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Results for “Mutually exclusive mutation”

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PubMed2005

Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance.

Approximately one third of acute myeloid leukemias (AMLs) are characterized by aberrant cytoplasmic localization of nucleophosmin (NPMc+ AML), consequent to mutations in the NPM putative nucleolar localization signal. These events are mutually exclusive with the major AML-associated chromosomal rearrangements, and are frequently associated with normal karyotype, FLT3 mutations, and multilineage involvement. We report the gene expression profiles of 78 de novo AMLs (72 with normal karyotype; 6 without major chromosomal abnormalities) that were characterized for the subcellular localization and mutation status of NPM. Unsupervised clustering clearly separated NPMc+ from NPMc- AMLs, regardless of the presence of FLT3 mutations or non-major chromosomal rearrangements, supporting the concept that NPMc+ AML represents a distinct entity. The molecular signature of NPMc+ AML includes up-regulation of several genes putatively involved in the maintenance of a stem-cell phenotype, suggesting that NPMc+ AML may derive from a multipotent hematopoietic progenitor.

Acute Disease↗

PubMed2006

Coexpression of NRASQ61R and BRAFV600E in human melanoma cells activates senescence and increases susceptibility to cell-mediated cytotoxicity.

Activating mutations in BRAF and NRAS oncogenes in human melanomas are mutually exclusive. This finding has suggested an epistatic relationship but is consistent even with synthetic lethality. To evaluate the latter possibility, a mutated NRAS(Q61R) oncogene was expressed, under a constitutive or a doxycycline-regulated promoter, in a metastatic melanoma clone (clone 21) harboring an activated BRAF(V600E) oncogene. After the first 10 to 12 in vitro passages, the constitutive NRAS(Q61R) transfectant displayed progressive accumulation in G(0)-G(1) phase of the cell cycle and stained for the senescence-associated beta-galactosidase activity (SA-beta-Gal). Inducible expression of NRAS(Q61R), by the Tet-Off system, in clone 21 cells (21NRAS(61ON)) led to overactivation of the RAS/RAF/mitogen-activated protein kinase signaling pathway and, after the 10th in vitro passage, led to promotion of senescence. This was documented by reduced proliferation, flattened cell morphology, reduced growth in Matrigel, positive staining for SA-beta-Gal, and expression of AMP-activated protein kinase and of the cell cycle inhibitor p21(waf1/Cip1). These effects were detected neither in 21 cells with silenced NRAS(Q61R) (21NRAS(61OFF)) nor in cells transfected with an inducible wild-type NRAS gene (21NRAS(WTON)). In addition, when compared with parental 21 cells, or with 21NRAS(61OFF), 21NRAS(61ON) and constitutive NRAS(Q61R) transfectants cells showed increased susceptibility to cytotoxicity by both HLA class I antigen-restricted and nonspecific T cells and up-regulation of several MHC class I antigen processing machinery components. These results suggest a relationship of synthetic lethality between NRAS and BRAF oncogenes, leading to selection against "double-mutant" cells.

Alleles↗

PubMed2006

Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms.

Sequence mutations and gene amplifications lead to activation of the PIK3CA-AKT2 signaling pathway and have been reported in several types of neoplasms including ovarian cancer. Analysis of such genetic alterations, however, is usually complicated by contamination of normal cell DNA, artifacts associated with formalin-fixed tissues and the sensitivity of the techniques employed. In this study, we analyzed the sequence mutations in PIK3CA and AKT2 genes using purified tumor cells that were isolated from high-grade ovarian serous carcinomas and serous borderline tumors (SBTs) and assessed gene amplification using a dual-color FISH on tissue microarrays. Somatic sequence mutations in the kinase domain of AKT2 were not detected in any of the 65 ovarian tumors analyzed. Mutations of PIK3CA were rare, occurring only in one (2.3%) of 44 high-grade serous carcinomas and in only one (4.8%) of 21 SBTs. Dual-color FISH demonstrated that PIK3CA and AKT2 were not amplified in SBTs but amplified in 13.3% and 18.2% high-grade carcinomas, respectively. High-level amplification (>3 fold) was more frequently observed in AKT2 than in PIK3CA. Unlike mutations in ERBB2, KRAS and BRAF which are mutually exclusive in SBTs, coamplification of PIK3CA and AKT2 was present in five high-grade carcinomas including the OVCAR3 cells. Amplification in either of the genes occurred in 27% high-grade serous carcinomas. In conclusion, the methods we employed provide unambiguous evidence that somatic sequence mutations of PIK3CA and ATK2 are rare in ovarian serous tumors but amplification of both genes may play an important role in the development of high-grade ovarian serous carcinoma.

Carcinoma↗

PubMed2006

Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis.

CONTEXT: Gastrointestinal stromal tumors (GISTs) are specific, generally Kit (CD117)-positive, mesenchymal tumors of the gastrointestinal tract encompassing a majority of tumors previously considered gastrointestinal smooth muscle tumors. They are believed to originate from interstitial cells of Cajal or related stem cells. OBJECTIVE: To review current clinicopathologically relevant information on GIST. DATA SOURCES: Literature in Medline and authors' own experience. CONCLUSIONS: GISTs usually occur in older adults (median age 55-60 years) and rarely in children in the second decade (<1%) throughout the gastrointestinal tract: 60% in stomach, 35% in small intestine, and less than 5% in rectum, esophagus, omentum, and mesentery; most GISTs in the latter 2 sites are metastatic. Five percent of GISTs occur in patients with neurofibromatosis type 1 syndrome (multiple small intestinal tumors) and in Carney triad (gastric epithelioid GISTs in young females). Familial GISTs occur in patients with inheritable germline Kit or platelet-derived growth factor receptor alpha (PDGFRA) mutations. Histologically GISTs vary from spindle cell tumors to epithelioid and pleomorphic tumors. Most GISTs (95%) express Kit (CD117), CD34 (70%), and heavy caldesmon (80%), whereas 25% are positive for smooth muscle actin and less than 5% for desmin. Tumor size and mitotic activity are best predictive prognostic features; small intestinal tumors behave more aggressively than gastric tumors with similar parameters. Mutually exclusive gain-of-function Kit or PDGFRA mutations occur in a majority of GISTs representing in-frame deletions, point mutations, duplications and insertions. Mutations in Kit juxtamembrane domain (exon 11) are the most common in GISTs of all sites, whereas rare Kit extracellular domain (exon 9) Ala502-Tyr503 duplication is specific for intestinal GISTs. Mutations in PDGFRA have been identified in juxtamembrane (exon 12) and tyrosine kinase domains (exons 14 and 18), nearly exclusively in gastric GISTs, mostly in epithelioid variants. Some Kit and PDGFRA mutations have a prognostic value. Kit/PDGFRA tyrosine kinase inhibitor imatinib has been successfully used in the treatment of metastatic GISTs for more than 5 years. However, primary and acquired secondary resistance linked to certain types of Kit and PDGFRA mutations is limiting long-term success necessitating the use of alternative treatments.

Biomarkers, Tumor↗

PubMed1994

A temperature-sensitive mutation of the temperature-regulated SerH3 i-antigen gene of Tetrahymena thermophila: implications for regulation of mutual exclusion.

The Ser genes of Tetrahymena thermophila specify alternative forms of a major cell surface glycoprotein, the immobilization or i-antigen (i-ag). Regulation of i-ag expression assures that at least one i-ag gene is expressed at all times. To learn more about the regulatory system and the possible role of i-ag itself, we studied SerH3-ts1, a temperature-sensitive allele of the temperature-regulated SerH3 gene normally expressed from 20-36 degrees. In homozygotes grown at the nonpermissive temperature (> 32 degrees), H3 is not present on the cell surface, but the gene continues to be transcribed until its 36 degrees cutoff. H3 formed at the permissive temperature is stable at nonpermissive temperatures, indicating that SerH3-ts1 is temperature-sensitive for synthesis rather than function. At nonpermissive temperatures, the S i-ag is expressed in place of H3. This result suggests that normal H protein may play a role in regulating S expression. SerH3-ts1 was isolated following mutagenesis with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Sequencing of SerH3-ts1 revealed a single A --> G transition at nucleotide 473, resulting in the substitution of glycine for aspartate. The affected residue is conserved in the internal repeats comprising the H protein, and the charge difference correlates with changes in electrophoretic mobility of the H3 protein.

Animals↗

PubMed2005

Multiple signaling pathways converge on beta-catenin in thyroid cancer.

The beta-catenin pathway has been conclusively demonstrated to regulate differentiation and patterning in multiple model systems. In thyroid cancer, alterations are often seen in proteins that regulate beta-catenin, including those of the RAS, PI3K/AKT, and peroxisome proliferation activated receptor-gamma (PPARgamma) pathways, and evidence from the literature suggests that beta-catenin may play a direct role in the dedifferentiation commonly observed in late-stage disease. RET/PTC rearrangements are frequent in thyroid cancer and appear to be exclusive from mutational events in RAS and BRAF. Activation of AKT by phosphatidylinositide-3 kinase (PI3K), a RAS effector, results in GSK3beta phosphorylation and deactivation and subsequent beta-catenin upregulation in thyroid cancer. Activating mutations in beta-catenin, which have been demonstrated in late-stage thyroid tumors, correlate with beta-catenin nuclear localization and poor prognosis. We hypothesize that activation of the RAS, PI3K/AKT, and PPARgamma pathways ultimately impinges upon beta-catenin. We further propose that if mutations in BRAF, RAS, and RET/PTC rearrangements are mutually exclusive in certain thyroid tumors or tumor types, as has already been shown for papillary thyroid cancer, then these interconnected pathways may cooperate in the initiation and promotion of the disease. We believe that clinical benefit for thyroid cancer patients could be derived from disrupting the middle or distal pathway effectors of these pathways, such as AKT or beta-catenin.

Genetic Therapy↗

PubMed2001

Functional impact of concomitant versus alternative defects in the Chk2-p53 tumour suppressor pathway.

Recent evidence identified a genetic and functional link between Chk2 kinase and p53 as a candidate genome integrity checkpoint and a tumour suppressor pathway. Here we report that in human cells, Chk2 and p53 form protein-protein complexes whose abundance increased upon DNA damage, and whose formation was abrogated through cancer associated mutations in the FHA domain of Chk2, or mutations in the tetramerization domain of p53. Whereas among Li-Fraumeni syndrome families mutations of Chk2 or p53 occur in a mutually exclusive manner, we document that the colon cancer cell line HCT-15 concomitantly lacks functions of both Chk2 and p53, the latter demonstrated by a non-invasive reporter assay monitoring p53-dependent transactivation in live cells. Despite the preserved ability of common cancer-derived mutant p53 proteins to bind and potentially 'titrate' activated Chk2, the integrity of the S phase checkpoint response to ionizing radiation remained largely intact and dependent on Chk2 in cells with wild-type, mutant, or no p53. These results provide new mechanistic insights into the Chk2-p53 interplay, suggest how mutations in Chk2 may abrogate its tumour suppressor function, and indicate that compared with individual defects in either Chk2 or p53, concomitant mutations in both of these cell cycle checkpoint regulators may provide some additional selective advantage to tumour cells.

Checkpoint Kinase 2↗

PubMed2005

PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes.

This review summarizes PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) mutations and genotype-phenotype correlations in Noonan syndrome (NS) and LEOPARD syndrome (LS). PTPN11 mutations have been identified in approximately 40% of NS patients and in >80% of LS patients. Since the vast majority of mutations reside in and around the broad intramolecular interaction surface between the N-SH2 and PTP domains of the PTPN11 protein, they have been suggested to affect the intramolecular N-SH2/PTP binding in the absence of a phosphopeptide, leading to excessive phosphatase activities. The type of mutations is diverse in NS and limited in LS, and is almost mutually exclusive between NS and LS. Clinical assessment in NS patients implies that cardiovascular anomalies and hematologic abnormalities are predominant in mutation positive patients, hypertrophic cardiomyopathy is predominant in mutation negative patients, and growth deficiency, mental retardation, and minor somatic anomalies are similar between the two groups of patients. Phenotypic evaluation in LS patients suggests that a hypertrophic cardiomyopathy rather than an electrocardiographic conduction abnormality is characteristic of PTPN11 mutation positive patients.

Cardiomyopathy, Hypertrophic↗

PubMed2006

Loss of parafibromin expression in a subset of parathyroid adenomas.

Inactivation of the hyperparathyroidism-jaw tumour syndrome (HPT- JT) gene, HRPT2, was recently established as a genetic mechanism in the development of parathyroid tumours. Its encoded protein parafibromin has tumour-suppressor properties that play an important role in tumour development in the parathyroids, jaws and kidneys. Inactivating HRPT2 mutations are common in HPT- JT and parathyroid carcinomas, and have been described in a few cases of parathyroid adenomas with cystic features. In this study, 46 cases of cystic parathyroid adenomas previously investigated for HRPT2 mutations were characterized with regard to MEN1 gene mutations, cyclin D1 expression and parafibromin expression. In normal tissues and cell lines, parafibromin was ubiquitously expressed. Furthermore, parafibromin was detected as a dominating nuclear and a weaker cytoplasmic signal in transfected cell lines. In the three parathyroid tumours with inactivating HRPT2 mutations parafibromin expression was not detectable, and in one of two cases with aberrantly sized parafibromin the protein was delocalized. Both high and low cyclin D1 levels were found among HRPT2-mutated and -unmutated tumours, suggesting that these events are not mutually exclusive in parathyroid tumour development. The presented data suggest that in the majority of benign parathyroid tumours the expression of parafibromin remains unaltered, while the loss of parafibromin expression is strongly indicative of gene inactivation through mutation of the HRPT2 gene.

Adenoma↗

PubMed1998

Involvement of the Xenopus laevis Ro60 autoantigen in the alternative interaction of La and CNBP proteins with the 5'UTR of L4 ribosomal protein mRNA.

In vertebrates the synthesis of ribosomal proteins is co-ordinately regulated at the translational level. The 5'-untranslated region (5'UTR) of this class of mRNAs contains conserved regions that are necessary and sufficient for translational regulation. Recently, we found that two proteins, the Xenopus laevis La autoantigen and the cellular nucleic acid binding protein (CNBP), are able to bind in vitro a pyrimidine tract at the 5' end and a downstream region, respectively. These regions are considered the common cis-acting elements of translational regulation. It was previously observed that the binding of both these putative trans-acting factors to their RNA sequences is assisted by a protease-sensitive factor(s) that dissociates from the complex after its formation. Here we provide evidence that the requirement for an ancillary factor assisting La binding to the pyrimidine tract of ribosomal protein mRNAs is typical of this RNA, and secondly that it may involve an RNA recognition motif of the La protein not clearly characterized previously. We also show that the Ro60 autoantigen is involved in the common factor activity necessary for the binding of La and CNBP proteins to their respective sequences. In addition, our findings suggest that an RNA also participates in this process. We show that CNBP can multimerise and that it binds to the 5'UTR as a dimer. Both La and CNBP compete for the interaction with the factor, and their binding to the 5'UTR is mutually exclusive. Our results from the binding analysis of mutations in the 5'UTR, which are known to disrupt the translational control in vivo, suggest a model in which the protein interactions and the 5'UTR RNA structure may co-operate in regulating the translational fate of ribosomal protein mRNAs.

Amino Acid Sequence↗

PubMed1976

The genetic instabilities of the mating type locus in fission yeast.

Certain genetic instabilities of the "mating type locus" in the yeast Schizosaccharomyces pombe are interpreted in terms of transposition: Homothallic strains are characterized by two adjacent mating type genes (mat1-mat2+) with sexually complementary functions. One of these genes (mat2+) is able to duplicate itself, and the duplicated copy maps at the position of mat1-. The former function of mat1-is lost (owing to insertion), and only becomes reactivated when the inserted sequence (mat1+) is again excised. Analyses of analogous instabilities expressed by the partially defective mutation mat2+ -B102 have substantiated this transposition scheme. Homothallism is acribed to alternate and mutually exclusive activation of mat1- or mat2+ genes.

Alleles↗

PubMed2005

Aberrant methylation of the negative regulators RASSFIA, SHP-1 and SOCS-1 in myelodysplastic syndromes and acute myeloid leukaemia.

Mutations in the receptor tyrosine kinase (RTK/RAS) signalling pathway frequently provide a proliferative signal in myeloid malignancies. However, the role of RASSF1A, SHP-1 and SOCS-1, negative regulators of RTK/RAS signalling, has not been extensively investigated in the myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML). This study employed methylation-specific polymerase chain reaction (MS-PCR) to determine if aberrant promotor methylation of RASSF1A, SHP-1 and SOCS-1 is involved in the pathogenesis of myeloid malignancies. Patients with MDS (n = 107), AML (n = 154) and juvenile myelomonocytic leukaemia (JMML, n = 5) were investigated, together with 15 normal controls. Primers were located in the promotor region of each gene as well as within exon 2 of SOCS-1. Methylation of RASSF1A was found in five of 55 (9%) MDS cases, but not in any of 57 AML cases studied. RASSF1A methylation was present in one case (20%) of JMML. SHP-1 methylation was present in 13 of 121 (11%) AML cases but was not found in MDS or JMML. SOCS-1 promoter methylation was present in eight of 74 (11%) MDS patients but was not seen in JMML or AML. Importantly, RAS mutations and RASSF1A and SOCS-1 methylation were mutually exclusive indicating that approximately 30% of MDS cases had a defect of the RTK/RAS pathway and its negative regulation. Finally, SOCS-1 exon 2 methylation may not be pathogenetically relevant, since it was detected in samples from normal individuals and did not correlate with promotor methylation.

Acute Disease↗

PubMed2002

A physical interaction between Gar1p and Rnt1pi is required for the nuclear import of H/ACA small nucleolar RNA-associated proteins.

During rRNA biogenesis, multiple RNA and protein substrates are modified and assembled through the coordinated activity of many factors. In Saccharomyces cerevisiae, the double-stranded RNA nuclease Rnt1p and the H/ACA snoRNA pseudouridylase complex participate in the transformation of the nascent pre-rRNA transcript into 35S pre-rRNA. Here we demonstrate the binding of a component of the H/ACA complex (Gar1p) to Rnt1p in vivo and in vitro in the absence of other factors. In vitro, Rnt1p binding to Gar1p is mutually exclusive of its RNA binding and cleavage activities. Mutations in Rnt1p that disrupt Gar1p binding do not inhibit RNA cleavage in vitro but slow RNA processing, prevent nucleolar localization of H/ACA snoRNA-associated proteins, and reduce pre-rRNA pseudouridylation in vivo. These results demonstrate colocalization of various components of the rRNA maturation complex and suggest a mechanism that links rRNA pseudouridylation and cleavage factors.

Amino Acid Sequence↗

PubMed2005

The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells.

In papillary thyroid carcinomas (PTCs), rearrangements of the RET receptor (RET/PTC) and activating mutations in the BRAF or RAS oncogenes are mutually exclusive. Here we show that the 3 proteins function along a linear oncogenic signaling cascade in which RET/PTC induces RAS-dependent BRAF activation and RAS- and BRAF-dependent ERK activation. Adoptive activation of the RET/PTC-RAS-BRAF axis induced cell proliferation and Matrigel invasion of thyroid follicular cells. Gene expression profiling revealed that the 3 oncogenes activate a common transcriptional program in thyroid cells that includes upregulation of the CXCL1 and CXCL10 chemokines, which in turn stimulate proliferation and invasion. Thus, motile and mitogenic properties are intrinsic to transformed thyroid cells and are governed by an epistatic oncogenic signaling cascade.

Animals↗

PubMed1996

Mutations in the B2 bradykinin receptor reveal a different pattern of contacts for peptidic agonists and peptidic antagonists.

The B2 bradykinin receptor, a seven-helix transmembrane receptor, binds the inflammatory mediator bradykinin (BK) and the structurally related peptide antagonist HOE-140. The binding of HOE-140 and the binding of bradykinin are mutually exclusive and competitive. Fifty-four site-specific receptor mutations were made. BK's affinity is reduced 2200-fold by F261A, 490-fold by T265A, 60-fold by D286A, and 3-10-fold by N200A, D268A, and Q290A. In contrast, HOE-140 affinity is reduced less than 7-fold by F254A, F261A, Y297A, and Q262A. The almost complete discordance of mutations that affect BK binding versus HOE-140 binding is surprising, but it was paralleled by the effect of single changes in BK and HOE-140. [Ala9]BK and [Ala6]BK are reduced in receptor binding affinity 27,000- and 150-fold, respectively, while [Ala9]HOE-140 affinity is reduced 7-fold and [Ala6]HOE-140 affinity is unchanged. NMR spectroscopy of all of the peptidic analogs of BK or HOE-140 revealed a beta-turn at the C terminus. Models of the receptor-ligand complex suggested that bradykinin is bound partially inside the helical bundle of the receptor with the amino terminus emerging from the extracellular side of helical bundle. In these models a salt bridge occurs between Arg9 and Asp286; the models also place Phe8 in a hydrophobic pocket midway through the transmembrane region. Models of HOE-140 binding to the receptor place its beta-turn one alpha-helical turn deeper and closer to helix 7 and helix 1 as compared with bradykinin-receptor complex models.

Adrenergic beta-Antagonists↗

PubMed2002

Interference between D30N and L90M in selection and development of protease inhibitor-resistant human immunodeficiency virus type 1.

We studied the evolutionary relationships between the two protease inhibitor (PI) resistance mutations, D30N and L90M, of human immunodeficiency virus type 1 (HIV-1). The former is highly specific for nelfinavir resistance, while the latter is associated with resistance to several PIs, including nelfinavir. Among patients with nelfinavir treatment failure, we found that D30N acquisition was strongly suppressed when L90M preexisted. Thus, D30N/L90M double mutations not only were detected in a very limited number of patients but also accounted for a minor fraction within each patient. In the disease course, the D30N and L90M clones readily evolved independently of each other, and later the D30N/L90M double mutants emerged. The double mutants appeared to originate from the D30N lineage but not from the L90M lineage, or were strongly associated with the former. However, their evolutionary pathways appeared to be highly complex and to still have something in common, as they always contained several additional polymorphisms, including L63P and N88D, as common signatures. These results suggest that D30N and L90M are mutually exclusive during the evolutionary process. Supporting this notion, the D30N/L90M mutation was also quite rare in a large clinical database. Recombinant viruses with the relevant mutations were generated and compared for the ability to process p55gag and p160pol precursor proteins as well as for their infectivity. L90M caused little impairment of the cleavage activities, but D30N was detrimental, although significant residual activity was observed. In contrast, D30N/L90M demonstrated severe impairment. Thus, the concept of mutual antagonism of the two mutations was substantiated biochemically and functionally.

Cloning, Molecular↗

PubMed2004

CpG island promoter hypermethylation of the Ras-effector gene NORE1A occurs in the context of a wild-type K-ras in lung cancer.

Imbalance of the Ras signaling pathway is a major hallmark of human cancer. In this context, activating point mutations of the K-ras oncogene are a common feature of many tumor types. The discovery of methylation-mediated silencing of the Ras-effector homologue RASSF1A has revealed another way by which this cellular pathway may be altered. Inactivation by hypermethylation of a RASSF1A homologue, NORE1A, has recently been observed in human cancers. If both K-ras and NORE1A act in the same pathway, simultaneous molecular lesions in the two genes in the same tumor should be a rare event. To test whether this inverse association exists, we have analysed the K-ras mutational status and NORE1A CpG island hypermethylation of 61 non-small-cell lung carcinomas and the methylation status of the two other Ras effectors, RASSF1A and HRASLS. No association was found between the methylation status of NORE1A, RASSF1A and HRASLS or the status of K-ras with respect to the latter two genes. However, our results demonstrate that the epigenetic alteration of NORE1A is confined to lung tumors with a wild-type K-ras: 88% (15 of 17) of the tumors with NORE1 hypermethylation did not harbor a K-ras mutation (P=0.008, Fisher's exact test). Thus, the mutual exclusivity of the epigenetic and genetic alterations in the two genes of the Ras pathway suggests that they play a critical and cooperative role in human tumorigenesis.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer.

Mutation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates the majority of colorectal (CR) cancers. One consequence of this inactivation is constitutive activation of beta-catenin/Tcf-mediated transcription. To further explore the role of the APC/beta-catenin/Tcf pathway in CR tumorigenesis, we searched for mutations in genes implicated in this pathway in CR tumors lacking APC mutations. No mutations of the gamma-catenin (CTNNG1), GSK-3alpha (GSK3A), or GSK-3beta (GSK3B) genes were detected. In contrast, mutations in the NH2-terminal regulatory domain of beta-catenin (CTNNB1) were found in 13 of 27 (48%) CR tumors lacking APC mutations. Mutations in the beta-catenin regulatory domain and APC were observed to be mutually exclusive, consistent with their equivalent effects on beta-catenin stability and Tcf transactivation. In addition, we found that CTNNB1 mutations can occur in the early, adenomatous stage of CR neoplasia, as has been observed previously with APC mutations. These results suggest that CTNNB1 mutations can uniquely substitute for APC mutations in CR tumors and that beta-catenin signaling plays a critical role in CR tumorigenesis.

Adenocarcinoma↗