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Yoshinao Oda

Publications and source records attributed to Yoshinao Oda.

At least 55 records · Page 3Linked to original sources
PubMed2004

Death-associated protein kinase (DAP kinase) alteration in soft tissue leiomyosarcoma: Promoter methylation or homozygous deletion is associated with a loss of DAP kinase expression.

The death-associated protein kinase (DAP kinase) was initially identified as a positive mediator of programmed cell death induced by interferon-gamma. To investigate the potential role and the alteration of the DAP kinase gene in soft tissue leiomyosarcoma (LMS), we first searched for homozygous deletion and promoter hypermethylation in 45 LMSs for which genomic DNA was available, using differential PCR and methylation-specific PCR, respectively. Promoter methylation was recognized in 10 of 45 cases (22%), and homozygous deletion was detected in 3 of 45 cases (7%). p53 mutation was detected in 11 of 45 LMS cases (24%). Cases with DAP kinase alteration or p53 mutation showed a close correlation with high French Federation of Cancer Centers grade or with poor prognosis (P = 0.0244, P = 0.0491, respectively). Next, to determine that DAP kinase promoter methylation or homozygous deletion is involved in the down-regulation of DAP kinase expression, we examined the expression of DAP kinase protein by immunohistochemistry. Decreased expression of DAP kinase protein was recognized in 13 of 45 LMS cases (29%). Seven of 13 cases (54%) with decreased expression of DAP kinase protein revealed promoter methylation or homozygous deletion of DAP kinase, and the methylation status or homozygous deletion of its gene showed a close correlation with decreased DAP kinase expression (P = 0.0300). In conclusion, although DAP kinase alteration was relatively rare, DAP kinase alteration and/or p53 mutation may associate with tumor progression in soft-tissue LMSs. Furthermore, although further detailed analyses are necessary, promoter methylation or homozygous deletion status of DAP kinase may present a major alternative mechanism of a loss of or decrease in DAP kinase expression.

Adult↗
PubMed2004

Frequent microsatellite instability in synchronous ovarian and endometrial adenocarcinoma and its usefulness for differential diagnosis.

Synchronous tumors of the ovary and endometrium are a well-known phenomenon. There are histological criteria for defining double primary tumors or metastasis from one organ to another, but in some cases a precise diagnosis is difficult. In this study we reviewed 17 cases of synchronous ovarian and endometrial adenocarcinoma by previously reported histological criteria and performed a microsatellite analysis, combined with X-linked clonality analysis. We also analyzed 8 cases of endometrial adenocarcinoma with pelvic lymph node metastasis as a control. Five dinucleotide microsatellite markers were selected, and microsatellite analysis was performed by a high-resolution method using fluorescence-labeled polymerase chain reaction and laser scanning. In synchronous tumors, 11 ovarian carcinomas (65%) and 10 endometrial carcinomas (59%)demonstrated microsatellite instability (MSI). In total, 13 of the 17 patients demonstrated MSI in the ovarian tumor, the endometrial tumor, or both. Four cases of endometrial carcinoma with pelvic lymph nodes metastases displayed MSI, and MSI findings of the endometrial tumor and lymph node metastasis were same in all cases. Based on these findings, we considered that similar MSI findings indicate metastatic tumors. According to the MSI findings, 13 of the 17 patients (76%) had single or double clonal tumors, 11 (67%) with double primary tumors and 2 (13%) with metastatic tumors. Using X-linked clonality analysis, 3 patients were diagnosed with double primary tumors. The molecular diagnosis corresponded with the histological criteria in all but 1 case. In conclusion, using both MSI and X-linked clonality analysis, most patients (82%) could be diagnosed as having single or double clonal tumors. The histological criteria are accurate and useful in most cases; however, in some cases where the relationship between the 2 tumors is difficult to determine, high-resolution MSI analysis may be helpful.

Adenocarcinoma↗
PubMed2004

Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma.

Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in children. Some reports have discussed the altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma; however, variable frequencies of occurrence have been noted. In the current study, among 72 cases of rhabdomyosarcoma, the authors evaluated for the expression of p53, MDM2, p16, p21/WAF1, p27, cyclin D1, cyclin E, pRb and E2F-1 protein immunohistochemically and assessed for proliferative activities using MIB-1. We also analyzed the mutation of the p53 gene in 45 cases, the amplification of the MDM2 gene in 18 cases and the mutation of the H-ras gene in 29 cases, using formalin-fixed paraffin-embedded materials. Furthermore, we assessed the correlation between clinicopathologic factors and the results of both immunohistochemical and molecular analyses. Alveolar type affected older patients, and it had a significantly higher mitotic rate compared with the embryonal type (P=0.0226). p53 overexpression was detected in 22 (30.6%) of 72 cases, and 10 (22.2%) of 45 cases had p53 gene abnormalities. As for MDM2, its overexpression was found in nine (12.5%) of 72 cases, and three (16.7%) of 18 cases showed MDM2 amplification. A statistically significant association was observed between immunoreaction for MDM2 and p53 overexpression (P=0.0002), and p53 and MDM2 overexpression was significantly correlated with high MIB-1 labeling indices. E2F-1 labeling indices showed a significantly higher score in alveolar type compared with that seen in embryonal type (P=0.0334), but MIB-1 did not. In conclusion, our study suggests that p53 overexpression may be related to tumor progression because tumors with p53 overexpression have a high proliferative activity in the current study. Alveolar type had a significantly higher both mitotic rate and E2F-1 labeling indices when compared with the embryonal type. The current study is the first report of the correlation of E2F-1 with alveolar rhabdomyosarcoma.

Adolescent↗
PubMed2004

Anatomical features of periprostatic tissue and its surroundings: a histological analysis of 79 radical retropubic prostatectomy specimens.

BACKGROUND: A proper understanding of prostatic and periprostatic anatomy is essential for surgical procedures and pathological diagnosis; however, the detailed features have not been commonly investigated and completely understood. METHODS: Seventy-nine non-nerve-sparing radical prostatectomy specimens were microscopically investigated for Denonvilliers' fascia, lateral pelvic fascia, prostatic capsule, anterior fibromuscular stroma and the neurovascular bundle. RESULTS: At the lateral aspect, the lateral pelvic fascia and the prostatic capsule were separated by adipose tissue in 41 cases (52%), whereas they adhered in 38 cases (48%). In only 41 cases (52%), the neurovascular bundle existed locally at the postero-lateral region with definite 'bundle' formations. Denonvilliers' fascia and the prostatic capsule adhered tightly at the center of the posterior aspect in 77 cases (97%). A smooth transition from the prostatic capsule to the anterior fibromuscular stroma was observed in all cases. In 70 cases (89%), no prostatic capsule was independently recognized at the anterior aspect. In the remaining 9 cases (11%), the capsule was recognizable as distinct from the anterior fibromuscular stroma. In 67 cases (85%), the lateral pelvic fascia connected and fused with the anterior fibromuscular stroma, and covered the outermost regions of the lateral and anterior surfaces. CONCLUSIONS: All the periprostatic structures are closely related and influence each other. The results support the rationale of anatomical radical prostatectomy, and should be taken into consideration for surgical procedures and pathological diagnosis.

Adipose Tissue↗
PubMed2004

c-kit and PDGFRA mutations in extragastrointestinal stromal tumor (gastrointestinal stromal tumor of the soft tissue).

Extragastrointestinal stromal tumor (EGIST) is a unique tumor that occurs outside the gastrointestinal tract. EGIST shows a c-kit expression and histologic appearance similar to those of gastrointestinal stromal tumor (GIST). Most GISTs have gain-of-functional mutation of the c-kit gene, and some have mutation of the platelet-derived growth factor receptor-alpha (PDGFRA) gene. However, the frequency of mutation of those genes in EGISTs remains unclear. We examined the clinicopathologic features, prognostic factors, and c-kit and PDGFRA mutation in 39 cases of EGIST. Tumors with high mitotic counts (>or=5/50 high power fields) or a high Ki-67 labeling index (>or=10%) were significantly correlated with worse prognoses. The c-kit mutation was found in the juxtamembrane domain (exon 11) and the extracellular domain (exon 9) in 12 of 29 cases (41.4%) and 2 of 29 cases (6.9%), respectively. The PDGFRA gene mutation was found at the juxtamembrane domain (exon 12) and the tyrosine kinase domain (exon 18) in one case each. The pattern of kit and PDGFRA mutation in EGIST was essentially similar to that in GIST. Our results suggest that the c-kit and PDGFRA mutations play an important role in the tumorigenesis of EGIST. High mitotic counts and a high Ki-67 labeling index may be useful for predicting the aggressive biologic behavior in EGIST. Furthermore, STI-571, targeting c-kit and PDGFR tyrosine kinase, seems to be a possible therapeutic strategy for EGISTs, especially advanced cases.

Adult↗
PubMed2004

Alterations of the p16INK4a/p14ARF pathway in clear cell sarcoma.

Clear cell sarcoma (CCS) is a very rare soft tissue sarcoma with a poor prognosis. It has become apparent through immunohistochemical, ultrastructural, and microarray analyses that CCS is a soft tissue melanocytic neoplasm. Alterations in the p16INK4a/p14ARF gene are common in malignant melanoma, which is the prototypical melanocytic neoplasm. In the present study, we performed a clinicopathologic analysis and investigated p16 and cyclin D1 expression by immunohistochemistry in 14 cases. Furthermore, we investigated genetic changes of various tumor suppressor genes and an oncogene, including p16INK4a/p14ARF, p53, beta-catenin, and APC, in 11 cases. The 5-year overall survival rate in all the patients was 33.3%. A high mitotic rate was a significant adverse prognostic factor (P = 0.004). Decreased expression of p16 was observed in 4 (28.6%) of 14 cases. Overexpression of cyclin D1 was observed in 9 cases (64.3%). SSCP analysis followed by DNA direct sequencing revealed point mutations of the p16INK4a gene in 2 of 11 cases (18.2%). In addition, one case with the p14ARF mutation and 2 cases with the p53 mutation were observed. None of the cases harbored mutation of the beta-catenin or APC gene. Homozygous deletion of the p16INK4a/p14ARF gene was detected in one case. Methylation-specific PCR did not reveal hypermethylation of the p16INK4a/p14ARF promoter region in any of the cases. Three cases harbored genetic alterations of the p16INK4a/p14ARF gene (27.3%). All tumors with genetic alterations of the p16INK4a/p14ARF or p53 gene showed a high mitotic rate or tumor necrosis. These alterations were considered to be influential in the poor prognosis of CCS patients.

Adult↗
PubMed2004

Multicentric papillary renal cell carcinoma associated with renal adenomatosis.

A case of multicentric papillary renal cell carcinoma (RCC) associated with renal adenomatosis in the bilateral kidneys is reported. Bilateral multiple renal cysts in a 46-year-old man were pointed out incidentally by ultrasonography. Some of the left renal lesions were considered to be RCC, and left radical nephrectomy was performed accordingly. The left kidney was occupied by numerous solid nodules, which ranged from yellow to tan in color, and some of the large ones had foci of hemorrhage and necrosis. Microscopically, most of the tumors showed papillary RCC associated with renal adenoma, while others consisted only of adenomas. Ten months later, multiple lesions of the right kidney, which were initially considered to be multiple cysts, were found to have become enlarged and some of them were diagnosed as RCC. Thus, right radical nephrectomy was also performed, and these tumors showed the same features as the left renal tumors. The patient's familial history was not remarkable. The kidneys revealed various histological features, ranging from dysplastic to adenoma or carcinoma, including transitional or overlapping features between them. The findings suggest an adenoma-carcinoma sequence in papillary RCC. It is worth considering such entities.

Adenoma↗
PubMed2004

Pulmonary synovial sarcoma with polypoid endobronchial growth: a case report, immunohistochemical and cytogenetic study.

A rare case of primary pulmonary synovial sarcoma with polypoid endobronchial growth in a 42-year-old Japanese woman is described. Left upper sleeve lobectomy was performed for the polypoid tumor measuring 2.5 cm in the left major bronchus and the patient was treated with adjuvant chemotherapy. Three years later, a recurrent tumor was discovered. Microscopically, this tumor was characterized by a proliferation of oval to spindle-shaped cells arranged in sheets and fascicles and covered by the thin normal bronchial epithelium. Immunohistochemically, tumor cells were positive for vimentin, and focally positive for pancytokeratin recognized by AE1/AE3, cytokeratin 7 and epithelial membrane antigen. A chimera gene, SYT-SSX1, was detected. Recently, primary pulmonary synovial sarcoma is an increasingly recognized clinical entity; however, most of these tumors present as a parenchymal mass. The present case is a unique example of primary synovial sarcoma of endobronchial polypoid type. This case suggests that pulmonary synovial sarcoma might originate from bronchial submucosal stromal tissue.

Adult↗
PubMed2004

H-ras mutation is an additional event of sarcomatous transformation in aerodigestive spindle cell carcinoma.

The conversion from a carcinomatous component to a sarcomatous one in spindle cell carcinoma (SPCC) of the upper aerodigestive tract is thought to occur via a series of molecular alterations; however the detailed mechanism is still unknown. We examined mutations at the H-ras and p53 genes in 16 SPCCs of upper aerodigestive tracts using PCR-RFLP, PCR-SSCP and direct sequencing analysis. The two distinct components, sarcomatous and carcinomatous components in SPCC, were analyzed independently. p53 mutations were detected in both components of SPCC (50.0%, 8/16), and those in the sarcomatous component were completely in accordance with those in the carcinomatous one. In contrast, H-ras mutations were detected only in the sarcomatous component (12.5%, 2/16), and not in the carcinomatous one (0%, 0/16). There was a statistically significant difference in prognosis between the patients with the H-ras mutation (n=2) and those without (n=14); the former had poorer prognosis (P=0.0049). Our results seem to suggest that the H-ras mutation is a relatively uncommon event in SPCC; however, the presence of H-ras mutations may be associated with a more malignant potential in SPCC, while actually occurring during the sarcomatous change itself.

Adult↗
PubMed2004

PTEN and other tumor suppressor gene mutations as secondary genetic alterations in synovial sarcoma.

Synovial sarcomas (SS) consistently show a characteristic chromosomal translocation, t(X;18)(p11;q11), which usually leads to the formation of 2 chimeric fusion transcripts, SYT-SSX1 and -SSX2. A recent multi-institutional retrospective study revealed that the SYT-SSX fusion type emerged as the only independent significant factor for overall survival in cases of SS. The aims of this study were; i). to investigate the frequency of PTEN gene alteration, ii). to evaluate whether the mutation status in various tumor suppressor genes (TSG) is responsible for the clinical and histologic heterogeneity in SS. Forty-nine cases of SS were examined for the presence of PTEN gene mutation by polymerase chain reaction - single-strand conformation polymorphism followed by DNA direct sequencing. The obtained data was combined with those of previously reported TSG mutations such as p53, adenomatous polyposis coli, and E-cadherin genes. Follow-up was available for 44 patients, and survival analysis was performed according to the mutation status of these TSG. PTEN mutations were detected in 7 cases (14.3%), and all of these were monophasic tumors. More than half of the mutations detected were located in exon 9, which has been shown to play a less important role in PTEN functioning, and the PTEN mutation was not associated with patients' prognosis. Mutations in these TSG other than silent mutations were detected in 20 out of 49 cases (40.8%), although the mutation status in TSG was not associated with overall survival rate in patients with SS. Secondary genetic alterations in these TSG seem to have a less important prognostic impact on patients with SS.

Adult↗
PubMed2004

The role of nuclear Y-box binding protein 1 as a global marker in drug resistance.

Gene expression can be regulated by nuclear factors at the transcriptional level. Many such factors regulate MDR1 gene expression, but what are the sequence elements and transcription factors that control the basal and inducible expression of this gene? The general principles through which transcription factors participate in drug resistance are now beginning to be understood. Here, we review the factors involved in the transcriptional regulation of the MDR1 gene. In particular, we focus on the transcription factor Y-box binding protein 1 and discuss the possible links between Y-box binding protein 1 expression and drug resistance in cancer, which are mediated by the transmembrane P-glycoprotein or non-P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Skull base and nonskull base chordomas: clinicopathologic and immunohistochemical study with special reference to nuclear pleomorphism and proliferative ability.

BACKGROUND: To the authors' knowledge, little is known regarding the relation between the proliferative ability and clinicopathologic parameters in skull base chordomas (SBCs) and nonskull base chordomas (NSBCs). METHODS: The authors investigated 122 conventional chordomas for their clinicopathologic parameters, proliferative ability (MIB-1 labeling index [LI]) and clinical outcome. RESULTS: Primary NSBCs were found to affect more elderly patients and demonstrated a higher MIB-1 LI compared with primary SBCs. Mitosis was more commonly noted in recurrent NSBCs compared with primary NSBCs. Apoptosis was more frequent in elderly patients than in younger patients with regard to both SBCs and NSBCs. Apoptosis also was found to be correlated with necrosis in SBCs, suggesting a common factor for the two different types of cell death. Mucoid matrix was reported to be more abundant in NSBCs than in SBCs, and appeared to occur more often in elder NSBC patients compared with younger NSBC patients. This indicates that it is produced in the later stages of tumorigenesis. In SBCs, several clinicopathologic parameters were found to be correlated with MIB-1 LI. Among them, increased age, recurrence, and nuclear pleomorphism were the only independent factors found to indicate a higher MIB-1 LI. No such parameters were found in NSBCs. However, in these lesions, prognosis was significantly poorer in those cases with nuclear pleomorphism compared with those without. CONCLUSIONS: The results of the current study suggest that nuclear pleomorphism is a prognostic indicator in NSBCs. The proliferative ability of SBCs appears to be closely associated with patient age, clinical status (recurrence), and nuclear pleomorphism.

Adolescent↗
PubMed2003

Primitive neuroectodermal tumor and extraskeletal Ewing sarcoma arising primarily around the spinal column: report of four cases and a review of the literature.

STUDY DESIGN: Report of four cases and a review of the literature. OBJECTIVES: To study the clinical features and prognosis of primitive neuroectodermal tumor or extraskeletal Ewing sarcoma arising around the spinal column. SUMMARY OF BACKGROUND DATA: Primitive neuroectodermal tumor or extraskeletal Ewing sarcoma that originates around the spinal column is very rare, and its prognosis is very poor. METHODS: Four patients were diagnosed and underwent treatment. RESULTS: Although all the patients received high-dose chemotherapy with or without radiotherapy after surgery, three patients died of the disease. Only one patient who received en bloc resection of the tumor combined with multiagent chemotherapy followed by high-dose chemotherapy with peripheral blood stem cell transplantation remains alive and continues to be disease free. CONCLUSION: The prognosis of the patients with primitive neuroectodermal tumor or extraskeletal Ewing sarcoma around the spinal column is very poor. Multiagent chemotherapy combined with en bloc resection and radiation therapy is the preferred treatment for patients with primitive neuroectodermal tumor or extraskeletal Ewing sarcoma around the spinal column.

Adolescent↗
PubMed2003

PTEN/MMAC1 gene mutation is a rare event in soft tissue sarcomas without specific balanced translocations.

The tumor suppressor gene PTEN/MMAC1 was identified on chromosome 10q23.3, which is homozygously deleted in many human malignancies. The loss of chromosome 10q was also frequently reported in some types of soft tissue sarcomas. Our study was designed to investigate the frequency of PTEN/MMAC1 gene mutation and to evaluate the role of the PTEN/MMAC1 gene in the tumorigenesis of soft tissue sarcomas without specific balanced translocations. We analyzed 51 cases of soft tissue sarcomas without specific balanced translocations for PTEN/MMAC1 mutations by polymerase chain reaction-single strand conformation polymorphism and direct sequencing. Mutations in the PTEN/MMAC1 gene were found in only 2 cases (3.9%). Both tumors with PTEN/MMAC1 mutation were leiomyosarcomas arising from the retroperitoneum and inferior vena cava, respectively. Two of 3 leiomyosarcomas arising from the intra-abdominal cavity examined harbored mutations of this tumor suppressor gene. This result suggests that leiomyosarcomas derived from the intra-abdominal cavity might have different tumorigenesis from those of an extremity or the trunk, from the viewpoint of PTEN/MMAC1 mutation, although PTEN/MMAC1 gene mutations are rare event in these soft tissue sarcomas.

Base Sequence↗
PubMed2003

Nuclear expression of Y-box-binding protein-1 correlates with P-glycoprotein and topoisomerase II alpha expression, and with poor prognosis in synovial sarcoma.

Nuclear expression of the Y-box-binding protein (YB-1) has been reported to correlate with the expression of P-glycoprotein in breast cancer and osteosarcoma. Overexpression of the ATP-binding cassette (ABC) superfamily, such as P-glycoprotein/multi-drug resistance (MDR) 1 and MDR-associated protein (MRP) 1, 2 and 3, has been reported in various malignant neoplasms. Fifty-four surgically resected synovial sarcomas were examined immunohistochemically for nuclear expression of YB-1 and intrinsic expression of P-glycoprotein, MRP1, MRP2, and topoisomerase II alpha, and the findings were compared with clinicopathological parameters, proliferative activities as evaluated by MIB-1 labelling index (LI), and the patients' prognoses. In addition, MDR1, MRP1, MRP2, and MRP3 mRNA levels were assessed using a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method in 22 concordant frozen specimens from these cases and the findings were compared with six control skeletal muscle tissues. Independent prognostic factors were investigated using the Cox proportional hazards regression model. Nuclear expression of YB-1 protein correlated with P-glycoprotein expression (p = 0.0126). Moreover, cases with nuclear expression of YB-1 correlated with poor survival (p = 0.0495) and showed a high topoisomerase II alpha labelling index (topo II alpha LI) (p = 0.0056) and a high MIB-1 LI (p = 0.01). Multivariate Cox analysis showed that only the nuclear expression of YB-1 (p = 0.0136) and high American Joint Committee on Cancer (AJCC) stage (ie stage III or IV) (p < 0.0001) were independent factors for poor prognosis, while the expression of the YB-1 responsive gene products examined was not. These results indicate that the nuclear expression of YB-1 protein is associated with P-glycoprotein expression and proliferative activity as shown by the topo II alpha LI and the MIB-1 LI, and that expression of this protein is an important independent prognostic factor in synovial sarcoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Mechanisms of inactivation of the p16INK4a gene in leiomyosarcoma of soft tissue: decreased p16 expression correlates with promoter methylation and poor prognosis.

The p16INK4a tumour suppressor gene, encoding p16 protein, plays a crucial role in regulation of the G1 cell-cycle phase. To investigate the potential role of p16 in soft tissue leiomyosarcoma (LMS), an immunohistochemical analysis was performed of 77 LMSs for p16 expression. Decreased expression of the p16 protein was identified in 25 of 77 LMSs (32%). Decreased expression of p16 correlated significantly with large tumour size (p=0.0038). In a univariate analysis, large tumour size and decreased expression of p16 were statistically significant adverse prognostic factors (p=0.025 and p=0.0021, respectively). In a multivariate analysis including conventional clinicopathological parameters, decreased expression of p16 protein was revealed as the only independent unfavourable prognostic factor (p=0.012). To elucidate the mechanisms of inactivation of the p16INK4a gene, 49 LMSs for which genomic DNA was available were examined; analysis for homozygous deletion, mutation, and promoter hypermethylation was conducted using differential PCR, PCR-SSCP, and methylation-specific PCR, respectively. Promoter hypermethylation was detected in 11 of 49 LMS cases (22%); homozygous deletion was detected in 3 of 49 cases (6%); and mutation was not recognized in any of the cases studied. Eight of 15 cases (53%) with decreased expression of p16 protein revealed methylation of the p16INK4a gene promoter. Promoter hypermethylation correlated closely with decreased expression and poor prognosis (p=0.0014 and p=0.0088, respectively). These results suggest that decreased expression of p16 protein can be considered as an independent reliable prognostic parameter in patients with soft tissue LMS. Furthermore, promoter methylation was more frequent than either homozygous deletion or mutation in this tumour, and promoter methylation was also shown to have a strong association with inactivation of the p16INK4a gene.

Adolescent↗
PubMed2003

Possible association between tumor-suppressor gene mutations and hMSH2/hMLH1 inactivation in alveolar soft part sarcoma.

Alveolar soft part sarcoma (ASPS) is a rare soft tissue tumor of unknown origin and pathogenesis. We clinicopathologically analyzed 16 cases of ASPS and screened for the genetic alterations of various tumor-suppressor genes and oncogenes, including p53, adenomatous polyposis coli (APC), E-cadherin, and beta-catenin, in 11 cases of ASPS. We also examined the expression of hMSH2/hMLH1 of DNA mismatch repair genes by immunohistochemistry, and promoter hypermethylation of these DNA mismatch repair genes by methylation-specific polymerase chain reaction (MS-PCR) to elucidate any possible association between mutation status of these genes and inactivation of the hMSH2/hMLH1 genes. Furthermore, microsatellite instability (MSI) analysis and loss of heterozygosity (LOH) on chromosome 5q analysis were used for some cases of ASPS where DNA derived from normal tissue was available. The 5-year overall survival rate for all of the patients in this study was 68.6%. The 5-year overall survival rates for patients presenting with localized ASPS and for patients with distant metastases were 83.3% and 47.6%, respectively. The high nuclear grade of tumor cells was a significantly adverse prognostic factor (P = 0.0085). Single-strand conformation polymorphism analysis followed by DNA direct sequencing revealed 4 point mutations of the p53 gene in 3 of 11 cases (27.3%), composed of 3 missense mutations and 1 silent mutation. In addition, 1 case with the E-cadherin missense mutation and 1 case with the APC missense mutations were observed, respectively. None of the cases harbored mutation of exon 3 of the beta-catenin gene. Loss of expression of the hMSH2 and hMLH1 genes was observed in 2 (18.2%) and 3 (27.3%) of 11 cases, respectively. All 3 cases with loss of hMLH1 gene expression harbored mutations of the p53 gene. There was a statistically significant correlation between the genetic alteration positive in these tumor-suppressor genes and loss of hMLH1 gene expression (P = 0.024). Methylation-specific PCR did not reveal hypermethylation of the hMSH2/hMLH1 promoter region in any of the cases examined. Three of 8 (37.5%) ASPS cases showed low MSI, and 2 of these 3 cases showed immunohistochemical lack of expression for either hMSH2 or hMLH1. LOH on 5q was present in 2 of 6 (33.3%) informative cases, and both cases showed LOH on the D5S346 marker, a microsatellite marker near the APC locus. Thus, inactivation of hMSH2/hMLH1 of DNA mismatch repair genes seems to have an important role to play in the mutagenesis of the tumor-suppressor genes in ASPS.

Adaptor Proteins, Signal Transducing↗