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PubMed1994

DNA polymerase beta gene mutation in human prostate cancer.

DNA polymerase beta is a nuclear protein essential to DNA repair in mammalian cells. A high frequency of mutations in this gene has been reported in colorectal cancers. To clarify the tumorigenesis steps of human prostate cancers in the molecular basis, we examined the entire coding region of the human DNA polymerase beta gene in human prostate cancer tissues using polymerase chain reaction, single-strand conformational polymorphism analysis of RNA, and sequencing analysis. Consequently, we detected DNA polymerase beta gene mutations in 2 of 12 cases (17%). The first case is an A to G transition at nucleotide 893, resulting in a substitution of the amino acid from tyrosine to cysteine. In the second case, we found an A to G transition at nucleotide 305, a T deletion at nucleotide 569, and an A insertion into the 6 repeats of A from nucleotide 612 to 617. This T deletion shifted the subsequent reading frame and resulted in the premature termination at codon 163 instead of 336. The two cases were advanced grade and stage. Present results suggest that polymerase beta gene mutations, although they occurred at relatively low frequency, are involved in certain cases of human prostate carcinogenesis.

Adenocarcinoma↗

PubMed2004

Detection of COL4A5 gene mutations in Chinese patients with Alport's syndrome.

BACKGROUND: Mutations in the COL4A5 gene, encoding the alpha 5 chain of type IV collagen, are responsible for X-linked Alport's syndrome (XLAS), a progressive nephropathy characterized by glomerular basement membrane abnormalities and usually associated with progressive hearing loss and ocular lesions. METHODS: In this study, we analysed all 51 exons of the COL4A5 gene in 20 Chinese patients with XLAS or suspected XLAS from 16 families by using polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) DNA sequencing. RESULTS: Five gene mutations identified in five families were considered to be pathogenic, including one nonsense mutation in exon 1 (266C-->T, Gln22Term), two missense mutations in exons 31 (2757G-->T, Gly852Val) and 43 (4142C-->T, Pro1314Ser), and two splice site mutations in introns 1 and 25 just next to the 3' end of their respective exons (283+1G-->T, 2150+1G-->T). According to GenBank, these five mutations have not been reported previously. All male patients have typical clinical manifestations and pathological findings that closely correspond to the effects of the mutations. Furthermore, seven gene polymorphisms were detected in introns 18 and 10 and exons 20, 27, 29, 39 and 46. Only the substitution in intron 18 (1234+25G-->A) had a gene frequency significantly higher in patients than in normal individuals. CONCLUSION: Our study demonstrated the critical role of COL4A5 gene mutations in the pathogenesis of XLAS. The linkage of the polymorphism to AS is still unknown.

China↗

PubMed1994

Germline p53 gene mutations in subsets of glioma patients.

BACKGROUND: Heritable germline mutations of the p53 gene have been described in patients with Li-Fraumeni syndrome, occasionally in nonfamilial malignancies such as multifocal osteosarcoma, in a small subgroup of young patients with two or more primary malignancies, and in patients with sporadic breast carcinoma. We recently reported that multifocal gliomas are frequently associated with other primary malignancies, and we hypothesized that genetic alterations may account for this phenomenon. PURPOSE: We examined the frequency of germline p53 gene mutations in patients with glioma and either multifocality of lesions, history of an additional primary (different) malignancy, or a family history of cancer. METHODS: Lymphocytes from 51 glioma patients were analyzed for germline p53 gene mutations using RNA-polymerase chain reaction analysis, single-strand conformation polymorphism, and gene sequencing techniques. RESULTS: Germline p53 gene mutations were detected in six of 19 patients with multifocal glioma, including two with family history of cancer, one with another primary malignancy, and two with all three risk factors; one of four patients with unifocal glioma, another primary malignancy, and a family history of cancer; and two of 15 patients with unifocal glioma and a family history of cancer but no second malignancies. No mutations were detected in the patient with unifocal glioma and another malignancy or in the 12 control patients with unifocal glioma and no second malignancies or family history of cancer. Patients having mutations were younger than other patients in the same group. CONCLUSIONS: Germline p53 mutations are frequent in patients with multifocal glioma, glioma and another primary malignancy, and glioma associated with a family history of cancer, particularly if these factors are combined. IMPLICATIONS: Relatives at high risk can be identified for genetic counseling, early cancer detection, and possible enrollment in chemoprevention trials.

Adult↗

PubMed1995

[The study of p53 gene mutation in human bladder cancer].

Alteration of p53 gene and the molecular biological difference between superficial and invasive bladder cancer were investigated by polymerase chain reaction-single strand conformation polymorphism analysis and direct sequencing technique. p53 gene mutations were examined in exon region 5 to 8 in 21 bladder cancers. Only one of 14 superficial bladder cancers was found to have p53 gene mutation. Four of 7 invasive bladder cancers with T2, T3 and T4 were found to have p53 gene mutation. p53 gene mutation was found none of the 4 cancers with grade 1, only one of cancers with grade 2, four of 12 cancers with grade 3. These results suggest that p53 gene play an important role in the development of human bladder cancer.

Carcinoma, Transitional Cell↗

PubMed1993

Influence of cigarette smoking and schistosomiasis on p53 gene mutation in urothelial cancer.

The mutation patterns of the p53 tumor suppressor gene have been shown to reflect the specific carcinogen(s) involved, or the epidemiological background in some cancers. To elucidate the impact of cigarette smoking or bilharzial infection on the p53 gene mutation pattern, 61 cases of urothelial cancer from Japan and 7 cases of bladder cancer with schistosomiasis from Egypt were examined for mutations of the p53 gene. In total, p53 gene mutations were detected in 20 Japanese cases (33%) and 6 Egyptian cases (86%). Although the incidence of p53 gene mutation was not significantly influenced by habitual smoking, a different mutation pattern was observed as follows: 4 of 10 mutations in smokers in Japan were A:T to G:C transitions, whereas such mutations were not detected in any of 10 mutations in nonsmokers, or in any of 6 mutations associated with schistosomiasis. Although no specific mutation pattern was detected for the squamous cell carcinomas with schistosomiasis, all 8 base substitutions observed in tumors with squamous cell carcinomas occurred at G:C sites, whereas base substitutions at A:T sites were observed in 33% (6 of 18) of mutations in transitional cell carcinomas. Our results suggest that cigarette smoking may have a significant impact on the mutations of the p53 gene in urothelial cancers. Furthermore, the distinct spectrum of the p53 gene mutation found in tumors with squamous cell carcinomas may reflect their unique etiological backgrounds.

Carcinoma, Squamous Cell↗

PubMed1997

Diversity of ATM gene mutations detected in patients with ataxia-telangiectasia.

The ataxia-telangiectasia mutated (ATM) gene, which is mutated in the autosomal recessive disorder ataxia-telangiectasia (AT), was isolated in 1995 by positional cloning. Although in vitro cell fusion studies had suggested that AT was genetically heterogeneous, all AT patients studied to date have been found to harbor mutations in the ATM gene. More that 100 ATM mutations occurring in AT patients have been documented. The mutations are broadly distributed throughout the ATM gene. Except for patients from families with known consanguinity, most AT patients are compound heterozygotes. The majority (> 70%) of mutations are predicted to lead to protein truncation. A significant number of the reported mutations affect mRNA splicing with at least half of the coding exons (32/62) having been observed to undergo exon skipping. The large size of the ATM gene, 66 exons spanning approximately 150 kb of genomic DNA, together with the diversity and broad distribution of mutations in AT patients greatly limits the utility of direct mutation screening as a diagnostic tool, or method of carrier identification, except where founder effect mutations are involved.

Ataxia Telangiectasia↗

PubMed1994

The mutator gene swi8 effects specific mutations in the mating-type region of Schizosaccharomyces pombe.

The swi8+ gene of Schizosaccharomyces pombe appears to be involved in the termination step of copy synthesis during mating-type (MT) switching. Mutations in swi8 confer a general mutator phenotype and, in particular, generate specific mutations in the MT region. Sequencing of the MT cassettes of the h90 swi8-137 mutant revealed three altered sites. One is situated at the switching (smt) signal adjacent to the H1 homology box of the expression locus mat1:1. It reduces the rate of MT switching. The alteration at the smt signal arose frequently in other h90 swi8 strains and is probably caused by gene conversion in which the sequence adjacent to the H1 box of mat2:2 is used as template. This change might be generated during the process of MT switching when hybrid DNA formation is anomalously extended into the more heterologous region flanking the H1 homology box. In addition to the gene conversion at mat1:1, two mutations were found in the H3 homology boxes of the silent cassettes mat2:2 and mat3:3.

Base Sequence↗

PubMed2004

c-kit gene mutations in intracranial germinomas.

Gain-of-function mutations of the c-kit gene and the expression of phosphorylated KIT are found in most gastrointestinal stromal tumors and mastocytosis. Further, almost all gonadal seminomas/dysgerminomas exhibit KIT membranous staining, and several reports have clarified that some (10-25%) have a c-kit gene mutation. But, whether intracranial germinomas also have a c-kit gene mutation remains unsolved. To elucidate the presence, frequency, and location of c-kit gene mutations in intracranial germinomas, we analyzed five mutational hot spots (exons 9, 10, 11, 13, and 17) in the c-kit genomic DNA of 16 germinomas using polymerase chain reaction and direct sequencing. We found c-kit gene mutations at exon 11 (W557C) or 17 (D816V, D820V, and N822Y) in four germinomas (25.0%), although no statistically significant difference in any clinicopathological factor was found between patients with or without mutations. These results are similar to those seen in gonadal seminoma/dysgerminoma patients, and confirm that intracranial germinomas are exact counterparts of gonadal seminomas/dysgerminomas, as would be expected on histological and immunohistochemical grounds. Moreover, molecular targeting drugs such as imatinib mesylate (STI571), which is a selective inhibitor of KIT, might be promising agents for the treatment of intracranial germinomas with c-kit gene mutations.

Adolescent↗

PubMed1998

Frequent p53 gene mutations in serrated adenomas of the colorectum.

Serrated adenoma has been recently proposed as a distinct histological lesion of the colorectum. This study examined p53 immunoreactivity, mutations of exons 5-8 of the p53 gene, codon 12 of the Ki-ras gene by PCR-SSCP analyses, and microsatellite instability in 19 serrated adenomas, ten adenocarcinomas in/with serrated adenomas, 23 hyperplastic nodules, four hyperplastic polyps and 29 tubular adenomas of the colorectum. Eleven of 11 (100 per cent) serrated adenomas had p53 immunoreactivity and all six (100 per cent) adenocacinomas in/with serrated adenomas exhibited moderate to severe p53 immunoreactivity. It was confirmed that 9 of 19 (47 per cent) serrated adenomas and 5 of 10 (50 per cent) adenocarcinomas in/with serrated adenomas harboured p53 gene mutations. On the other hand, no p53 gene mutation was detected in the other colorectal lesions. Meanwhile, 11 (58 per cent) serrated adenomas and six (60 per cent) adenocarcinomas in/with serrated adenomas had Ki-ras gene mutations, as also did 9 of 23 (39 per cent) hyperplastic nodules, 3 of 4 (75 per cent) hyperplastic polyps, and 12 of 29 (41 per cent) tubular adenomas. Microsatellite instability was detected in one (5 per cent) serrated adenoma and one (10 per cent) adenocarcinoma in a serrated adenoma. The other lesions did not show microsatellite instability. Serrated adenomas had significantly frequent p53 gene mutations compared with hyperplastic lesions or tubular adenomas (p < 0.005). On the other hand, they did not exhibit significant differences in mutations of the Ki-ras gene or in microsatellite instability. Genetic changes were then examined in small parts of serrated adenomas, such as the upper or lower parts of crypts, to determine the extent of gene mutations by using a microdissection technique. Exon 15 of the APC gene and the DCC gene, in addition to the p53 and Ki-ras genes and microsatellite instability, were analysed. Identical mutations of the p53 gene were found in both invasive adenocarcinomas and adjacent serrated adenomas by direct sequencing, suggesting single clonal origins for those lesions. Mutations of the APC gene and microsatellite instability were heterogeneous in some lesions. No loss of heterozygosity (LOH) of the DCC gene was found. These findings suggest that mutations of the p53 gene are the most characteristic genetic alterations in serrated adenomas, as a relatively early event in a multistep carcinogenic pathway of this type of colorectal lesion, that might be distinct from the ordinary adenoma-carcinoma sequence or from carcinogenesis via mutations of mismatch repair genes.

Adenocarcinoma↗

PubMed2003

Lack of association between HFE gene mutations and hepatocellular carcinoma in patients with cirrhosis.

BACKGROUND: Liver cirrhosis may lead to hepatocellular carcinoma (HCC), regardless of its cause. Genetic and/or environmental factors may modulate the risk of HCC. Mutations in the HFE gene are responsible for genetic haemochromatosis, a condition known to be associated with liver cirrhosis, HCC, or both. It has recently been suggested that the C282Y HFE gene mutation may be more frequent in patients with HCC that have developed in the non-cirrhotic liver than in the general population. Whether or not HFE gene mutations are associated with an increased risk of HCC in patients with cirrhosis is unknown. AIM: To assess the prevalence of HFE gene mutations in cirrhotic patients with and without HCC. PATIENTS AND METHODS: A total of 133 consecutive cirrhotic patients with HCC were prospectively studied for the presence of C282Y and H63D mutations. The control group consisted of 100 cirrhotic patients without HCC. We used restriction enzyme digestion of polymerase chain reaction amplified genomic DNA for determination of HFE genotypes. Iron loading was assessed on non- tumoral liver biopsy samples from 89 patients with HCC and 73 patients without HCC. RESULTS: The prevalence of C282Y heterozygotes was similar in patients with and without HCC (5% v 4%, respectively; p=0.65) and did not differ from that expected in the general population. None of the HCC patients was found to be homozygous for C282Y or H63D, nor compound heterozygous. The prevalence of H63D heterozygotes was similar in patients with and without HCC (31% v 38%, respectively; p=0.25). No relation was detected between HFE genotypes and hepatic iron loading in patients with or without HCC. CONCLUSION: C282Y and H63D mutations do not appear to be associated with an increased risk of HCC in patients with cirrhosis.

Carcinoma, Hepatocellular↗

PubMed2006

Cooperation of activating Ras/rtk signal transduction pathway mutations and inactivating myeloid differentiation gene mutations in M0 AML: a study of 45 patients.

According to a two hit model of leukaemogenesis, the association between acute myeloid leukaemia (AML)1 mutations and FLT3 gene alterations has been recently described in M0 AML. To further document this model in M0 AML, we screened a cohort of 45 patients to find an association between genes implicated in myeloid differentiation (AML1, Pu1) and genes contributing to cell proliferation: (FLT3, N-RAS, K-RAS, c-KIT, PTPN11). No mutation of the Pu1 gene was observed, whereas mutation in the Runt domain of AML1 gene was observed in 12 of 45 patients (27%). No point mutation or insertion-deletion in the c-kit gene was found. Three point mutations (7%) and 11 internal tandem duplications (22%) were seen in FLT3 gene. Two N-Ras and one PTPN11 mutations were found. No significant correlation between AML1 mutation and FLT3 alteration was found. On the other hand, abnormal cytogenetic findings, especially unfavourable ones, were significantly more frequent in patients without detectable molecular abnormality. These findings suggest at least two different pathogenetic pathways in M0 AML: one associated with AML1 mutation, sometimes in combination with the activating lesion of the tyrosine kinase pathway and generally with normal karyotype, and the other with unfavourable cytogenetic findings.

Acute Disease↗

PubMed2005

Hematologically important mutations: bilirubin UDP-glucuronosyltransferase gene mutations in Gilbert and Crigler-Najjar syndromes.

Gilbert and Crigler-Najjar syndromes are familial unconjugated hyperbilirubinemias caused by genetic lesions involving a single complex locus encoding for bilirubin UDP-glucuronosyltransferase (UGT1A1) gene. Over the last years a number of different mutations affecting this gene have been characterized. In this report is provided a summary of reported Gilbert and Crigler-Najjar syndromes associated UGT1A1 gene mutations.

Crigler-Najjar Syndrome↗

PubMed2004

[NOTCH3 gene mutations in four Chinese families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy].

OBJECTIVES: To search for mutations in NOTCH3 gene in four Chinese families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: Four probands from four unrelated families with typical manifestations of CADASIL were studied. The 1 approximately 12 coding exons and their flanking intron sequences of NOTCH3 gene were amplified by PCR and sequenced. Some family members in the pedigree 2 and 4 were also examined for the NOTCH3 gene mutations. RESULTS: Four heterozygous missense mutations were identified in the four families: the proband 1 carrying a 268C-->T mutation in exon 3, the proband 2 a 322 C-->T mutation in exon 3, the proband 3 a 328 C-->T mutation inexon 3, and the proband 4 a 1819 C-->T mutation in exon 11, which resulted in the amino acid substitutions of R90C, C108R, R110C, and R607C respectively. Among them the C108R is a novel mutation not reported previously. Additionally, some members in the pedigree 2 and 4 also harbored the same mutations with the probands. CONCLUSION: Four heterozygous missense mutations in NOTCH3 gene have been found in four Chinese families with CADASIL. Different point mutations in NOTCH3 lead to similar phenotype of the disease. To search for mutations in NOTCH3 in related patients will help further understand and accurately diagnose the disease and perform prenatal diagnosis in CADASIL families.

Adult↗

PubMed2000

Frequency of somatic MEN1 gene mutations in monoclonal parathyroid tumours of patients with primary hyperparathyroidism.

OBJECTIVES: Investigation of small numbers of parathyroid tumours by X-chromosome inactivation analysis suggests that the majority of them are monoclonal lesions most likely caused by a somatic mutation. Somatic mutations in the MEN1 gene located on chromosome 11q13 have recently been identified in 12-17% of solitary parathyroid tumours in patients with sporadic primary hyperparathyroidism, and they may be the precipitating genetic defect leading to monoclonal cell proliferation in these tumours. DESIGN: To determine the prevalence of MEN1 gene mutations in monoclonal parathyroid neoplasias we investigated 33 parathyroid tumours of patients with primary hyperparathyroidism for clonality and mutations in the MEN1 gene. METHODS: X-chromosome inactivation analysis was used to assess the clonal status of the tumours, direct sequencing of the complete coding region was applied to identify mutations in the MEN1 gene. RESULTS: Twenty-eight female patients (26 patients with solitary adenoma, 2 patients with hyperplasia) were informative for the polymorphism of the androgen receptor on the X-chromosome and could be tested for inactivation pattern. Nineteen of twenty-six (73%) solitary adenomas were monoclonal. Somatic mutations in the MEN1 gene were identified in nine cases. Six of them were found in the relatively large second exon of the MEN1 gene (A49D, 193del36, 402delC, 482del22, 547delT, W126X). One was found in exon 5 (904del9), one in exon 7 (Y327X) and one in exon 9 (R415X). Of the monoclonal tumours, 5 out of 19 (26%) harboured a somatic MEN1 gene mutation. CONCLUSIONS: In summary, 73% of the solitary parathyroid adenomas were monoclonal. In 26% of the monoclonal tumours a somatic MEN1 gene mutation has been identified. However, for 74% of monoclonal tumours of the parathyroids the underlying genetic defects are still not known.

Adenoma↗

PubMed2005

Low density lipoprotein--receptor (LDL-R) gene mutations among Filipinos with familial hypercholesterolemia.

BACKGROUND: Familial Hypercholesterolemia (FH) is an autosomal dominant disease resulting from mutations of the LDL (LDLR) receptor gene leading to a diminished catabolism and elevated level of LDL cholesterol (LDL-C). It is associated with an increased risk for cardiovascular disease (CVD). The MEDPED (Make Early Diagnosis-Prevent Early Death) program, an initiative cited by the WHO Human Genetics Programme in their report on FH, initiated international collaboration to identify and follow-up patients with FH globally. From Asia-Pacific, only 6 countries are participating and no data among Filipinos particularly on genetic profiles is available at present. This study attempts to initiate data collection and participation in the global initiative. OBJECTIVES: Primary: 1. To describe the phenotype of Filipino patients with FH. 2. To determine and characterize the LDL-R gene mutations among Filipino patients with clinical features of FH. Secondary: To determine the association of the clinical characteristics of FH with the presence of LDLR gene mutations. DESIGN: Cross- Sectional Study. SETTING: Multicenter, Outpatient Clinic. PARTICIPANTS: 60 unrelated patients, 18 y/o and above from UP-PGH, Manila Doctors Hospital and Cardinal Santos Medical Center. FH was diagnosed according to the Dutch Lipid Clinic Network Criteria cited by WHO which is based on a history of premature CVD, family history, tendon xanthoma, arcus cornealis, and LDL C levels. METHODS: With informed consent, clinical history, physical examination and lipid profile data were determined. Blood samples were extracted, processed to isolate DNA specimens at the National Institutes of Health, Institute of Human Genetics, and sent to Canterbury Health Laboratories at Christchurch, New Zealand for DNA analysis. ANALYSIS: Descriptive statistics, Fisher's exact test and Student's t-test using Stata version 6.0 software. RESULTS: Sixty patients with a mean age of 55 y/o were included, including 39 (65%) females. The mean LDL level was 227 mg/dl. Cardiovascular Disease and a family history of dyslipidemia were present in 55 & 60% of the samples, respectively. Twenty percent had documented LDL-R gene mutations. Six of the mutations were considered novel. A family history of dyslipidemia, an elevated LDL-C level, and a high FH score exhibited a statistically significant association with mutations. The study population has a high prevalence of CVD at an average age of 55 years with a strong family history of dyslipidemia and very high average LDL-C levels. One out of every 5 patients had LDL-R gene mutations, 6 of which were considered novel. LDL-R gene mutation was significantly associated with family history of dyslipidemia, LDL-C Level and FH score. CLINICAL AND RESEARCH IMPLICATION: This is the first international collaborative genetic study among Filipinos with FH. Data could allow the country to participate in the WHO/MEDPED global program. Collaborative efforts will lead to more effective detection, treatment and prevention of CV events. Novel mutations were discovered and further analysis of these genes will be done.

Adult↗

PubMed1999

Loricrin gene mutation in a Japanese patient of Vohwinkel's syndrome.

Vohwinkel's syndrome (VS) is a rare, dominantly inherited keratoderma with pseudoainhum. Recently, a mutation in loricrin gene has been reported in two VS families of British extraction. In the present study, we examined the loricrin gene mutation in a Japanese VS patient. The patient was a 20-year-old woman. She had palmoplantar keratoderma, constricting bands encircling all the fingers, fifth toes, wrist, and neck. She also had generalized mild ichthyosis and suffered from acoustic impairment. Her parents and a brother showed no skin abnormality. Histopathology of the patient revealed hyperkeratosis with parakeratosis, together with hypergranulosis. The clinical and histopathological findings were consistent with an ichthyotic (or Camisa) variant of VS. The sequence analysis of the loricrin gene revealed that the patient had a heterozygous mutation identical to that described in previous reports, i.e. a G insertion producing a frameshift at codon 231 with an abnormal C-terminus. These results clearly demonstrate that a common loricrin gene mutation underlies VS in different ethnic groups.

Adult↗

PubMed2005

[Detection of p53 gene mutation in the plasma of gastric cancer patients].

OBJECTIVE: To investigated p53 gene mutation in plasma of gastric cancer patients. METHODS: DNA extracted from plasma and matched tumor and tumor-adjacent normal tissues of 96 gastric cancer patients, and DNA from 20 healthy people were studied. Exons 5, 6, 7, and 8 of p53 were amplified by PCR. The mutation status was analyzed by denaturing high-performance liquid chromatography (DHPLC), followed by direct sequencing of cases with aberrant chromatographic patterns. RESULTS: Heterozygous mutations of p53 gene were detected in 19.9% (19/96) of primary tumor tissues and 5.2% (5/96) of corresponding plasma. All p53 gene mutations detected in plasma DNA consisted with mutations in the matched primary tumor samples. Neither the tumor-adjacent gastric mucosa tissues nor control plasma from healthy volunteers showed p53 gene mutation. No correlation was found between p53 mutation status and clinicopathological features of gastric cancer patients. CONCLUSION: p53 gene mutation in plasma can be detected in tissues and plasma of gastric cancer patients, which could be applied in screening and surveillance of this disease.

Adenocarcinoma↗

PubMedDate not supplied

Amplification of the CDK4 gene in sarcomas: tumor specificity and relationship with the RB gene mutation.

Amplification of the CDK4 gene, which encodes a key molecule in the cell cycle, has been shown in some types of human neoplasms, including bone and soft tissue tumors. It is also reported that the CDK4 gene is coamplified with other sequences in the 12q13-15 region, including the MDM2 and SAS genes. Using 146 DNA samples derived from a variety of bone and soft tissue tumors, we have studied the pattern of amplification of these three genes, CDK4, MDM2, and SAS, to investigate whether there are any tumor type specific patterns of amplification. Amplification of at least one of these three genes was found in 18 tumors, and five different patterns of amplification were observed. Amplification of all of these three genes was detected in 9 cases. Amplification of the CDK4 gene without MDM2 amplification was observed in osteosarcomas and a chondrosarcoma but not in soft tissue tumors, whereas amplification of MDM2 gene alone was observed in malignant fibrous histiocytomas (MFHs), liposarcomas, and lipomas, but not in bone tumors. These results suggested that the CDK4 region is the primary target for amplification in bone tumors, whereas the MDM2 region is in soft tissue tumors. We also investigated the relationship of CDK4 amplification with retinoblastoma (RB) gene mutations in osteosarcomas, for which we have already performed the mutation analyses in detail. Interestingly, contrary to the prevailing theory that CDK4 amplification is an alternative mechanism for RB gene mutation, we found that three of four cases with amplification of the CDK4 gene showed loss of expression of the RB protein, one of which was proved to have an gross DNA alteration in the RB locus. This redundancy of mutations may indicate that the amplification of CDK4 may have some roles other than the inactivation of the RB protein in the development of osteosarcomas.

Bone Neoplasms↗