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1.
Anticancer Res ; 41(9): 4295-4304, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475049

RESUMO

BACKGROUND/AIM: Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults. The aim of this study was to elucidate the molecular pathogenesis of sporadic RCC in Taiwan. MATERIALS AND METHODS: Fifteen patients with RCC were screened for mutations in the von Hippel-Lindau (VHL) gene by PCR and Sanger sequencing. The methylation status of promoters of 24 tumor suppressor genes by methylation sensitive multiplex ligation-dependent probe amplification analysis was also determined. RESULTS: Inactivation of the VHL gene was observed in 5 cases: three missense somatic mutations, one promoter methylation, and one small deletion. In RCCs, methylation was most frequently observed in APC (100%), CDKN2B (92.9%), CASP8, MLH1_167, and KLLN (85.7.4%), but not in FHIT, MLH1_463, DAPK1, or HIC1 (0%). CONCLUSION: In addition to VHL inactivation, promoter methylation of APC may be a universal pathognomonic event in the tumorigenesis of RCC and a candidate diagnostic and therapeutic biomarker.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Carcinoma de Células Renais/diagnóstico , Metilação de DNA , Neoplasias Renais/diagnóstico , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Detecção Precoce de Câncer , Epigênese Genética , Feminino , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Mutação de Sentido Incorreto , Estadiamento de Neoplasias , Regiões Promotoras Genéticas , Análise de Sequência de DNA , Deleção de Sequência
2.
Toxicol Lett ; 352: 17-25, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34571076

RESUMO

Angiopoietin-like protein 4 (ANGPTL4) is a hypoxia-induced gene, and its high expression is associated with poor prognosis and promotion of tumour progression in several cancers. Some studies reported that ANGPTL4 is affected by epigenetic regulation. Our previous results demonstrated that ANGPTL4 is highly expressed in most lung cancer cell lines than in normal cell lines and is upregulated by HIF-1α accumulation under NiCl2 exposure. The accurate role of ANGPTL4 and its methylation status caused by nickel in the lung carcinogenesis is not fully explored yet. In this study, we found that ANGPTL4 and HIF-1α in lung adenocarcinoma (LUAD) tissues were significantly upregulated compared with those in normal tissues in The Cancer Genome Atlas (TCGA) cohort (p < 0.001). The ANGPTL4 expression was statistically correlated to advanced stage (p = 0.019) and N value (p = 0.002). The Kaplan-Meier analysis revealed that ANGPTL4 and HIF-1α expression levels were independently associated with the 5-year survival of patients with LUAD in TCGA database and immunohistochemistry staining. In vitro experiments indicated that ANGPTL4 was upregulated by the demethylation agent. The methylation-specific PCR and bisulfite sequencing assessed the methylation status of the ANGPTL4 promoter, and results showed that NiCl2-treated cells had low ANGPTL4 methylation status. We further demonstrated that the DNA demethylase, TET1, was significantly increased under NiCl2 exposure. The knockdown of TET1 expression repressed the NiCl2-induced ANGPTL4. We also showed that nickel-induced TET1 was stimulated by HIF-1α. Our work established ANGPTL4 as a potential oncogene that contributes to lung cancer progression and nickel-elicited carcinogenesis.

3.
J Breast Cancer ; 23(4): 430-437, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32908792

RESUMO

A 51-year-old woman presented with metachronous tumor development in bilateral breasts, thyroid, and endometrium. Additional signs and symptoms fulfilled the National Comprehensive Cancer Network criteria for Cowden syndrome. Immunohistochemistry showed loss of PTEN expression in all tumors. Single nucleotide variants, 647 germline variants (including one each in PTEN and MSH3), and 21 somatic mutations within exons were detected in all tumors after whole-exome sequencing. There were 0, 11, and 46 specific somatic mutations in bilateral breasts, thyroid, and endometrial cancers, respectively. Although PTEN mutation is key to the development of Cowden syndrome, DNA repair dysfunction might be the initial driver of mutations. Fewer mutations were required to induce initial bilateral breast carcinomas, with subsequent thyroid and endometrial carcinomas requiring more mutations for induction. When genetic screening is unavailable, breast cancer patients with clinical manifestations of Cowden syndrome must be carefully assessed for secondary malignancies, such as thyroid and endometrial carcinomas.

4.
Pathol Oncol Res ; 26(4): 2153-2159, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32157637

RESUMO

Wilms tumor is the most common pediatric renal malignancy. Several genetic loci have been shown to be associated with its formation. Genetic or epigenetic aberrations at WT1 and WT2 loci have been implicated in the etiology of the majority of sporadic Wilms tumors. In our previous study, most Wilms tumors tested negative for both constitutional mutations and somatic mutations in the WT1 gene. Thus, WT2 may play an important role in these tumors. In the present study, we analyzed the methylation statuses of WT2 at 11p15 using methylation sensitive multiplex ligation-dependent probe amplification in six Wilms tumors. Paternal uniparental disomy at WT2 was observed in two Wilms tumors with epithelial components due to hypermethylation at H19DMR and hypomethylation at KvDMR. Our findings highlight the benefits of testing for 11p15 epigenetic abnormalities to identify Wilms tumors with epithelial components.

5.
Pathol Oncol Res ; 25(3): 1199-1206, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30671724

RESUMO

Wilms tumor, or nephroblastoma, is the most common pediatric renal malignancy. Its diagnosis is principally based on histology. Several genetic loci have been shown to be associated with Wilms tumor formation, including WT1, WT2, FWT1, FWT2, CTNNB1, WTX, and TP53. Other loci, such as 1p, 2q, 7p, 9q, 12q, 14q, 16q, 17p, and 22, have also been implicated in the etiology of Wilms tumor. The aim of this study is to elucidate the molecular pathogenesis of this tumor. In the present study, we analyzed the histological appearance and copy number aberrations using array comparative genomic hybridization of six Wilms tumors without somatic mutation in the WT1 gene. Many chromosomal aberrations on array comparative genomic hybridization analysis revealed that the genetics of Wilms tumors are extremely complex. Amplifications and deletions of large DNA fragments were observed in some samples. Amplifications of NDUFV1, ZIC2, SIX1, NR2F2, MIR1469, SOX9, JAG1, MIR6870, and GNAS were found in all six Wilms tumors. Moreover, amplifications of five genes were identified in the Wilms tumors of stromal type and amplifications of at least 10 genes were identified in the Wilms tumors of epithelial type. Our results indicated that amplifications of nine genes are the essential events in the tumorigenesis of Wilms tumor, which may inform its clinical and therapeutic management. In addition, mixed type Wilms tumor may be the heterogeneous group able to be classified using genetic results of epithelial and stromal components based on immunohistochemistry.


Assuntos
Biomarcadores Tumorais/genética , Aberrações Cromossômicas , Hibridização Genômica Comparativa/métodos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Tumor de Wilms/genética , Tumor de Wilms/patologia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Mutação , Prognóstico
6.
7.
J Ovarian Res ; 10(1): 17, 2017 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-28288660

RESUMO

BACKGROUND: Mature cystic teratomas are usually found in the ovaries. They are bilateral in 10 to 15% of cases and multiple cystic teratomas may be present in one ovary. The aim of this study is to clarify if development of mature cystic teratomas of the ovaries in a single host is metachronous or due to autoimplant or recurrence. CASE PRESENTATION: We report a woman with bilateral mature cystic teratomas of the ovaries. DNA profiles of these teratomas were investigated via short tandem repeat (STR) analysis and methylation statuses were determined via methylation sensitive multiplex ligation-dependent probe amplification methods. The results showed that the cystic teratomas originated from different stages of oogonia or primary oocyte before germinal vesicle stage failure of meiosis I in female gametogenesis. Potentially relevant literature was searched in PubMed database. Cases of bilateral or multiple mature cystic teratomas of the ovaries were analyzed. To date, there has been no reported case of multiple mature cystic teratomas in which clarification of the origin was achieved using molecular genetic methods. CONCLUSIONS: The results of this case study provide evidence of metachronous development of mature cystic teratomas of the ovaries and may serve as a reference in the management of patients following laparoscopic cystectomy.


Assuntos
Segunda Neoplasia Primária/diagnóstico , Neoplasias Ovarianas/diagnóstico , Teratoma/diagnóstico , Adulto , Variações do Número de Cópias de DNA , Metilação de DNA , Feminino , Loci Gênicos , Humanos , Perda de Heterozigosidade , Repetições de Microssatélites , Gradação de Tumores , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/cirurgia , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/cirurgia , Análise de Sequência de DNA , Teratoma/etiologia , Teratoma/cirurgia
8.
J Ovarian Res ; 10(1): 22, 2017 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-28347324

RESUMO

BACKGROUND: Granulosa cell tumors are rare ovarian malignancies. Their characteristics include unpredictable indolent growth with malignant potential and late recurrence. Approximately 95% are of adult type. Recent molecular studies have characterized the FOXL2 402C > G mutation in adult granulosa cell tumor. Our previous case report showed that unique FOXL2 402C > G mutation and defective DNA mismatch repair system are associated with the development of adult granulosa cell tumor. FINDINGS: In this study, the DNA sequences of four genes, MSH2, MLH1, MSH6, and PMS2, in the DNA mismatch repair system were determined via direct sequencing to elucidate the exact mechanism for the development of this granulosa cell tumor. The results showed that two missense germline mutations, T485K and N775L, inactivate the PMS2 gene. CONCLUSIONS: The results of this case study indicated that although FOXL2 402C > G mutation determines the development of granulosa cell tumor, PMS2 mutation may be the initial driver of carcinogenesis. Immunohistochemistry-based tumor testing for mismatch repair gene expression may be necessary for granulosa cell tumors to determine their malignant potential or if they are part of Lynch syndrome.


Assuntos
Reparo de Erro de Pareamento de DNA , Tumor de Células da Granulosa/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Adulto , Alelos , Biomarcadores Tumorais , Éxons , Feminino , Proteína Forkhead Box L2 , Fatores de Transcrição Forkhead/genética , Genótipo , Humanos , Íntrons , Mutação , Análise de Sequência de DNA
9.
Hum Pathol ; 52: 128-35, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27210027

RESUMO

The most accepted theory regarding mature cystic teratomas of the ovary is that they are of parthenogenetic origin from oocyte after the completion of first division. Our previous study demonstrated that the origin of mature cystic teratoma of the uterus is not related to the parthenogenetic process, but is most likely pluripotential stem cell or primordial germ cell before meiosis I. Further studies are needed to clarify the origin of benign mature cystic teratomas of the ovary in Taiwan. In the present study, we investigated the DNA profiles of 9 mature cystic teratomas of the ovary using short tandem repeat analysis with AmpFLSTR SGM Plus, Profiler PCR amplification kits. The methylation statuses of the HhaI sites in the SNRPN, H19DMR, and KvDMR regions were determined on methylation-sensitive multiplex ligation-dependent probe amplification analysis. DNA profiling data from the 9 mature cystic teratomas of the ovary excluded parthenogenetic origin, as most of the 15 short tandem repeat loci were heterozygous on genotyping. There were varying degrees of hypermethylation of SNRPN gene and KvDMR locus in the presence of maternal uniparental disomy in all 9 mature cystic teratomas of the ovary. In light of these results, we further postulated that the origin of these mature cystic teratomas of the ovary is oogonia or primary oocyte before germinal vesicle stage failure of meiosis I.


Assuntos
Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Metilação de DNA , Repetições de Microssatélites , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Ovarianas/genética , Teratoma/genética , Proteínas Centrais de snRNP/genética , Adulto , Transformação Celular Neoplásica/patologia , Feminino , Predisposição Genética para Doença , Impressão Genômica , Heterozigoto , Humanos , Meiose , Reação em Cadeia da Polimerase Multiplex , Neoplasias Císticas, Mucinosas e Serosas/patologia , Oócitos/patologia , Oogônios/patologia , Neoplasias Ovarianas/patologia , Partenogênese , Fenótipo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Taiwan , Teratoma/patologia , Dissomia Uniparental , Adulto Jovem
10.
J Ovarian Res ; 7: 88, 2014 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-25297715

RESUMO

Granulosa cell tumors are rare ovarian malignancies. Their characteristics include unpredictable late recurrent and malignant behavior. Recent molecular studies have characterized the FOXL2 402C > G mutation in adult-type granulosa cell tumor. In this study, we report an 80-year-old woman with a granulosa cell tumor arising from ovary. She presented with a huge pelvic mass with postmenopausal bleeding. No obvious intraperitoneal tumor implants were observed during operation. Final diagnosis was granulosa-theca cell tumor without capsule invasion. No recurrent disease was noted during 3-year post-operation follow-up period. Molecular studies showed a heterozygous FOXL2 402C > G mutation in the tumor by direct gene sequencing. In addition, DNA replication error, on analysis of the lengths of CAG repeats in androgen receptor gene, revealed defective DNA mismatch repair system in the granulosa cell tumor. We propose that the 402C > G mutation in FOXL2 is critical to the development of adult granulosa cell tumor. However, the malignant behavior of this tumor is driven by DNA mismatch repair deficiency. Unequal DNA copy numbers were noted on array comparative genomic hybridization. This implies that there is malignant potential even in the early stage of the granulosa cell tumor. Late malignant recurrence may be a late event of DNA repair function disability, not directly related to pathognomonic FOXL2 mutation.


Assuntos
Fatores de Transcrição Forkhead/genética , Tumor de Células da Granulosa/genética , Mutação , Neoplasias Ovarianas/genética , Idoso de 80 Anos ou mais , Biópsia , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Feminino , Proteína Forkhead Box L2 , Genótipo , Tumor de Células da Granulosa/diagnóstico , Humanos , Imuno-Histoquímica , Perda de Heterozigosidade , Neoplasias Ovarianas/diagnóstico
11.
BMC Res Notes ; 7: 638, 2014 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-25217002

RESUMO

BACKGROUND: Renal cell carcinoma, a common malignant tumor arising from the kidney, occurs in 3.62 and 1.95 cases per one hundred thousand people among men and women, respectively, in Taiwan each year. Approximately 80% of cases are classified as clear-cell renal cell carcinoma. Inactivation of the von Hippel-Lindau tumor suppressor gene has been implicated in the tumorigenic pathway of renal cell carcinoma. Two single nucleotide polymorphisms, rs779805 and rs1642742, located in the promoter and 3' untranslated regions of the von Hippel-Lindau gene are informative and implicated in the occurrence of renal cell carcinoma worldwide. The aim of this study is to clarify whether these polymorphisms are associated with renal cell carcinoma in Taiwanese. Genomic DNA was isolated from normal and tumor tissues of 19 renal cell carcinoma patients. The samples were screened for allelic polymorphisms by restriction fragment length polymorphism with BsaJ I and Acc I digestion. Reconfirmation was carried out by direct sequencing. RESULTS: Consistent with Knudson's two-hit theory, AA to AG somatic mutations were observed in rs779805. In addition, loss of heterozygosity in both rs779805 and rs1642742 was demonstrated in 10 out of 15 RCC patients aged 50 or over. The G allele or AG heterozygote frequencies at these two loci were much higher in patient germline DNA when compared with the control group. After adjusting for age, the frequency of the G allele in both loci was much higher for late onset renal cell carcinoma in the Taiwanese population. CONCLUSIONS: Our current results confirmed that the existence of G allele in both rs779805 and rs1642742 in the von Hippel-Lindau tumor suppressor gene is of importance in renal cell carcinoma tumorigenesis. However, more comprehensive and detailed research is needed to address the clinical relevance. Larger sample size is required to determine the exact power of correlation between these two genetic polymorphisms and renal cell carcinoma.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Polimorfismo de Nucleotídeo Único , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Primers do DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Taiwan
13.
J Formos Med Assoc ; 110(10): 646-51, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21982469

RESUMO

BACKGROUND: The von Hippel-Lindau (VHL) tumor suppressor gene located on chromosome 3p25-26 is implicated in VHL disease. Two informative single nucleotide polymorphisms are at positions 19 and 1149 on the nucleotide sequence from Gene Bank NM_000551. In this study we examined the allele frequencies at these two loci in the Taiwanese population and compared the results to those from European ethnic populations. METHODS: The allele frequency was examined in 616 healthy individuals including 301 university students and 315 neonates. Both A/G polymorphisms were investigated using restriction fragment length polymorphism analysis created by restriction enzymes, BsaJ I and Acc I. RESULTS: Among these subjects, the allele frequencies at 19 SNP and 1149 SNP for variant G were 0.130 and 0.133, respectively. And these results were significant differences from those of the Caucasian populations. In addition, 90% of the tested subjects had identical genotypes at these two loci suggesting the existence of nonrandom association of alleles. CONCLUSION: We found that the G allele frequency at these two loci in the Taiwanese population is much lower than that in people from Western countries. This phenomenon may be attributed to ethnic effects.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Adulto , Alelos , Humanos , Recém-Nascido , Polimorfismo de Nucleotídeo Único , Taiwan , Adulto Jovem
14.
Int J Gynecol Pathol ; 30(6): 544-8, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21979590

RESUMO

Mature cystic teratomas are usually found in the ovaries and rarely in the uterus. Most teratomas of the uterus are of cervical origin. There are only a handful of reports to date of uterine teratomas arising from uterine corpus. The teratomas of the ovaries and the cervix are thought to be of parthenogenetic origin from oocyte after the completion of the first division. However, the origin of a uterine teratoma has not been established by molecular methods. In this study, we report a 46-year-old woman with a teratoma within uterine corpus. Computed tomography scanning and histological studies after tumor resection confirmed the diagnosis of teratoma. The DNA profiles of normal uterine tissue and teratoma tissue were compared using short tandem repeats analysis and showed that the teratoma did not originate from the parthenogenetic process. Our results suggest that the origin of this uterine teratoma is most likely pluripotential stem cell of uterus or primordial germ cell before meiosis I.


Assuntos
Teratoma/patologia , Neoplasias Uterinas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Reação em Cadeia da Polimerase , Teratoma/genética , Neoplasias Uterinas/genética
15.
J Formos Med Assoc ; 108(11): 886-93, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19933033

RESUMO

One of the known causal molecular events in renal cell carcinoma is somatic mutation in the von Hippel-Lindau (VHL) gene. Our study describes a 51-year-old Taiwanese man who had bilateral renal cell carcinoma. The patient underwent radical nephrectomy without postoperative chemotherapy or radiotherapy, and is still alive after renal transplantation without tumor recurrence after > 5 years. To clarify his predisposition for bilateral tumors, we performed molecular genetic analysis of the VHL gene in this study. Polymerase chain reaction-single-strand conformation polymorphism and direct sequencing were performed on DNA of blood samples and paraffin-embedded tumor specimens from this patient. DNA from peripheral blood lymphocytes tested negative for germline mutations. However, there were two heterozygous alleles in the promoter and 3 untranslated regions of this gene. Nonetheless, the DNA from his tumors showed loss of heterozygosity (LOH) in these two loci. In addition to the LOH, we identified some different somatic mutations in his tumor tissues: C287T and G460A in the right-sided tumor, and G244A and G390A in the left-sided tumor. The possible roles of these genetic polymorphisms and point mutations in his renal tumorigenesis are discussed. This report provides new insights into renal cell carcinoma that result from VHL gene alterations in Taiwan.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Mutação , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/genética , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
16.
J Assist Reprod Genet ; 26(5): 257-61, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19597981

RESUMO

PURPOSE: The lengths of CAG repeats in two spinocerebellar ataxia genes, SCA1 and SCA3, were analyzed to determine whether such repeats exist in higher numbers in infertile males. METHODS: Blood samples were collected from healthy controls, oligozoospermia patients, and azoospermia patients. DNA fragments containing target CAG repeats were amplified by PCR with template DNA purified from the blood samples. CAG repeats in PCR fragments were determined, using ABI PRISM 310 Gene Analyzer. RESULTS: In SCA1, the distribution of CAG repeats in oligozoospermic males was different from that of the control group: More alleles had a repeat number that exceeded 32. Conversely, for SCA3, the examined oligozoospermia and azoospermia patients exhibited no differences in distribution of CAG repeats in comparison with the control group. CONCLUSIONS: SCA1 in a subset of oligozoospermia patients has an increased number of CAG repeats.


Assuntos
Azoospermia/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Oligospermia/genética , Expansão das Repetições de Trinucleotídeos , Adulto , Alelos , Ataxina-1 , Ataxina-3 , Ataxinas , Estudos de Casos e Controles , Humanos , Infertilidade Masculina/genética , Masculino , Reação em Cadeia da Polimerase , Proteínas Repressoras/genética , Análise de Sequência de DNA , Fatores de Tempo
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