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PubMed1996

Truncation at the C-terminus of the DAX-1 protein impairs its biological actions in patients with X-linked adrenal hypoplasia congenita.

The DAX-1 [DSS (dosage-sensitive sex)-AHC critical region in the X, gene 1] gene has been reported to be responsible for X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism. However, the function and structure of the DAX-1 protein have not been characterized. In this study, molecular analysis of the DAX-1 gene from 6 patients with AHC, including 2 siblings, identified 5 novel mutations with 3 nonsense mutations and 2 frameshift mutations. Case 1 had a nonsense mutation at position 395 (Q395X). Cases 2 and 3, who were siblings, had a nonsense mutation at position 91 (Y91X). Case 4 had a 2-base deletion (AT) at nucleotides 1610 and 1611 and a 1-base insertion (G) resulting in a premature stop codon at position 462 (1610-1611 del AT ins G). Case 5 had a nonsense mutation at position 271 (Y271X). Case 6 had a 1-base deletion (C) at nucleotide 1169, which induced a frame shift and a premature stop codon at position 371 (1169 del C). All mutated DAX-1 proteins had truncated C-terminal domains. In addition, reverse transcription-PCR and direct sequencing characterized the mutant messenger ribonucleic acid in testis from case 1. Our results suggest that these 5 novel mutations are responsible for X-linked AHC and that the C-terminus of the DAX-1 protein, especially the terminal 11 amino acids, is necessary for normal adrenal cortical embryogenesis.

Adolescent↗
PubMed2001

Somatic mutations in MEN type 1 tumors, consistent with the Knudson "two-hit" hypothesis.

MEN type 1 is an autosomal dominant disorder characterized by the combined occurrence of tumors of the parathyroids, anterior pituitary, and pancreatic islet cells. The MEN1 gene, which is located on chromosome 11q13, consists of 10 exons and encodes a 610-amino acid protein named MENIN. The observation of LOH involving 11q13 in MEN type 1 tumors and the inactivating germline mutations found in patients suggest that the MEN1 gene acts as a tumor suppressor, in keeping with the "two-hit" model of hereditary cancer. The second hit in MEN type 1 tumors typically involves large chromosomal deletions that include 11q13. However, this only represents one mechanism by which the second hit may occur, and the other mechanisms, such as intragenic deletions or point mutations that inactivate the gene, have not been reported in MEN type 1 tumors. We have therefore undertaken studies to search for such mutations in six MEN type 1 tumors (four parathyroid tumors, one insulinoma, and one lipoma) that did not have LOH at 11q13 as assessed using the flanking markers D11S480, D11S1883 and PYGM centromerically and D11S449 and D11S913 telomerically. This revealed four somatic mutations, which consisted of two missense mutations and two frameshift mutations in two parathyroid tumors, one insulinoma, and one lipoma. Thus, our results, which represent the first small intragenic somatic mutations reported in MEN type 1 tumors, provide further evidence that the role of the MEN1 gene is consistent with that of a tumor suppressor gene, as postulated by Knudson's "two-hit" hypothesis.

Adult↗
PubMed1998

A family of MEN1 with a novel germline missense mutation and benign polymorphisms.

The gene responsible for multiple endocrine neoplasia type 1 (MEN1) has recently been cloned, and its germline mutations were identified in patients with this syndrome. The majority of the mutations, frameshift or nonsense mutations, are expected to result in a loss of function of the gene product menin. Since the consequence of less common missense or in-frame deletion mutations is not clear, careful judgment is necessary regarding the role(s) of such mutations in MEN1 disease. Here we describe a large multigenerational MEN1 family with a novel germline missense mutation and three benign polymorphisms. The proband was a man with hyperparathyroidism and thymic carcinoid. We performed biochemical studies and DNA analyses of the MEN1 gene simultaneously and independently as family screening studies. Seven patients including the proband were identified, and all of them carried a heterozygous germline missense mutation E45G, but 5 members with normal biochemical results did not. This mutation was not observed in 50 normal volunteers. This novel missense mutation is therefore almost conclusively responsible for the disease. Although all of the mutant gene carriers in the present study already had clinical diseases, an MEN1 gene analysis in younger individuals at risk would be very useful in identifying carriers before the onset of the symptoms.

Adult↗
PubMed2006

Clinical and genetic characteristics of Chinese hereditary nonpolyposis colorectal cancer families.

AIM: To analyze the clinical characteristics of Chinese hereditary nonpolyposis colorectal cancer (HNPCC) families and to screen the germline mutations of human mismatch repair genes hMLH1 and hMSH2 in the probands. METHODS: Thirty-one independent Chinese HNPCC families were collected in Zhejiang Province. All of them met Chinese HNPCC criteria. Clinical data about patient gender, site of colorectal cancer, age of onset, history of multiple colorectal cancer, associated extracolonic cancer were recorded. PCR and denaturing high performance liquid chromatography (DHPLC) were employed to screen the mutations. Sequencing analysis was used to find out the exact mutation site and characteristics of the samples showing abnormal DHPLC profiles. RESULTS: One hundred and thirty-six malignant neoplasms were found in 107 patients including 14 multiple cancers. One hundred and six of the 136 neoplasms (77.9%) were diagnosed as colorectal cancer, with an average age of onset at 48.57 +/- 29.00 years. Gastric cancer was the most common extracolonic cancer (10.3%) in these families. Twenty-three different sequence variations in hMLHl and hMSH2 genes were detected in these 17 families. Fifteen sequence variations were located in the exons, including 5 SNPs, 3 silent mutations, 3 missense mutations, 2 nonsense mutations and 2 frameshift mutations. The latter seven mutations seemed to be pathogenic. CONCLUSION: Germline mutations of hMLH1 and hMSH2 genes are identified in about one-third HNPCC kindreds fulfilling Chinese HNPCC criteria. Chinese HNPCC families have some particular clinical characteristics, such as a left-sided predominance, less synchronous or metachronous colorectal cancer, and frequent occurrence of gastric cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2001

PTEN mutation located only outside exons 5, 6, and 7 is an independent predictor of favorable survival in endometrial carcinomas.

Although the prognostic impact of PTEN mutation in endometrial carcinoma is beginning to be analyzed, the prognostic significance of mutated PTEN exons has not ever been described. Sixty-seven endometrial carcinomas were analyzed for PTEN mutations using single-strand conformation polymorphism analysis and DNA sequencing. First, survival rates were compared according to PTEN status and mutated PTEN exons. Subsequently, univariate and multivariate analyses of various favorable prognostic factors for survival were conducted. The associations between PTEN mutation and clinicopathological features were also statistically evaluated. PTEN mutations were detected in 37 of 67 (55%) specimens. Among 47 mutations, frameshifts (57%) and mutations in exon 8 (38%) were most frequent. In univariate analysis, a factor of PTEN mutation only outside exons 5-7 was associated with significantly better survival (P = 0.02), although mutation in any exon of PTEN was not (P = 0.33). Subsequent multivariate analysis revealed that factors of mutation only outside exons 5-7 of PTEN, stage I/II, and G1 were significant and independent prognostic indicators for favorable survival (P = 0.004, 0.004, and 0.0006, respectively). In the subset of advanced-stage disease, mutation only outside exons 5-7 was associated with a trend toward better survival (P = 0.13). No significant correlation was observed between PTEN mutation and estrogen-related clinicopathological features. In conclusion, we find that PTEN mutation located only outside exons 5-7 is a significant and independent positive prognostic indicator for survival. The current observation has prognostic and therapeutic implications for the management of patients with endometrial carcinoma.

Adult↗
PubMed2002

[Familial glucocorticoid deficiency due to the ACTH receptor gene mutations].

Familial glucocorticoid deficiency(FGD) is a rare autosomal recessive disorder, characterized by resistance to ACTH leading to glucocorticoid deficiency, but not mineralocorticoid deficiency. Recently, mutations in the ACTH receptor gene were identified in several families with FGD. Thus far, twelve missense mutations, one nonsense mutation and three frameshift mutations causing FGD were described. Functional expression studies demonstrated that most of the missense mutations results in loss of specific binding to ACTH and impaired production of cAMP in response to ACTH. However, the genotype-phenotype correlation was poor. Interestingly and unexpectedly, the FGD patients with the ACTH receptor gene mutations were shown to be tall.

Glucocorticoids↗
PubMedDate not supplied

[2470insG, represents the commonest mutation in Mexican patients with dystrophic bullous epidermolysis. A study of 21 families].

BACKGROUND: Type VII collagen gene (COL 7 Al) mutations are the cause of dystrophic epidermolysis bullosa (DEB), but most mutations are specific to individual families and there is limited data on the nature of COL 7 Al mutations in certain ethnic populations. OBJECTIVE: To determine the molecular basis of DEB in Mexican patients and describe the most frequent mutation among this ethnic population. METHODS: Most subjects were approached at FUNDACION DEBRA MEXICO AC. Molecular analysis was performed by polymerase chain reaction (PCR) of genomic DNA using COL 7 A l-specific primers, heteroduplex analysis, and direct nucleotide sequencing. RESULTS: Fifty nine of 67 COL 7 Al possible mutations (88%) were identified; 36 individuals (31 recessive, five dominant) from 21 families. Recessive mutations included six frameshift mutations, four silent glycine substitutions and two splice site mutations. CONCLUSIONS: The present study informs a different kind of mutation observed in our patient population. Only two mutations informed in this study had been described earlier among another ethnic group. The most frequent mutation was 2470insG, affecting 21 (58.3%) out of 36 patients with DEB. These new data will be helpful in facilitating the accurate diagnosis of an DEB subtype, and will add further insight into the pathophysiology of this mechanobullous disease.

Collagen Type VII↗
PubMed1995

Lecithin: cholesterol acyltransferase deficiency: identification of two defective alleles in fibroblast cDNA.

Previous mutations associated with lecithin:cholesterol acyltransferase (LCAT) deficiency have been identified using genomic DNA. To facilitate mutation analysis, we used cDNA from cultured fibroblasts which were shown to express LCAT mRNA. Using reverse-transcriptase PCR, LCAT cDNA was obtained from a 13-year-old boy with complete LCAT deficiency, characterized by low HDL-C (3 mg/dl), nondetectable initial cholesterol esterification rate, LCAT activity, and minimal LCAT mass (0.16 vs. 5-7.5 micrograms/ml). Sequencing of LCAT cDNA clones identified two mutations. A novel frameshift mutations caused by deletion of cytosine at the third nucleotide position of amino acid 168 (exon 5) predicts a disrupted protein catalytic site by converting Ser181-->Ala and creates a Pvu-II restriction site prior to premature truncation at amino acid 238. A C-->T transition results in a substitution of methionine for threonine at amino acid position 321 and creates an Nla-III restriction site on the maternal allele. Expression studies of mutant LCAT cDNA confirmed the virtual absence of LCAT activity in transfected COS-1 cells. The molecular defect in a young male with complete LCAT deficiency has been identified using fibroblast cDNA.

Adolescent↗
PubMedDate not supplied

The p53 gene in soft tissue sarcomas: prognostic value of DNA sequencing versus immunohistochemistry.

BACKGROUND: The aim of this study was to compare sequencing and immunohistochemistry (IHC) for their ability to detect p53 mutations and to assess their prognostic value in soft tissue sarcomas (STS). MATERIAL AND METHODS: 146 STS samples were investigated by single strand DNA conformation polymorphism (SSCP)-sequencing for p53 mutations. Additionally, IHC with five p53 antibodies (CM-1, Pab1801, Pab240, DO1, DO-7) was performed. RESULTS: In 65 to 131 tumor samples (44.5% to 90.4%) elevated levels of p53 protein were recorded by IHC, depending on the antibody applied. Sixteen out of 146 STS tumor samples (11%) had p53 gene mutations. 13 cases (81.2%) of the 16 tumors with p53 mutations could be detected by DO-1. However, of the 93 DO-1 positive tumors 79 were negative by SSCP-sequencing analysis. Using multivariate regression analysis (Cox proportional hazards model) both p53 mutations (non-frameshift mutations) and IHC detection of p53 protein overexpression were prognostic predictors for poor survival. CONCLUSIONS: This study suggests that IHC is valuable for assessing p53 mutations in STS, but sequencing provides additional important information on the molecular characteristics of the alterations.

DNA, Neoplasm↗
PubMed2005

Molecular phenotype of inflammatory bowel disease-associated neoplasms with microsatellite instability.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC). We sought to determine the frequency of high-level microsatellite instability (MSI-H) and the mutational and methylation profile of MSI-H IBD-related neoplasms (IBDNs). METHODS: A total of 124 IBDNs (81 cancers, 43 dysplasias) from 78 patients were studied for the frequency of MSI-H and hypermethylation of 3 target genes: MLH1 , HPP1 , and RAB-32 . Fifteen MSI-H IBDNs were characterized according to their profile of frameshift mutations in 28 mononucleotide repeats and compared with 46 sporadic MSI-H CRCs. RESULTS: Nineteen of 124 IBDNs were MSI-H. The frequency of frameshift mutations in coding mononucleotide repeats was significantly lower in MSI-H IBDNs than in sporadic MSI-H CRCs for TGFBR2 (7 of 14 vs 34 of 43 samples; P = .047) and ACVR2 (3 of 14 vs 25 of 43 samples; P = .029). In contrast, ICA1 was mutated in 3 of 9 MSI-H IBDNs vs 2 of 54 sporadic MSI-H CRCs ( P = .028). HPP1 and RAB32 methylation was independent of MSI status and was observed in 4 of 59 and 0 of 64 nondysplastic mucosae, 20 of 38 and 1 of 25 dysplasias, and 28 of 61 and 20 of 60 carcinomas, respectively. CONCLUSIONS: The profiles of coding microsatellite mutations (instabilotypes) differ significantly between MSI-H IBDNs and MSI-H sporadic CRCs. Specifically, TGFBR2 and ACVR2 mutations are significantly rarer in MSI-H IBDNs than in MSI-H sporadic CRCs. Furthermore, HPP1 methylation occurs early, in 7% of nondysplastic and approximately half of dysplastic mucosae, whereas RAB32 methylation occurs at the transition to invasive growth, being rarer in dysplasias.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Induction of a low level of microsatellite instability by overexpression of DNA polymerase Beta.

Microsatellite instability (MSI) is the condition in which high rates of frameshift mutations are observed in short tandem repeat sequences. Mutations in sequences of this type in coding regions of cancer-related genes can contribute to the development of cancer. Although defects in mismatch repair are usually responsible for high levels of MSI, low levels of MSI have been observed in some cancers with no known mismatch repair defects. We have investigated whether overexpression of an error-prone polymerase, polbeta, is sufficient to induce MSI in the presence of mismatch repair. Because overexpression of polbeta has been observed in several types of cancer, we hypothesized that polbeta overexpression might increase genetic instability and, thus, contribute to carcinogenesis. Microsatellite mutation rate analyses were conducted using a drug-resistance reversion assay, where G(17) or A(17) microsatellites were inserted into a plasmid upstream of a neomycin-resistance gene (neo), such that the neo gene was shifted out of frame. When frameshift mutations occur in the microsatellite, the neo gene can be restored, allowing for selection of revertants in G418. Microsatellite-containing plasmids were transfected into telomerase-immortalized normal human fibroblasts (hTERT-1604), where they integrated into the nuclear genome. polbeta-expressing episomal vectors or empty control vectors were then introduced for analysis of the effect of polbeta overexpression on these microsatellites. Mutation rates were determined by fluctuation analysis. Mutation rates in G(17) repeats were elevated for the polbeta transfectants at all levels of overexpression ( approximately 2-fold to >100-fold compared with vector-only controls), with up to a 3-fold increase in mutation rates compared with the vector-only controls in cells with the highest expression. A similar magnitude of elevation in mutation rates was observed for A(17) microsatellites. No difference was observed between vector-only controls and nontransfected cells in either microsatellite sequence. Cells with high polbeta expression showed an approximately 1.5-fold increase in population doubling time and a 2-fold reduction in mitotic index compared with controls. Cells with both modest and high elevations in microsatellite mutation rates had these altered growth properties. These results suggest that polbeta overexpression may affect cell cycle progression and increase genetic instability.

Blotting, Western↗
PubMed2003

The Rapp-Hodgkin syndrome results from mutations of the TP63 gene.

The Rapp-Hodgkin syndrome (RHS, MIM 129400) corresponds to a rare form of anhydrotic ectodermal dysplasia, which shares some features with the ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome (EEC, MIM 604292) resulting from TP63 mutations. We report here, in two unrelated patients with RHS, the identification of two distinct TP63 mutations, corresponding to a novel frameshift mutation (1709DelA, exon 14) located downstream the sterile alpha motif (SAM) domain and to a missense mutation (R279H, exon 7) within the DNA binding domain. Functional analysis of the R279H mutation, which had previously been reported in several EEC families, shows that this mutation disrupted the dominant negative activity of the DeltaNp63alpha and gamma isoforms on the transcriptional activity of TP53. This report shows, on a molecular basis, that RHS is also an EEC-like syndrome resulting from mutations of the TP63 gene, and highlights the wide phenotypic spectrum associated to TP63 mutations.

Adult↗
PubMed2004

GTP-cyclohydrolase I gene mutations in patients with autosomal dominant and recessive GTP-CH1 deficiency: identification and functional characterization of four novel mutations.

GTP-cyclohydrolase I (GTP-CH1, EC 3.5.4.16) is encoded by the GCH1 gene. Mutations in the GCH1 gene cause both dopa-responsive dystonia (McKusick 128230) and recessive GTP-CH1 deficiency (McKusick 600225). The exact molecular mechanism resulting in decreased GTP-CH1 activity in the patients is still obscure. We report the clinical features and molecular and functional study of the GCH1 gene in eight Italian patients affected by dominant and recessive GTP-CH1 deficiency. All the studied patients had mutations in the GCH1 gene. Three missense mutations (V205G, K224R, P199A), a frameshift mutation (Delta G693), and a splice-site mutation (ivs5 + 1g > c) were found. Except for K224R these are all novel mutations. To analyse the defect caused by the novel mutations, an in vivo functional assay in a Saccharomyces cerevisiae strain lacking the endogenous gene encoding GTP-CH1 ( FOL2 ) was performed. Complementation analysis showed that the Delta G693 and V205G mutations abolish the enzymatic function, while the P199A mutation causes a conditional defect. In conclusion, the clinical phenotypes displayed by our patients confirm the wide clinical spectrum of the disease and further support the lack of correlation between a given mutation and a clinical phenotype. Complementation analysis in yeast is a useful tool for confirming the pathogenetic effect of GCH1 mutations.

Adult↗
PubMed1995

DNA nick processing by exonuclease and polymerase activities of bacteriophage T4 DNA polymerase accounts for acridine-induced mutation specificities in T4.

Acridine-induced frameshift mutagenesis in bacteriophage T4 has been shown to be dependent on T4 topoisomerase. In the absence of a functional T4 topoisomerase, in vivo acridine-induced mutagenesis is reduced to background levels. Further, the in vivo sites of acridine-induced deletions and duplications correlate precisely with in vitro sites of acridine-induced T4 topoisomerase cleavage. These correlations suggest that acridine-induced discontinuities introduced by topoisomerase could be processed into frameshift mutations. The induced mutations at these sites have a specific arrangement about the cleavage site. Deletions occur adjacent to the 3' end and duplications occur adjacent to the 5' end of the cleaved bond. It was proposed that at the nick, deletions could be produced by the 3'-->5' removal of bases by DNA polymerase-associated exonuclease and duplications could be produced by the 5'-->3' templated addition of bases. We have tested in vivo for T4 DNA polymerase involvement in nick processing, using T4 phage having DNA polymerases with altered ratios of exonuclease to polymerase activities. We predicted that the ratios of the deletion to duplication mutations induced by acridines in these polymerase mutant strains would reflect the altered exonuclease/polymerase ratios of the mutant T4 DNA polymerases. The results support this prediction, confirming that the two activities of the T4 DNA polymerase contribute to mutagenesis. The experiments show that the influence of T4 DNA polymerase in acridine-induced mutation specificities is due to its processing of acridine-induced 3'-hydroxyl ends to generate deletions and duplications by a mechanism that does not involve DNA slippage.

Aminacrine↗
PubMed1998

Inactivation of DNA proofreading obviates the need for SOS induction in frameshift mutagenesis.

Translesion synthesis at replication-blocking lesions requires the induction of proteins that are controlled by the SOS system in Escherichia coli. Of the proteins identified so far, UmuD', UmuC, and RecA* were shown to facilitate replication across UV-light-induced lesions, yielding both error-free and mutagenic translesion-synthesis products. Similar to UV lesions, N-2-acetylaminofluorene (AAF), a chemical carcinogen that forms covalent adducts at the C8 position of guanine residues, is a strong replication-blocking lesion. Frameshift mutations are induced efficiently by AAF adducts when located within short repetitive sequences in a two-step mechanism; AAF adducts incorporate a cytosine across from the lesion and then form a primer-template misaligned intermediate that, upon elongation, yields frameshift mutations. Recently, we have shown that although elongation from the nonslipped intermediate depends on functional umuDC+ gene products, elongation from the slipped intermediate is umuDC+-independent but requires another, as yet biochemically uncharacterized, SOS function. We now show that in DNA Polymerase III-proofreading mutant strains (dnaQ49 and mutD5 strains), elongation from the slipped intermediate is highly efficient in the absence of SOS induction-in contrast to elongation from the nonslipped intermediate, which still requires UmuDC functions.

2-Acetylaminofluorene↗
PubMed1998

A first missense mutation in the delta sarcoglycan gene associated with a severe phenotype and frequency of limb-girdle muscular dystrophy type 2F (LGMD2F) in Brazilian sarcoglycanopathies.

Among the heterogeneous group of autosomal recessive limb-girdle muscular dystrophies (AR LGMDs), the sarcoglycanopathies (LGMD2C-2F) represent a subgroup characterised by defects in the gamma, alpha, beta, and delta sarcoglycan genes, respectively. Genotype-phenotype correlations in these forms of AR LGMD are important to enhance our understanding of protein function. Regarding LGMD2F, only two homozygous frameshift mutations have been reported to date in patients with a severe phenotype. In the present report, through screening 23 unrelated AR LGMD patients, we identified three subjects with LGMD2F, two with a previously reported frameshift mutation and the other homozygous for a new missense mutation in the delta sarcoglycan gene. Interestingly, this new mutation is also associated with a severe clinical course. In addition, our results suggest that this form of severe AR LGMD is not very rare in our population.

Brazil↗
PubMed2000

A rapid fluorescent multiplexed-PCR analysis (FMPA) for founder mutations in the BRCA1 and BRCA2 genes.

Mutations of the BRCA1 and BRCA2 genes account for approximately 80% of hereditary breast/ovarian cancer families, but the size of these two genes makes mutation analysis time-consuming and technically challenging. In some populations such as the Ashkenazi Jewish and the French-Canadian, a small number of recurrent founder mutations account for the majority of mutations in cancer families. We have therefore developed two rapid genetic screening tests, which allow us to detect three frequent frameshift mutations in the Ashkenazi Jewish population and five frameshift mutations in the French-Canadian population. These fluorescent non-radioactive methods permit the simultaneous detection of multiple mutations by generating multiplexed PCR-amplified gene fragments, and by discriminating these on the basis of their size in a denaturing polyacrylamide gel. Using these methods, we were able to correctly identify all mutants in a blinded analysis of 276 DNA samples, including 30 derived from paraffin-embedded tumor samples and 10 from buccal-cell brushes, with no false positive or false negative results. These techniques designed for the direct detection of recurrent mutations in the BRCA1 and BRCA2 genes, have the advantages of being efficient, sensitive, cost-effective, and are applicable to large scale screening for epidemiologic studies.

BRCA2 Protein↗
PubMed1993

p53 gene mutations in gastric adenomas.

p53 gene alterations in ten gastric adenomas and one carcinoma arising in an adenoma were analyzed by deoxynucleotide sequencing. Three (30%) of the ten gastric adenomas had p53 gene mutations, one adenoma showing a frameshift mutation and two others showing silent mutations. In addition, two missense mutations occurred in the carcinoma arising in an adenoma. Histologically, the adenomas containing silent mutations revealed moderate dysplasia. Immunoreactivity to p53 protein was also examined in 61 gastric adenomas, 19 carcinomas arising in adenomas and 48 early well-differentiated adenocarcinomas of the stomach (these included the tumors analyzed by deoxynucleotide sequencing). No staining for p53 was seen in the pure adenomas, but positive immunoreactivity was observed in 27% of the adenocarcinomas and 10.5% of the carcinomas arising in adenomas. These results suggest that p53 gene mutation is an early event in gastric carcinogenesis and missense mutation may play a crucial role in the conversion from adenoma to adenocarcinoma.

Adenoma↗