/Free Full Text]
35. Lengauer C., Kinzler K. W., Vogelstein B. Genetic instabilities in human cancers. Nature (Lond.), 396: 643-649, 1998.[Medline]
36. Gurin C. C., Federici M. G., Kang L., Boyd J. Causes and consequences of microsatellite instability in endometrial carcinoma. Cancer Res., 59: 462-466, 1999.[Abstract/Free Full Text]
37. Kim H., Jen J., Vogelstein B., Hamilton S. R. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am. J. Pathol., 145: 148-156, 1994.[Abstract]

This article has been cited by other articles:

				M. J. Hayes, D. Thomas, A. Emmons, T. J. Giordano, and C. G. Kleer Genetic Changes of Wnt Pathway Genes Are Common Events in Metaplastic Carcinomas of the Breast Clin. Cancer Res., July 1, 2008; 14(13): 4038 - 4044. [Abstract] [Full Text] [PDF]

				T. Imai, K. Fukuta, M. Hasumura, Y.-M. Cho, Y. Ota, S. Takami, H. Nakagama, and M. Hirose Significance of inflammation-associated regenerative mucosa characterized by Paneth cell metaplasia and {beta}-catenin accumulation for the onset of colorectal carcinogenesis in rats initiated with 1,2-dimethylhydrazine Carcinogenesis, October 1, 2007; 28(10): 2199 - 2206. [Abstract] [Full Text] [PDF]

				A. Sanchez-de-Abajo, M. de la Hoya, M. van Puijenbroek, A. Tosar, J.A. Lopez-Asenjo, E. Diaz-Rubio, H. Morreau, and T. Caldes Molecular Analysis of Colorectal Cancer Tumors from Patients with Mismatch Repair Proficient Hereditary Nonpolyposis Colorectal Cancer Suggests Novel Carcinogenic Pathways Clin. Cancer Res., October 1, 2007; 13(19): 5729 - 5735. [Abstract] [Full Text] [PDF]

				J R Jass and J Behrens Wnt pathway may not be implicated in all routes to colorectal cancer * Author's reply Gut, February 1, 2007; 56(2): 309 - 310. [Full Text] [PDF]

				J. L. Hecht and G. L. Mutter Molecular and Pathologic Aspects of Endometrial Carcinogenesis J. Clin. Oncol., October 10, 2006; 24(29): 4783 - 4791. [Abstract] [Full Text] [PDF]

				D. Black, R. A. Soslow, D. A. Levine, C. Tornos, S. C. Chen, A. J. Hummer, F. Bogomolniy, N. Olvera, R. R. Barakat, and J. Boyd Clinicopathologic Significance of Defective DNA Mismatch Repair in Endometrial Carcinoma J. Clin. Oncol., April 10, 2006; 24(11): 1745 - 1753. [Abstract] [Full Text] [PDF]

				C. P. Giacomini, S. Y. Leung, X. Chen, S. T. Yuen, Y. H. Kim, E. Bair, and J. R. Pollack A Gene Expression Signature of Genetic Instability in Colon Cancer Cancer Res., October 15, 2005; 65(20): 9200 - 9205. [Abstract] [Full Text] [PDF]

				F. Tissier, C. Cavard, L. Groussin, K. Perlemoine, G. Fumey, A.-M. Hagnere, F. Rene-Corail, E. Jullian, C. Gicquel, X. Bertagna, et al. Mutations of {beta}-Catenin in Adrenocortical Tumors: Activation of the Wnt Signaling Pathway Is a Frequent Event in both Benign and Malignant Adrenocortical Tumors Cancer Res., September 1, 2005; 65(17): 7622 - 7627. [Abstract] [Full Text] [PDF]

				V Johnson, E Volikos, S E Halford, E T Eftekhar Sadat, S Popat, I Talbot, K Truninger, J Martin, J Jass, R Houlston, et al. Exon 3 {beta}-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome Gut, February 1, 2005; 54(2): 264 - 267. [Abstract] [Full Text] [PDF]

				A. Ougolkov, B. Zhang, K. Yamashita, V. Bilim, M. Mai, S. Y. Fuchs, and T. Minamoto Associations Among {beta}-TrCP, an E3 Ubiquitin Ligase Receptor, {beta}-Catenin, and NF-{kappa}B in Colorectal Cancer J Natl Cancer Inst, August 4, 2004; 96(15): 1161 - 1170. [Abstract] [Full Text] [PDF]

				R.C. Sills, H.L. Hong, G. Flake, C. Moomaw, N. Clayton, G.A. Boorman, J. Dunnick, and T.R. Devereux o-Nitrotoluene-induced large intestinal tumors in B6C3F1 mice model human colon cancer in their molecular pathogenesis Carcinogenesis, April 1, 2004; 25(4): 605 - 612. [Abstract] [Full Text] [PDF]

				I.-J. Kim, H. C. Kang, J.-H. Park, Y. Shin, J.-L. Ku, S.-B. Lim, S. Y. Park, S.-Y. Jung, H. K. Kim, and J.-G. Park Development and Applications of a {beta}-Catenin Oligonucleotide Microarray: {beta}-Catenin Mutations Are Dominantly Found in the Proximal Colon Cancers with Microsatellite Instability Clin. Cancer Res., August 1, 2003; 9(8): 2920 - 2925. [Abstract] [Full Text] [PDF]

				C. M. Ribic, D. J. Sargent, M. J. Moore, S. N. Thibodeau, A. J. French, R. M. Goldberg, S. R. Hamilton, P. Laurent-Puig, R. Gryfe, L. E. Shepherd, et al. Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer N. Engl. J. Med., July 17, 2003; 349(3): 247 - 257. [Abstract] [Full Text] [PDF]

				D. R. Schwartz, R. Wu, S. L. R. Kardia, A. M. Levin, C.-C. Huang, K. A. Shedden, R. Kuick, D. E. Misek, S. M. Hanash, J. M. G. Taylor, et al. Novel Candidate Targets of {beta}-Catenin/T-cell Factor Signaling Identified by Gene Expression Profiling of Ovarian Endometrioid Adenocarcinomas Cancer Res., June 1, 2003; 63(11): 2913 - 2922. [Abstract] [Full Text] [PDF]

				M. P.A. Ebert, J. Yu, J. Hoffmann, A. Rocco, C. Rocken, S. Kahmann, O. Muller, M. Korc, J. J. Sung, and P. Malfertheiner Loss of Beta-Catenin Expression in Metastatic Gastric Cancer J. Clin. Oncol., May 1, 2003; 21(9): 1708 - 1714. [Abstract] [Full Text] [PDF]

				F.-S. Liu, J.-T. Dong, J.-T. Chen, Y.-T. Hsieh, E. S.-C. Ho, M.-J. Hung, C.-H. Lu, and L.-C. Chiou KAI1 Metastasis Suppressor Protein Is Down-Regulated during the Progression of Human Endometrial Cancer Clin. Cancer Res., April 1, 2003; 9(4): 1393 - 1398. [Abstract] [Full Text] [PDF]

				K.-J. Sohn, M. Choi, J. Song, S. Chan, A. Medline, S. Gallinger, and Y.-I. Kim Msh2 deficiency enhances somatic Apc and p53 mutations in Apc+/-Msh2-/- mice Carcinogenesis, February 1, 2003; 24(2): 217 - 224. [Abstract] [Full Text] [PDF]

				M. Zysman, A. Saka, A. Millar, J. Knight, W. Chapman, and B. Bapat Methylation of Adenomatous Polyposis Coli in Endometrial Cancer Occurs More Frequently in Tumors with Microsatellite Instability Phenotype Cancer Res., July 1, 2002; 62(13): 3663 - 3666. [Abstract] [Full Text] [PDF]

				J. E. Pawlowski, J. R. Ertel, M. P. Allen, M. Xu, C. Butler, E. M. Wilson, and M. E. Wierman Liganded Androgen Receptor Interaction with beta -Catenin. NUCLEAR CO-LOCALIZATION AND MODULATION OF TRANSCRIPTIONAL ACTIVITY IN NEURONAL CELLS J. Biol. Chem., May 31, 2002; 277(23): 20702 - 20710. [Abstract] [Full Text] [PDF]

				Y. Zhai, R. Wu, D. R. Schwartz, D. Darrah, H. Reed, F. T. Kolligs, M. T. Nieman, E. R. Fearon, and K. R. Cho Role of {beta}-Catenin/T-Cell Factor-Regulated Genes in Ovarian Endometrioid Adenocarcinomas Am. J. Pathol., April 1, 2002; 160(4): 1229 - 1238. [Abstract] [Full Text] [PDF]

				P. Laiho, V. Launonen, P. Lahermo, M. Esteller, M. Guo, J. G. Herman, J.-P. Mecklin, H. Jarvinen, P. Sistonen, K.-M. Kim, et al. Low-Level Microsatellite Instability in Most Colorectal Carcinomas Cancer Res., February 1, 2002; 62(4): 1166 - 1170. [Abstract] [Full Text] [PDF]

				S. Halford, P. Sasieni, A. Rowan, H. Wasan, W. Bodmer, I. Talbot, N. Hawkins, R. Ward, and I. Tomlinson Low-Level Microsatellite Instability Occurs in Most Colorectal Cancers and Is a Nonrandomly Distributed Quantitative Trait Cancer Res., January 1, 2002; 62(1): 53 - 57. [Abstract] [Full Text] [PDF]

				M. P.A. Ebert, G. Fei, S. Kahmann, O. Muller, J. Yu, J. J.Y. Sung, and P. Malfertheiner Increased {beta}-catenin mRNA levels and mutational alterations of the APC and {beta}-catenin gene are present in intestinal-type gastric cancer Carcinogenesis, January 1, 2002; 23(1): 87 - 91. [Abstract] [Full Text] [PDF]

				J. Young, L. A. Simms, K. G. Biden, C. Wynter, V. Whitehall, R. Karamatic, J. George, J. Goldblatt, I. Walpole, S.-A. Robin, et al. Features of Colorectal Cancers with High-Level Microsatellite Instability Occurring in Familial and Sporadic Settings : Parallel Pathways of Tumorigenesis Am. J. Pathol., December 1, 2001; 159(6): 2107 - 2116. [Abstract] [Full Text] [PDF]

				R. Wu, Y. Zhai, E. R. Fearon, and K. R. Cho Diverse Mechanisms of {beta}-Catenin Deregulation in Ovarian Endometrioid Adenocarcinomas Cancer Res., November 1, 2001; 61(22): 8247 - 8255. [Abstract] [Full Text] [PDF]

				E. Sadot, B. Geiger, M. Oren, and A. Ben-Ze'ev Down-Regulation of {beta}-Catenin by Activated p53 Mol. Cell. Biol., October 15, 2001; 21(20): 6768 - 6781. [Abstract] [Full Text] [PDF]

T. Liu, J. Chen, S. Salahshor, S. Kuismanen, E. Holmberg, H. Gronberg, P. Peltomaki, and A. Lindblom Screening families with endometrial and colorectal cancers for germline mutations J. Med. Genet., September 1, 2001; 38(9): e29 - 29. [Full Text] [PDF]