Browsing by Author "Wistuba Oyarzún, Ignacio"
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- ItemAberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis(American Association Cancer Research, 2004) Takahashi, Takao; Shivapurkar, Narayan; Riquelme Sánchez, Erick Marcelo; Shigematsu, Hisayuki; Reddy, Jyotsna; Suzuki, Makoto; Miyajima, Kuniharu; Zhou, Xian; Bekele, B. Nebiyou; Gazdar, Adi F.; Wistuba Oyarzún, IgnacioPurpose: Aberrant methylation of 5' gene promoter regions is an epigenetic phenomenon that is a major mechanism for silencing of tumor suppressor genes in many cancer types. There is limited information about the molecular changes involved in the pathogenesis of gallbladder carcinoma (GBC), including methylation status. Experimental Design: We investigated the aberrant promoter methylation profile of 24 known or suspected tumor suppressor genes in 50 GBCs and compared those results with the findings in 25 chronic cholecystitis (CC) specimens without cancer. The methylation-specific polymerase chain reaction and combined restriction analysis methods were used to detect methylation, and the results were confirmed by sequencing of cloned polymerase chain reaction products. Results: In GBC, gene methylation frequencies varied from 0% to 80%. Ten genes demonstrated relatively high frequencies of aberrant methylation: SHP1 (80%), 3-OST-2 (72%), CDH13 (44%), P-15(INK4B) (44%), CDH1 (38%), RUNX3 (32%), APC (30%), RIZ1 (26%), P16(INK4A) (24%), and HPP1 (20 %). Eight genes (P73, RARbeta2, SOCS-1, DAPK, DcR2, DcR1, HIN1, and CHFR) showed low frequencies (2-14%) of methylation, and no methylation of the remaining six genes (TIMP-3, P57, RASSF1A, CRBP1, SYK, and NORE1) was detected. In CC, methylation was detected for seven genes: SHP1 (88 %), P15(INK4B) (28 %), 3-OST-2 (12%), CDH1 (12 %), CDH13 (8 %), DcR2 (4 %), and P16(INK4A) (4%) Significantly higher frequencies of methylation in GBC compared with CC were detected for eight genes (3-OST-2, CDH13, CDH1, RUNX3, APC, RIZ1, P16(INK4A), and HPP1). Of those, four genes showed frequent methylation (>30%) in GBCs. The mean methylation index, an expression of the amount of methylated genes by case, was significantly higher in GBC (0.196 +/- 0.013) compared with CC (0.065 +/- 0.008; P < 0.001). Conclusions: Our study constitutes the most comprehensive methylation profile report available in GBC and demonstrates that this neoplasm has a distinct pattern of abnormal gene methylation. Whereas gallbladders from healthy individual were not available, our finding of methylation in CC cases without cancer suggests that this phenomenon represents an early event in the pathogenesis of GBC.
- ItemDetection of lymphatic micrometastases in patients with stages I and II colorectal cancer: Impact on five-year survival(2004) Kronberg, Udo; López Köstner, Francisco; Soto, Gonzalo; Zuñiga A., Alvaro; Wistuba Oyarzún, Ignacio; Miranda, Vanessa; Pinto, Eliana; Viviani García, Paola; Marshall Rivera, Guillermo
- ItemEpidemiology and Molecular Pathology of Gallbladder Cancer(2001) Lazcano-Ponce, Eduardo; Miquel Poblete, Juan Francisco; Muñoz, Nubia; Herrero, Rolando; Ferrecio, Catterina; Wistuba Oyarzún, Ignacio; Alonso de Ruiz, Patricia; Aristi Urista, Gerardo; Nervi Oddone, FlavioGallbladder cancer is usually associated with gallstone disease, late diagnosis, unsatisfactory treatment, and poor prognosis, We report here the worldwide geographical distribution of gallbladder cancer, review the main etiologic hypotheses, and provide some comments on perspectives for prevention. The highest incidence rate of gallbladder cancer is found among populations of the Andean area, North American Indians, and Mexican Americans. Gallbladder cancer is up to three times higher among women than men in all populations. The highest incidence rates in Europe are found in Poland, the Czech Republic, and Slovakia. Incidence rates in other regions of the world are relatively low. The highest mortality rates are also reported from South America, 3.5-15.5 per 100,000 among Chilean Mapuche Indians, Bolivians, and Chilean Hispanics. Intermediate rates, 3.7 to 9.1 per 100,000, are reported from Peru, Ecuador, Colombia, and Brazil. Mortality rates are low in North America, with the exception of high rates among American Indians in New Mexico (11.3 per 100,000) and among Mexican Americans.", "The main associated risk factors identified so far include cholelithiasis (especially untreated chronic symptomatic gallstones), obesity, reproductive factors, chronic infections of the gallbladder, and environmental exposure to specific chemicals. These suspected factors likely represent promoters of carcinogenesis. The main limitations of epidemiologic studies on gallbladder cancer are the small sample sizes and specific problems in quantifying exposure to putative risk factors. The natural history of gallbladder disease should be characterized to support the allocation of more resources for early treatment of symptomatic gallbladder disease in high-risk populations. Secondary prevention of, gallbladder cancer could be effective if supported by cost-effective studies of prophylactic cholecystectomy among asymptomatic gallstone patients in high-risk areas."]
- ItemExpression of insulin-like growth factor I receptor as a biomarker for predicting prognosis in biliary tract cancer patients(2015) Suzuki, Hideo; Roa Strauch, Juan Carlos Enrique; Kawamoto, Toru; Ishige, Kazunori; Wistuba Oyarzún, Ignacio; Li, Donghui; Thomas, Melanie B.; Shoda, Junichi
- ItemFragile histidine triad gene abnormalities in the pathogenesis of gallbladder carcinoma(2002) Wistuba Oyarzún, Ignacio; Ashfaq, Raheela; Maitra, Anirban; Álvarez Pando, Héctor Andrés; Riquelme Sánchez, Erick Marcelo; Gazdar, Adi F.There is limited information about the molecular changes involved in the pathogenesis of gallbladder carcinoma (GBC). Our recent allelotyping analyses have indicated that chromosome 3p loss of heterozygosity (LOH), including the fragile histidine triad (FHIT) candidate tumor-suppressor gene locus at 3p14.2, is frequently detected in this neoplasm. To investigate the role of the FHIT abnormalities in the multistage sequential development of GBC, 33 formalin-fixed paraffin-embedded invasive GBC specimens and 76 accompanying histologically normal (n = 43) and dysplastic (n = 33) epithelia were examined by nostaining for expression of Fhit protein. Allele loss at the FHIT gene locus (3p14.2) was studied in all GBCs and in a subset of accompanying gallbladder epithelia by polymerase chain reaction-based LOH analysis, using three 3p14.2 microsatellite markers. In addition, histologically normal epithelium from chronic cholecystitis (n = 19) and dysplasia (it = 13) from gallbladder specimens without cancer were examined for immunostaining and LOH. There was a progressive increase in both the frequency of loss of Fhit expression and LOH at FHIT with increasing severity of histopathological changes. FHIT abnormalities were occasionally demonstrated in histologically normal gallbladder epithelium. Dysplastic foci demonstrated frequent reduction or absence of Fhit immunostaining (38 to 55%) and FHIT allelic loss (33 to 46%). In invasive tumors, these abnormalities were even higher, with 79% reduction or absence of Fhit immunostaining and 76% FHIT allele loss. A high correlation (70%) was observed between Fhit immunostaining abnormalities and allele loss in GBC specimens (P < 0.05). Although a high frequency of FHIT locus breakpoints; were detected in both invasive and dysplastic gallbladder specimens, no intronic homozygous deletions on FHIT were detected in GBCs. FHIT gene abnormalities are nearly universal in GBC and these changes are detected early in the sequential development of this neoplasm. Our findings indicate that the FHIT gene is one of the chromosome 3p putative tumor suppressor genes involved in the pathogenesis of this highly malignant neoplasm.
- ItemHigh resolution chromosome 3p, 8p, 9q and 22q allelotyping analysis in the pathogenesis of gallbladder carcinoma(2002) Wistuba Oyarzún, Ignacio; Maitra, A.; Carrasco, R.; Tang, M.; Troncoso Carrasco, Pablo Arnoldo; Minna, J. D.; Gazdar, A. F.
- ItemRol patogénico del gen supresor de tumores PTEN en cáncer ovárico asociado a endometriosis(2006) Castiblanco Galvis, Adriana; Pires, Yumay; Wistuba Oyarzún, Ignacio; Riquelme Sánchez, Erick Marcelo; Andrade M., Leonardo; Corvalán R., AlejandroBackground: Endomeotrioid carcinoma and clear cell carcinoma of the ovary are associated to endometriosis. Somatic mutations of PTEN (10q23.3) are present in endothelial endometrioid carcinoma. Therefore, these mutations could be also present in ovarian tumors Molecular studies show that solitary endometriotic cysts are monoclonal, have aneuploid DNA, have a loss of 9p, 11q and 22q heterozygosity (LOH) and a higher cellular proliferation index of the epithelial component. Aim: To determine the cellular proliferation index using Ki 67, the immunohistochemical expression of PTEN and LOH in patients with ovarian endometriosis without atypia (EN), ovarian endometriosis with atypia (P-A) and endometriosis with adjacent ovarian carcinoma (0). Material and methods: Paraffin embedded samples of 37 endometrioid and clear cell carcinomas of the ovary (CC/CE), 15 solitary ovarian EN and 15 ovarian EA, were studied. Expression of Ki 67 and PTEN was measured by immunohistochemistry. LOH of 10q23-3 locus was measured by polymerase chain reaction. Results: Ki 67 was 5.5 and 23% in EA and EN, respectively (p < 0.005). There was a histological correlation between LA and a higher cellular proliferation index. PTEN was negative in 5 of 15 EN, 9 of 15 EA and 30 of 37 CE/CC. There was a correlation between LOH and loss of PTEN protein in EN, EA and ET(60%), Conclusions: Negative expression on PTEN in EN; EA; ET and CE/CC is a manifestation of the inactivation of this gene. The mechanisms that cause this inactivation, must be elucidated.