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PubMed1997

Muir-Torre syndrome: clinical features and molecular genetic analysis.

We report a 62-year-old man with rectal cancer, two keratoacanthomas and multiple sebaceous adenomas, epitheliomas and sebaceous hyperplasia. His brother and father died from colorectal cancer. A subgroup of patients with the Muir-Torre syndrome (MTS) is allelic to the cancer family syndrome. This genetic disorder is caused by an autosomal dominant inherited germline mutation in one of the DNA mismatch repair genes. It is thought that a somatic mutation of the other allele leads to a genomic instability responsible for tumorigenesis. In the patient presented here the instability was detected in two characteristic skin lesions; sebaceous adenoma and epithelioma. The search for a causal germline mutation revealed a frameshift mutation in the mismatch repair gene hMSH2 leading to a truncated protein. A presymptomatic molecular diagnosis can be offered to the children of the patient.

Carcinoma↗
PubMedDate not supplied

The red blood cell band 3 variant (band 3Biceêtrel:R490C) associated with dominant hereditary spherocytosis causes defective membrane targeting of the molecule and a dominant negative effect.

Hereditary spherocytosis (HS), a common human inherited haemolytic anaemia, is associated with partial deficiency of different erythrocyte membrane proteins. In a subset of dominant HS, a partial membrane expression deficiency of band 3, the erythrocyte anion exchanger (AE1), have previously been characterized, and several mutations in the band 3 gene have been found: amino acid substitutions at conserved positions in the membrane domain, nonsense and frameshift mutations. In HS patients bearing missense mutations, the mutated transcript was present, whereas only the normal transcript was found in HS patients with frameshift mutations. In the former group, the membrane expression deficiency of band 3 was significantly more important than that observed in the latter group of HS patients with frameshift mutations, suggesting that missense mutations may have a dominant negative effect. In the present study, transient and stable transfections of K562 and COS-7 cells were used to demonstrate, by immunoblots of cell lysates and immunofluorescence studies, that the band 3 membrane domain bearing the R490C mutation (band 3Bicetrel) is not targeted to the plasma membrane and is retained in the endoplasmic reticulum. Transient cotransfections of K562 cells with plasmid coding for the normal membrane domain of band 3, together with increasing amounts of plasmid coding for the mutated R490C membrane domain, demonstrated that the band 3 mutant polypeptide exerts a dominant negative effect on the plasma membrane targeting of the normal band 3.

Animals↗
PubMed2003

[Cell cycle analysis and P53 gene mutation detection of fibroblasts derived from the surrounding skin of keloids].

OBJECTIVE: To investigate whether there are abnormal fibroblasts in the surrounding skin of keloids for better understanding of the etiological feature of keloids. METHODS: Fresh samples were used for cell culture. Flow cytometry was used for analyzing cell cycles of fibroblasts derived from keloids and the surrounding skin. Proliferative cell proportions were compared between every two groups. P53 exon 4, 5 and 6 were amplified by PCR. DNA was sequenced to examine the structure of the destination gene. RESULTS: The proliferative cell proportion of the fibroblasts derived from the surrounding skin is not so high as that from the verge of keloids, but is higher than the normal skin fibroblasts derived from other part of the keloid patients or persons without keloids (P < 0.05). Mutations (point and frameshift mutations) of P53 exon 4 (6/6) and exon 5(2/6) in fibroblasts derived from the surrounding skin of keloids were identified. Fibroblasts derived from keloids have the same mutations as its surrounding skin. CONCLUSION: There are abnormal fibroblasts in the surrounding skin of keloids. It may be the consequence of keloid infiltrative growth and a reason of easy recurrence of keloid after therapy.

Cell Cycle↗
PubMed2006

Recessive cornea plana in the Kingdom of Saudi Arabia.

OBJECTIVE: To characterize the molecular genetics of clinically diagnosed recessive cornea plana in the Kingdom of Saudi Arabia and establish the presence of common or limited founders (ancestors who originally harbored the disease-causing mutation) in the country's historically isolated population. DESIGN: Prospective interventional case series. PARTICIPANTS: Twelve affected patients from apparently unrelated Saudi Arabian nuclear families with clinically diagnosed recessive cornea plana. METHODS: Clinical ophthalmic examination and venous blood sampling for DNA sequencing. MAIN OUTCOME MEASURES: Age, gender, keratometry, best-corrected visual acuity, ocular alignment, cycloplegic refraction, significant findings of a complete ophthalmic examination, and keratocan gene (KERA) haplotype analysis. RESULTS: All 12 individuals had classic phenotypic features of recessive cornea plana and were homozygous for 1 of 2 KERA mutations--a novel frameshift mutation (1634delC) or a previously reported nonsense mutation (R313X). Haplotype analysis was consistent with a separate distinct common founder effect for each instance. An additional Saudi KERA mutation (R279X) has been reported previously in one family. CONCLUSION: Specific for mutation in KERA, the ophthalmic phenotype of recessive cornea plana does not significantly vary with different KERA mutations. The occurrence of a rare inherited disease in a historically isolated population is not always due to a single common founder effect; it may be explained by cultural preferences such as consanguinity (intrafamilial marriage) and endogamy (intratribal marriage), which enhance expression of recessively inherited diseases.

Adolescent↗
PubMed2004

APC mutations in sporadic colorectal carcinomas from The Netherlands Cohort Study.

The adenomatous polyposis coli (APC) gene is considered to be a gatekeeper in colorectal tumourigenesis. Inactivating mutations in APC have been reported in 34-70% of sporadic colorectal cancer patients, the majority of which occur in the mutation cluster region (MCR). In this study, tumour tissue from 665 incident colorectal cancer patients, who originate from 120 852 men and women (55-69 years of age at baseline) participating in The Netherlands Cohort Study, was evaluated for the occurrence and type of APC mutations with regard to age at diagnosis, gender, family history of colorectal cancer, Dukes' stage, tumour differentiation and sub-localization. Mutation analysis of the MCR, which spans codons 1286-1513, was performed on archival adenocarcinoma samples using macrodissection, nested PCR and direct sequencing of purified PCR fragments. A large number of genetic aberrations (n = 978), including point mutations (n = 833), deletions (n = 126) and insertions (n = 19) was detected in the MCR in 72% of patients (479/665). In particular, we observed a large number of missense mutations, more than reported previously. This may indicate involvement in colorectal carcinogenesis, although their significance for APC functions is unclear. Truncating mutations were found in 37% of patients (248/665). Patients with rectosigmoid and rectum tumours relatively more frequently harboured C > T nonsense mutations and truncating frameshift mutations as compared with patients with proximal and distal colon tumours (P = 0.009 and P = 0.045, respectively). Differences in occurrence of truncating mutations with regard to tumour sub-localization suggest a different aetiology of tumourigenesis in colon and rectum.

Adenomatous Polyposis Coli Protein↗
PubMed1999

Alterations of Fas (APO-1/CD95) gene in transitional cell carcinomas of urinary bladder.

Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signaling. The key role of the Fas system in negative growth regulation has been studied mostly within the immune system, and somatic mutations of Fas in cancer patients have been described solely in lymphoid-lineage malignancies. We analyzed somatic mutations and loss of heterozygosity of Fas gene in 43 transitional cell carcinomas of urinary bladder. Overall, 12 tumors (28%) were found to have Fas mutations, including 11 missense mutations and 1 frameshift mutation. Ten of the 12 mutations were located in the death domain known to be involved in the transduction of an apoptotic signal, and 8 of these 10 mutations showed an identical G to A transition at bp 993, indicating a potential hotspot in bladder cancers. Three of eight (38%) informative tumors carrying Fas mutations showed LOH at polymorphic sites in the promoter region. This is the first report on the Fas gene mutations in nonlymphoid malignancies, and our data suggest that alterations of the Fas gene might lead to the loss of its apoptotic function and contribute to the pathogenesis of some bladder cancers.

Amino Acid Substitution↗
PubMed2001

Two families with blepharophimosis/ptosis/epicanthus inversus syndrome have mutations in the putative forkhead transcription factor FOXL2.

Blepharophimosis/ptosis/epicanthus inversus syndrome (BPES) is an autosomal dominant disorder that is characterized by distinctive eyelid abnormalities. Two clinical subtypes have been described in which type I, but not type II, is associated with premature ovarian failure. Both types of BPES are linked to 3q22-23, and the gene has recently been identified as the putative forkhead transcription factor FOXL2. We report mutation screening of FOXL2 in two families with this condition. The two mutations detected were frameshift mutations resulting from a small insertion or duplication within the gene. Both mutations would result in the production of novel carboxyl terminii, one terminating the predicted protein earlier than the wild type, and the other giving rise to a larger protein product, assuming these proteins or their mRNA were not degraded. Based on the present data, this would suggest that the first family should be type I and the second, type II. Although there is evidence of infertility in the first family, all 3 females in the youngest generation have normal pelvic ultrasound and hormone levels, suggesting that the divide between types I and II may not be as distinct as has been suggested.

Blepharophimosis↗
PubMed1987

Nucleotide sequence changes in thymidine kinase gene of herpes simplex virus type 2 clones from an isolate of a patient treated with acyclovir.

To identify the nucleotide changes that occur in drug-induced thymidine kinase (TK) mutants of herpes simplex virus type 2 (HSV-2), we compared the nucleotide sequences of the tk genes of two mutant HSV-2 clones isolated from a patient who had been treated with acyclovir [9-(2-hydroxyethoxymethyl)guanine; ACV] with the nucleotide sequence of the parental TK+ HSV-2(8703) strain isolated from the same patient. One of the mutants, TK-altered (TKA) HSV-2(9637), was ACV resistant but induced the incorporation of [14C]thymidine into the DNA of infected rabbit skin cells. The nucleotide sequence of the tk gene of mutant TKA HSV-2(9637) had a single change (G to A) at nucleotide 668, which would cause an arginine-to-histidine substitution at amino acid residue 223 of the TK polypeptide. The second ACV-resistant mutant, TK- HSV-2(8710), did not induce detectable incorporation of [14C]thymidine into the DNA of infected rabbit skin cells. This mutant exhibited a deletion of a single base at nucleotide 217 of its nucleotide sequence. This deletion would cause a frameshift mutation at amino acid residue 73 and chain termination at amino acid residue 86 of the TK polypeptide. The nucleotide sequence of TK+ HSV-2(8703) was the same as that of the laboratory strain, TK+ HSV-2(333). The nucleotide sequence of a bromodeoxyuridine-resistant TK- HSV-2(333) mutant of TK+ HSV-2(333) also exhibited a single-base deletion, but at nucleotide 439. This deletion would cause a frameshift mutation at amino acid residue 147 and chain termination at amino acid residue 182. The frameshift mutations of TK- HSV(8710) and TK- HSV-2(333), respectively, occurred in sequences in which C was repeated three times and G was repeated seven times. The results raise the possibility that TK- frameshift mutations of HSV-2 may be common.

Acyclovir↗
PubMed2002

Comparative potencies of induction of point mutations and genetic duplications by the methylating agents methylazoxymethanol and dimethyl sulfate in bacteria.

Methylazoxymethanol (MAM) and dimethyl sulfate (DMS) are mutagens whose genetic effects can be ascribed to the methylation of DNA. While both methylate the N7 position of guanine heavily, only MAM strongly methylates the O(6) position of guanine. We evaluated the relative effectiveness and specificity of MAM and DMS in bacterial assays for the induction of point mutations and the formation of chromosomal duplications by genetic recombination. Salmonella typhimurium strain TS1121 was used to measure the formation of genetic duplications on the basis of the aroC321 allele and mutations by reversion of the hisG46 allele. Specific base pair substitutions and frameshift mutations were measured in a reversion assay based on lacZ alleles of Escherichia coli. The results show MAM to be the more potent mutagen and DMS the stronger recombinagen in the Salmonella assay. In the lacZ assay DMS induced several classes of base pair substitutions (GC-->AT transitions, GC-->TA transversions and AT-->TA transversions), as well as lower frequencies of +1, -1 and -2 frameshift mutations. The activity of MAM as a base pair substitution mutagen was more specific than that of DMS, inducing only GC-->AT transitions. It also induced +G, -G, -A and -CG frameshift mutations, though more weakly than it induced GC-->AT transitions. Long known as a base pair substitution mutagen, the induction of frameshifts by MAM was unexpected. The results show that both DMS and MAM are effective inducers of base pair substitutions and modest inducers of frameshifts and that DMS exhibits a broader spectrum of mutagenic activity than does MAM.

Alleles↗
PubMedDate not supplied

Construction of a vector for site-specific frameshift mutagenesis containing the mutable hotspot of Salmonella typhimurium TA98 on an M13 bacteriophage.

Frameshift mutations demonstrate a high degree of sequence specificity. In order to provide a vector for site-specific frameshift mutagenesis experiments, a recombinant M13 phage (M13MB102) was constructed by substitution of 27 base pairs of the Salmonella typhimurium hisD3052 sequence for 27 base pairs of the polylinker region of M13mp19. The inserted sequence contains most of the hotspot for frameshift mutations in hisD3052 and its derivative strain TA98. Structural elements of the insert include reiterated bases, direct repeats, and palindromes, and four unique restriction endonuclease cleavage sites. The recombinant phage produced blue plaques when grown in Escherichia coli strain JM105 on X-Gal indicator plates and exhibited a spontaneous mutation frequency similar to that of M13mp19. Methodology is described for preparation, isolation, and purification of closed circular duplex M13MB102 genomes containing an adduct between the SphI and BssHII cleavage sites in the (-)-strand and uracil residues in the (+)-strand. The latter modification decreases replication of the (+)-strand by 4 orders of magnitude and maximizes use of the adducted (-)-strand for in vivo replication. The structure of M13MB102 and the procedures described for introducing adducts at defined positions in its hisD3052 insert provide a convenient approach for evaluating the potential of individual carcinogen-DNA adducts to induce frameshift mutations.

Bacteriophage M13↗
PubMed2005

Molecular mechanisms of beta-lactam resistance mediated by AmpC hyperproduction in Pseudomonas aeruginosa clinical strains.

The molecular mechanisms of beta-lactam resistance mediated by AmpC hyperproduction in natural strains of Pseudomonas aeruginosa were investigated in a collection of 10 isogenic, ceftazidime-susceptible and -resistant pairs of isolates, each sequentially recovered from a different intensive care unit patient treated with beta-lactams. All 10 ceftazidime-resistant mutants hyper-produced AmpC (beta-lactamase activities were 12- to 657-fold higher than those of the parent strains), but none of them harbored mutations in ampR or the ampC-ampR intergenic region. On the other hand, six of them harbored inactivating mutations in ampD: four contained frameshift mutations, one had a C-->T mutation, creating a premature stop codon, and finally, one had a large deletion, including the complete ampDE region. Complementation studies revealed that only three of the six ampD mutants could be fully trans-complemented with either ampD- or ampDE-harboring plasmids, whereas one of them could be trans-complemented only with ampDE and two of them (including the mutant with the deletion of the ampDE region and one with an ampD frameshift mutation leading to an ampDE-fused open reading frame) could not be fully trans-complemented with any of the plasmids. Finally, one of the four mutants with no mutations in ampD could be trans-complemented, but only with ampDE. Although the inactivation of AmpD is found to be the most frequent mechanism of AmpC hyperproduction in clinical strains, our findings suggest that for certain types of mutations, AmpE plays an indirect role in resistance and that there are other unknown genes involved in AmpC hyperproduction, with at least one of them apparently located close to the ampDE operon.

Bacterial Proteins↗
PubMed1993

Synergism and antagonism between N-methyl-N'-nitro-N-nitroso-guanidine and 9-aminoacridine in mutation induction in Escherichia coli K12.

When bacteria were treated simultaneously with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and low concentrations of 9-aminoacridine (9AA), the yield of frameshift mutations was much greater than that expected on the basis of independent action of both mutagens. In combination with a high concentration of 9AA, however, MNNG had an antagonistic effect upon the induction of frameshift mutations. There was no synergistic interaction between the two mutagens in bacteria in which the adaptive response to methylating agents had been induced. 9AA not only induced frameshift mutations, but also caused a small increase in reversions of a nonsense (ochre) mutation and, in combination with low MNNG concentrations, it had a small synergistic effect.

Aminacrine↗
PubMed1993

A cosmid-based system for constructing mutants of herpes simplex virus type 1.

Cosmids containing large fragments of herpes simplex virus type 1 DNA were prepared using a vector that allows intact inserts to be excised using the restriction endonuclease PacI. Two independent sets (A and B) of five cosmids were identified whose inserts overlap and represent the entire viral genome, and set C was obtained by replacing two cosmids in set B. Each set gave rise to viral plaques when digested with PacI and transfected into cells in culture. Two cosmids common to sets B and C ostensibly contain one of the origins of viral DNA replication (oriL) in a region of overlap between inserts, but both actually consist of a minority of apparently intact (ori+L) forms and a majority of deleted (ori-L) forms. These sets yielded exclusively ori+L viral progeny. When either of these cosmids was replaced by a derivative comprising only ori-L forms, ori+L and ori-L progeny were obtained, and only ori-L progeny were produced when both were replaced. One cosmid in set A contains the oriL locus in a nonoverlapping region and lacks ori+L forms. This set generated only ori-L virus. Viral mutants with lesions in either or both of genes UL2 and UL44, which are not essential for growth in cell culture, were constructed using cosmids containing specifically introduced frameshift mutations. A mutant with a frameshift mutation in an essential gene (UL33) was isolated by transfecting a complementing cell line. These results indicate that a cosmid-based system will facilitate isolation of large numbers of defined viral mutants.

Animals↗
PubMed1987

Specific strand loss in N-2-acetylaminofluorene-modified DNA.

N-2-Acetylaminofluorene (AAF), a well-known chemical carcinogen, when covalently linked to guanine residues constitutes a premutagenic lesion that is converted in vivo into frameshift mutations. In Escherichia coli, it is thought that -AAF adducts block the replication fork and that the mutagenic processing of the -AAF adducts is mediated by the SOS response. The construction in vitro of plasmids containing -AAF adducts in one strand only of a double-stranded DNA molecule enabled us to investigate the segregation of the strands and the mutagenicity of the lesions in vivo. The two DNA strands were "genetically labelled" by means of a single base-pair mismatch in the tetracycline-resistance gene, one strand carrying the wild-type allele and the other strand a mutant tetracycline-sensitive allele. The two strands contained either no -AAF adducts, -AAF adducts in one strand or -AAF adducts in both strands. When such constructions are used to transform bacterial cells the following are found. When no -AAF adducts are present on either strand of the DNA, a mixture of plasmids having information from both parent strands is found in 80% of the transformed bacterial clones. With -AAF adducts present in one strand only, in 90% of the transformants there is a consistent loss of the parent strand information that contained the -AAF adducts. In the constructions having -AAF adducts in both strands, the transformed bacteria carry either one or the other allele in a pure form. Our results suggest that when blocking lesions (-AAF adducts) are present in one strand only, they trigger the specific loss of that strand. The forward mutation frequency (i.e. the tetracycline-resistance gene inactivation frequency) was found to be more than ten times lower when the -AAF adducts are bound to one strand only compared with the situation where both strands carry the premutagenic lesions. Moreover, when the isolated mutants were sequenced, the mutations were found to consist of a mixture of true -AAF-induced mutations (i.e. -1 or -2 frameshift mutation at previously determined mutation hot spots) and of mutations that are not targeted at -AAF adducts. We suggest that these "background" mutants arose from the mutagenic processing of cryptic lesions present in our DNA. The low mutagenic efficiency of -AAF adducts, when present in one strand only of a duplex DNA, most probably results from the above-described loss of the damaged strand.(ABSTRACT TRUNCATED AT 400 WORDS)

2-Acetylaminofluorene↗
PubMed1994

Molecular analysis of Polish patients with factor VII deficiency.

We analyzed the mutations in patients from 10 Polish kindreds with a bleeding diathesis due to factor VII deficiency. Patients from eight families had plasma levels of factor VII coagulant activity (VII:C) and factor VII antigen (VII:Ag) that were less than 4% of normal. The coding sequence of the factor VII gene was amplified from genomic DNA by polymerase chain reaction (PCR). Sequencing demonstrated a C to T transition at position 10798 resulting in Ala294Val, a G to A transition at 10976 resulting in Arg353Gln, and a single bp deletion at 11125 to 11128 causing a frameshift mutation in the triplet encoding amino acid 404. Homozygosity for the three sequence alterations was confirmed with the restriction enzymes AvaII and MspI and allele specific PCR, respectively. A homozygous patient from a ninth family with levels of VII:C and VII:Ag of 4% and 17%, respectively, had Ala294Val and the frameshift mutation, but not Arg353Gln. Investigation of a homozygous patient from a tenth kindred with VII:C and VII:Ag of 11% and 47%, respectively, demonstrated Ala294Val and Arg353Gln, but not the frameshift mutation. Based on the above data, we conclude that the frameshift mutation in the codon for amino acid 404 is associated with marked reductions in VII:C, Arg353Gln can decrease plasma levels of factor VII in the presence of other mutations in the factor VII gene, and Ala294Val results in a dysfunctional factor VII molecule.

Alleles↗
PubMed2000

Synchronous multiple primary gastrointestinal cancer exhibits frequent microsatellite instability.

Colorectal (CRC) and gastric cancers (GC), the most common gastrointestinal malignancies, have been known to develop occasionally in a same patient. Previous studies have focused on the etiology of patients with multiple primary gastric and colorectal cancer (MPGCC); however, the carcinogenic process of MPGCC remains unclear. In this study, we have examined the genetic alterations in MPGCC in order to clarify the carcinogenic pathway. Twenty patients with sporadic MPGCC were examined for microsatellite instability (MSI) and frameshift mutations of target genes such as TGFbetaRII, BAX and IGFIIR. In 10 (50%) of 20 patients with MPGCC, MSI was present at least at 1 lesion of GC or CRC. Four (50%) of 8 cases with synchronous MPGCC displayed MSI in both GC and CRC, while only 1 (8%) of 12 cases of metachronous MPGCC exhibited MSI in both organs. Carcinogenic process of MPGCC was fairly associated with the MSI pathway, particularly in cases of synchronous MPGCC. MSI was found in 5 (25%) of 20 GCs and in 10 (50%) of 20 CRCs. MSI was involved more closely in CRC than in GC among MPGCC. Although most frameshift mutations at target genes were found in the MSI-positive MPGCC, infrequent mutations were observed in the genes. Frameshift mutation was found in only 1 of 5 cases of MSI-positive GC at TGFbetaRII. Only 2 of 10 cases of CRC with MSI showed mutation at TGFbetaRII, and 1 case also showed mutation at BAX and IGFIIR. Our findings suggest that TGFbetaRII, BAX and IGFIIR are not the main target genes for carcinogenesis in MSI-positive MPGCC.

Aged↗
PubMed2006

Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn's disease.

BACKGROUND: Abnormal barrier function may be genetically determined in Crohn's disease. AIM: To examine the role of abnormal intestinal permeability in genetic predisposition in multiplex vs. sporadic Crohn's disease families. METHODS: Intestinal permeability was measured in patients, relatives and partners by means of lactulose/mannitol test. Healthy subjects from the hospital staff served as controls. CARD15 mutations were investigated in sporadic and familial Crohn's disease patients and in a group of blood donors. RESULTS: The median lactulose/mannitol ratio was increased significantly in Crohn's disease patients vs. their relatives [0.03 (0.01-0.24) vs. 0.01 (0.003-0.19), P=0.005]. The percentage of abnormal tests was significantly higher in familial vs. sporadic first-degree relatives of Crohn's disease patients (29% vs. 11%, P=0.0281). Abnormal permeability occurred significantly more frequent in patients with familial Crohn's disease carrying the frameshift mutation. The frameshift mutation 3020 insC was associated with increased permeability in 75% in the multiplex and in 61% of the sporadic CD patients. One partner had abnormal lactulose/mannitol ratio. Conclusion Intestinal permeability is raised in Crohn's disease patients and relatives, with higher rates in familial vs. sporadic healthy relatives. CARD15 mutations are associated with abnormal permeability in ileal Crohn's disease.

Adult↗
PubMed2003

Biallelic inactivation of the RIZ1 gene in human gastric cancer.

The distal short arm of chromosome 1 is commonly deleted in a variety of human neoplasms including gastrointestinal cancer. Genetic alterations of the retinoblastoma protein-interacting zing-finger gene (RIZ)1 including loss of heterozygosity (LOH) at 1p36, frameshift mutations, and promoter hypermethylation were reported previously in several cancers. In this study, we evaluated RIZ1 in 30 primary gastric cancers and found frameshift mutations in two cases (6.7%). Moreover, using real-time quantitative methylation-specific PCR, methylation of the RIZ1 promoter was detected in 11 (37%) cases. In all 11 cases with methylation, inactivation of the second allele occurred through frameshift mutation, LOH or promoter methylation. Our results suggest that RIZ1 is a specific target of inactivation in human gastric cancer.

Adult↗