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Sanjay Kakar

Publications and source records attributed to Sanjay Kakar.

At least 19 recordsLinked to original sources
PubMed2006

Chromosomal instability in microsatellite-unstable and stable colon cancer.

PURPOSE: The genomic instability in colon cancer can be divided into at least two major types, microsatellite instability (MSI) or chromosomal instability (CIN). Although initially felt to be mutually exclusive, recent evidence suggests that there may be overlap between the two. The aim of this study was to identify chromosomal alterations at high resolution in sporadic colon cancers with high-level microsatellite instability (MSI-H) and to compare them to those present in a set of matched microsatellite stable (MSS) tumors. EXPERIMENTAL DESIGN: Array-based comparative genomic hybridization was used to analyze a set of 23 sporadic MSI-H and 23 MSS colon cancers matched for location, gender, stage, and age. The arrays consisted of 2,464 bacterial artificial chromosome clones. RESULTS: MSI and MSS colon cancers differed significantly with respect to frequency and type of chromosomal alterations. The median fraction of genome altered was lower among MSI-H tumors than MSS tumors (2.8% versus 30.7%, P=0.00006). However, the MSI-H tumors displayed a range of genomic alterations, from the absence of detectable alterations to extensive alterations. Frequent alterations in MSI-H tumors included gains of chromosomes 8, 12, and 13, and loss of 15q14. In contrast, the most frequent alterations in MSS tumors were gains of 7, 13, 8q, and 20, and losses of 8p, 17p, and 18. A small, previously uncharacterized, genomic deletion on 16p13.2, found in 35% of MSI-H and 21% of MSS tumors, was confirmed by fluorescence in situ hybridization. CONCLUSION: MSI and CIN are not mutually exclusive forms of genomic instability in sporadic colon cancer, with MSI tumors also showing varying degrees of CIN.

Adenocarcinoma↗
PubMed2006

HATH1 expression in mucinous cancers of the colorectum and related lesions.

PURPOSE: Mucinous cancers and signet ring carcinomas are distinct classes of colon cancers characterized by their production of copious quantities of intestinal goblet cell mucin, MUC2. Deletion of transcription factor HATH1 ablates the biogenesis of goblet cells in developing mouse intestine, and forced expression of HATH1 results in elevated expression of MUC2 in colon cancer cells. The aim of this study was to assess the possible role of HATH1 in the development of mucinous cancers and signet ring carcinomas. EXPERIMENTAL DESIGN: Immunohistochemistry and confocal microscopy was used to examine HATH1 expression and subcellular distribution in normal colon and small intestine, mucinous cancers, signet ring carcinomas, and nonmucinous cancers and in precursor lesions, including hyperplastic polyps, serrated adenomas, tubular adenomas, and villous adenomas. We also analyzed the transactivation of MUC2 promoter/reporter constructs by a HATH1 expression vector. RESULTS: HATH1 expression transactivated MUC2 promoter/reporter constructs, an activity that was significantly inhibited by mutation of putative HATH1-binding sites. HATH1 was expressed in the nuclei of goblet cells and in the cytoplasm and nuclei of enteroendocrine cells of the colon. In the small intestine, only cytoplasmic expression of HATH1 in enteroendocrine cells was detected. HATH1 was found to be strongly expressed in the nuclei of hyperplastic polyps, serrated adenomas, villous adenomas, mucinous cancers, and signet ring carcinomas but repressed in nonmucinous cancers and tubular adenomas. CONCLUSIONS: This study confirms the importance of HATH1 for the development of intestinal secretory cells. The results further suggest that HATH1 is an important factor in the up-regulation of MUC2 expression that occurs in mucinous cancers and signet ring carcinomas. In addition, the expression of HATH1 in hyperplastic polyps, serrated adenomas, and villous adenomas lends support to the hypothesis that these neoplasms are frequent precursors in mucinous cancer and signet ring carcinoma development.

Adenocarcinoma, Mucinous↗
PubMed2006

Regional hypermethylation and global hypomethylation are associated with altered chromatin conformation and histone acetylation in colorectal cancer.

Regional DNA hypermethylation and global DNA hypomethylation are 2 epigenetic alterations associated with colorectal cancers. However, their correlation with microsatellite instability (MSI) and chromosomal instability (CIN) in colorectal cancer, and their relationship with chromatin conformation and histone modification are not clear. In this study, we analyzed regional and global methylation in 16 cell lines and 64 primary colorectal cancers. We found that MSI and CIN are 2 alternative events in most cell lines and tumors. Furthermore, regional hypermethylation and global hypomethylation are also alternative events in most cases. We also observed a strong correlation between MSI and regional hypermethylation and between CIN and global hypomethylation. We further analyzed chromatin conformation and histone acetylation in cell lines with CIN or MSI. CIN cancers had open chromatin conformation and enriched histone acetylation in repetitive as well as in gene-specific regions. MSI cancers, on the other hand, had closed chromatin conformation and low levels of histone acetylation. After a MSI cell line was treated with 5-aza-2'-deoxycytidine or trichostatin A, the closed chromatin conformation became open, and histone acetylation was enriched. These observations support our hypothesis that in colorectal cancer, regional hypermethylation and global hypomethylation are associated with altered chromatin conformation and histone acetylation, which might have a causal correlation with MSI and CIN, respectively.

Acetylation↗
PubMed2006

BRAF mutation, CpG island methylator phenotype and microsatellite instability occur more frequently and concordantly in mucinous than non-mucinous colorectal cancer.

Mucinous colorectal cancer (CRC) has been reported to have distinct clinicopathological and genetic characteristics. However, the incidence and the relationship among microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and BRAF and KRAS mutations in mucinous and non-mucinous CRC are not known. Activating mutations of BRAF and KRAS and their relationship with MSI and CIMP were examined in 83 sporadic CRC specimens (26 mucinous and 57 non-mucinous CRC). MSI, CIMP, BRAF and KRAS mutation were observed in 17, 24, 25 and 36% of the tumors, respectively. BRAF mutation was highly correlated with MSI (p < 0.001) and CIMP (p < 0.001). A higher incidence of MSI (27% vs. 12%), CIMP (38% vs. 18%, p < 0.05) and BRAF mutation (46% vs. 16%, p < 0.01) was observed in mucinous CRC. KRAS mutation (27% vs. 40%) was observed more frequently in non-mucinous CRC. Significantly higher percentages of mucinous CRC (54%, p < 0.05) had MSI or CIMP or BRAF mutations. Concordant occurrence of 2 or more of these alterations was observed in 39% of mucinous CRC and only 11% of non-mucinous CRC (p < 0.01). The more frequent occurrence and closer association among MSI, CIMP and BRAF mutation in mucinous CRC observed in our study further supports the idea that its pathogenesis may involve distinct genetic and epigenetic changes.

Adenocarcinoma, Mucinous↗
PubMed2006

Epidermal growth factor receptor expression and gene copy number in fibrolamellar hepatocellular carcinoma.

Increased expression of epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase, is associated with tumor progression in many carcinomas. Epidermal growth factor receptor inhibitors have shown promise in treating some of these tumors. Fibrolamellar hepatocellular carcinoma (FL-HCC) is an aggressive neoplasm that occurs in young patients with no history of cirrhosis. This study examines the expression and gene copy number of EGFR in FL-HCC. Formalin-fixed, paraffin-embedded FL-HCC (n = 13) sections were stained with a monoclonal antibody against EGFR. Fluorescence in situ hybridization analysis was performed using probes against EGFR gene and centromeric region of chromosome 7 (CEP 7). Epidermal growth factor receptor and CEP 7 signals were counted in 50 tumor nuclei per case as well as 300 normal hepatocyte nuclei. The EGFR to CEP 7 signal ratio was calculated for each case. Most (92%, 12/13) of FL-HCC showed strong and diffuse staining with anti-EGFR antibody. Fluorescence in situ hybridization was informative in 11 cases, 10 of which showed extra EGFR gene copy numbers (mean, 3.69; range, 3.13-5.0). Epidermal growth factor receptor was overexpressed in all these cases. The mean number of EGFR signals per cell in FL-HCC was double that of normal hepatocytes (3.69 versus 1.80); the mean EGFR/CEP 7 ratio in tumor cells was 1.05. In conclusion, EGFR is strongly overexpressed on the cell membrane in nearly all cases of FL-HCC. Similar gains of chromosome 7 are observed, indicating that the extra EGFR gene copies are due to polysomy rather than gene amplification. The strong expression of EGFR in FL-HCC tumors suggests that they may respond to treatment with EGFR antagonists.

Adolescent↗
PubMed2006

Contributions to hepatic fibrosis in HIV-HCV coinfected and HCV monoinfected patients.

OBJECTIVES: The aim of this study was to further explore the severity of liver disease and its predictors in a cohort of hepatitis C virus (HCV) infected patients, some of whom were coinfected with the human immunodeficiency virus (HIV). METHODS: This is a retrospective, cross-sectional study of patients undergoing liver biopsy to stage HCV disease prior to consideration of anti-HCV therapy. RESULTS: A total of 92 HIV-HCV coinfected and 372 HCV monoinfected patients were included. As might be expected, coinfected patients differed from monoinfected patients in a number of ways, including having lower body mass index (BMI), and lower alcohol intake. Liver disease was very similar between the two groups, with mean fibrosis score of 1.45 u for coinfected and 1.53 u for monoinfected (p = NS). Histological inflammation score dominated multivariate models of fibrosis when it was included in them. When only clinical predictors were used in multivariate models, BMI and type 2 diabetes had independent associations in monoinfected patients, whereas low CD4 count, current or nadir, was the only variable with an independent association in coinfected patients. CONCLUSIONS: Coinfected patients do not have uniformly worse liver disease than monoinfected patients. Immune compromise plays an important role in liver disease in coinfected patients, and the role of other clinical factors in liver disease may differ between these two groups, as well.

Biopsy↗
PubMed2005

The relationship between global methylation level, loss of heterozygosity, and microsatellite instability in sporadic colorectal cancer.

PURPOSE: The relationship between global hypomethylation, chromosomal instability (CIN), and microsatellite instability (MSI) remains unclear in colorectal cancer. The aim of this study was to investigate the relationship between global methylation status, loss of heterozygosity (LOH), and MSI in sporadic colorectal cancer. EXPERIMENTAL DESIGN: We determined global methylation levels in 80 sporadic colorectal cancers, 51 adjacent normal tissues, and 20 normal tissues using the long interspersed nucleotide elements-combined bisulfite restriction analysis method. We also analyzed 80 colorectal cancers for MSI status and LOH at chromosomes 5q21, 8p12-22, 17p13, and 18q21. RESULTS: We identified 14 cases of MSI (17.5%) and 58 cases of LOH (72.5%). LOH was observed more frequently in microsatellite stable (MSS) cancers than in MSI cancers at all loci. Colorectal cancers showed significantly lower global methylation levels than did normal tissues (41.0+/-9.7% versus 54.3+/-6.5%; P<0.001). MSS cancers showed significantly lower global methylation levels when compared with MSI cancers (39.5+/-9.4% versus 48.2+/-8.2%; P=0.003). Tumors with global hypomethylation (with <or=40% of methylation levels) had a significantly increased number of chromosomal loci with LOH than did tumors without global hypomethylation (1.9 versus 0.9; P<0.001); 11 tumors (13.9%) lacked both MSI and LOH. This subgroup had significantly higher global methylation levels (46.8+/-8.7%) than did MSS cancers with LOH (38.0+/-9.0%; P=0.006). CONCLUSIONS: These data showed a significant association between global hypomethylation and chromosomal instability in sporadic colorectal cancer. This suggests that global hypomethylation plays an important role in inducing genomic instability in colorectal carcinogenesis.

Adult↗
PubMed2005

Array-based comparative genomic hybridization reveals recurrent chromosomal aberrations and Jab1 as a potential target for 8q gain in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide. We have previously characterized global gene expression patterns in HCC using microarrays. Here, we report the analysis of genomic DNA copy number among 49 HCC samples using BAC array-based comparative genomic hybridization (CGH). We observed recurrent and characteristic chromosomal aberrations, including frequent DNA copy number gains of 1q, 6p, 8q and 20q, and losses of 4q, 8p, 13q, 16q and 17p. We correlated gene expression with array CGH data, and identified a set of genes whose expression levels correlated with common chromosomal aberrations in HCC. Especially, we noticed that high expression of Jab1 in HCC significantly correlated with DNA copy number gain at 8q. Quantitative microsatellite analysis further confirmed DNA copy number gain at the Jab1 locus. Overexpression of Jab1 in HCC was also validated using real-time RT-PCR, and Jab1 protein levels were studied by immunohistochemistry on tissue microarrays. Functional analysis in HCC cell lines demonstrated that Jab1 may regulate HCC cell proliferation, thereby having a potential role in HCC development. In conclusion, this study shows that array-based CGH provides high resolution mapping of chromosomal aberrations in HCC, and demonstrates the feasibility of correlating array CGH data with gene expression data to identify novel oncogenes and tumor suppressor genes.

COP9 Signalosome Complex↗
PubMed2005

Hepatic steatosis in HIV/hepatitis C coinfection: prevalence and significance compared with hepatitis C monoinfection.

Liver disease in patients coinfected with HIV and hepatitis C virus (HCV) has received increasing attention in recent years. Steatosis is accepted as an important contributor to liver disease in patients with HCV, but despite coinfected patients having several reasons to have steatosis, the prevalence and significance of such changes has received scant attention. We examined steatosis in an unselected cohort of coinfected patients and compared its prevalence and predictors with findings in monoinfected patients, where these relationships have been established. We studied 92 coinfected and 372 monoinfected patients undergoing staging liver biopsy. Baseline characteristics of the two groups differed significantly, pointing at different contributors to steatosis in each. Histological inflammation and fibrosis were very similar in the two groups, but steatosis was less in coinfected patients. Steatosis had a univariate association with fibrosis in both groups, but retained a multivariate association only in monoinfected patients. Other multivariate predictors of steatosis in monoinfected patients were the accepted variables of elevated body mass index, male sex, and genotype 3a infection, as well as age. In coinfected patients, however, age was the only multivariate predictor. Undetectable HIV viral load was associated with steatosis in coinfected patients in univariate analysis, but highly active antiretroviral therapy or its individual components could not be initially linked to steatosis. In conclusion, steatosis is less common in HIV/HCV coinfected patients than similar HCV monoinfected patients, and predictors of steatosis differ between the two groups.

Adult↗
PubMed2005

Signet ring cell carcinoma of the colorectum: correlations between microsatellite instability, clinicopathologic features and survival.

Colorectal cancer with microsatellite instability has a characteristic clinicopathologic profile, featuring right-sided, lymphocyte-rich tumors with a better prognosis than microsatellite stable (MSS) carcinoma. Mucinous and signet ring cell carcinomas are both over-represented among microsatellite instability-high cancers. The clinicopathologic features of mucinous microsatellite instability-high cancer parallel those of the overall microsatellite instability-high set, but it is not known whether the same is true for signet ring cell carcinoma, particularly given the fact that signet ring histology is a well-documented adverse prognostic factor. We recorded age, sex, tumor size, site, grade, stage, histologic pattern, growth pattern, Crohn-like reaction, vascular invasion and tumor-infiltrating lymphocytes in 72 resected signet ring cell carcinomas of the colorectum. Microsatellite instability was determined by a combination of polymerase chain reaction and immunohistochemical stains for hMLH1, hMSH2 and hMSH6. Tumors with instability at >30% of informative markers and/or loss of hMLH1 or hMSH2 expression were designated microsatellite instability-high; all others were classified as MSS. A total of 22 (31%) signet ring cell carcinomas were microsatellite instability-high. Compared to MSS signet ring cell carcinoma, they were more likely to be right-sided (81 vs 45%, P=0.005) and to affect older patients (68 vs 26%, P=0.0007) of female sex (59 vs 28%, P=0.03). Crohn-like reaction (45 vs 16%, P=0.02) and high tumor infiltrating lymphocyte counts (32 vs 8%, P=0.03) were more common in the microsatellite instability-high setting. There was no significant difference in 5-year survival in microsatellite instability-high vs MSS patients (41 vs 34%, P=0.3). In conclusion, approximately one-third of signet ring carcinomas of the colorectum are microsatellite instability-high. Microsatellite instability-high signet ring carcinomas share clinicopathologic features with other microsatellite instability-high cancers: older age group, female preponderance, right-sided location, Crohn-like reaction and numerous tumor-infiltrating lymphocytes. Microsatellite instability status does not appear to be a significant predictor of survival in signet ring cell carcinoma of the colorectum.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Clinicopathologic features and survival in fibrolamellar carcinoma: comparison with conventional hepatocellular carcinoma with and without cirrhosis.

Fibrolamellar carcinoma arises in noncirrhotic livers of young individuals and has been considered to be less aggressive than conventional hepatocellular carcinoma. This study compares survival and clinicopathologic features of fibrolamellar carcinoma with hepatocellular carcinoma arising in noncirrhotic and cirrhotic livers. Clinical and pathologic features including age, gender, tumor size, stage and survival were recorded in 20 resected cases of fibrolamellar carcinoma. Survival was compared with resected hepatocellular carcinoma without (n=32) and with cirrhosis (n=30). Proliferative activity was determined by immunohistochemistry for Ki-67. In all, 12 (60%) patients with fibrolamellar carcinoma died during follow-up; the 5-year survival was 45%. Mortality in fibrolamellar carcinoma was higher with metastatic disease at presentation (6/7, 86% vs 5/13, 39%, P=0.06). Age, gender and tumor size did not correlate with survival. The 5-year (45 vs 56%, P=0.4) as well as overall survival (40 vs 56.3%, P=0.3) was similar in fibrolamellar carcinoma and hepatocellular carcinoma without cirrhosis. The 5-year and overall survival in hepatocellular carcinoma with cirrhosis was 27 and 23.3%, respectively, which was not significantly different compared to fibrolamellar carcinoma (P=0.2). Among the cases without metastases at presentation, 5-year survival in fibrolamellar carcinoma (62%) and hepatocellular carcinoma without cirrhosis (57%) was significantly better (P=0.03) than hepatocellular carcinoma with cirrhosis (27%). The mean Ki-67 index was similar in all three groups (P=0.1). In conclusion, fibrolamellar carcinoma is an aggressive neoplasm with 45% 5-year survival and overall mortality of 60%. Nearly half the patients develop lymph node or distant metastasis. The prognosis of fibrolamellar carcinoma is similar to conventional hepatocellular carcinoma. Among nonmetastatic cases, the prognosis is better in fibrolamellar carcinoma and hepatocellular carcinoma without cirrhosis compared to hepatocellular carcinoma with cirrhosis. The better outcome in fibrolamellar carcinoma appears to be due to the absence of cirrhosis rather than its distinct clinicopathologic features.

Adolescent↗
PubMed2005

Prognostic significance of DCC and p27Kip1 in colorectal cancer.

The progression of colorectal cancer is a multistage process associated with specific molecular alterations. The stepwise accumulation of these multiple genetic mutations progressively results in the acquisition of neoplastic cell behavior. The genetic abnormalities associated with the expression of metastatic phenotype, therefore, may be of prognostic significance in the clinical treatment of colorectal cancer patients. In this study, the immunohistochemical expression of the deleted in colorectal cancer gene (DCC) and p27Kip1 was assessed in 168 paraffin-embedded, formalin-fixed tumors of patients with stage II and III colorectal cancer. Kaplan-Meier survival curves and log-rank statistics were used to analyze survival times after curative primary tumor resection, and Cox proportional hazards models were used to adjust the assessment of demographic and clinical covariates. Loss of DCC or p27Kip1 expression had no influence on survival in patients with stage II or III colorectal cancer. The 5-year survival rates of DCC-positive and DCC-negative tumors were 51.8% and 35.7% (P=0.40), respectively. The 5-year survival rate of patients with p27Kip1-positive tumors was 47.9%, whereas the rate for patients with p27Kip1-negative tumors was 38.8% (P=0.68). After adjustment for all evaluated variables, neither DCC or p27Kip1 was found to be a predictor of survival (risk ratio for DCC, 0.98; 95% confidence interval, 0.66-1.56; P=0.92; risk ratio for p27Kip1, 0.87; 95% confidence interval, 0.58-1.29; P=0.49). The present study demonstrated that the expression of neither DCC nor p27Kip1 was predictive in poor survival outcome in patients with stage II or III colorectal cancer.

Biomarkers, Tumor↗
PubMed2005

Low rate of microsatellite instability in young patients with adenomas: reassessing the Bethesda guidelines.

BACKGROUND AND AIM: Screening adenomas for microsatellite instability (MSI) in patients younger than 40 yr of age has been recommended by the Bethesda Guidelines as a means of identifying patients at risk for hereditary nonpolyposis colorectal cancer (HNPCC). We sought to determine the rate of MSI in adenomas removed from individuals under 40 yr of age over a 5-yr period in a university general gastroenterology practice. METHODS: We identified patients between 18 and 39 yr of age with endoscopically removed adenomatous colorectal polyps. Patients with polyposis syndromes, inflammatory bowel disease, or colorectal carcinoma were excluded. A three-generation family history was obtained via telephone interview. Endoscopic and histology reports were reviewed. Adenomas were tested for MSI using the BAT26 and BAT40 microsatellite markers, and expression of the MSH2 and MLH1 proteins was assessed by immunostaining. RESULTS: A total of 34 patients had 46 adenomas removed endoscopically. Out of 34 patients, 14 (41%) had a family history of colorectal cancer and 3 were from Amsterdam criteria positive families. A total of 28 of 46 adenomas (61%) were distal to the splenic flexure. Polyps ranged in size from 2 to 20 mm and averaged 6.6 mm. Five polyps (11%) were tubulovillous adenomas, and the remainder were tubular adenomas. None of the polyps were serrated adenomas and none demonstrated high-grade dysplasia. Among the 40 adenomas available for testing, none demonstrated MSI using either BAT26 (0/40) or BAT40 (0/21), nor did any of the polyps tested demonstrate loss of either MSH2 or MLH1 expression (0/16). CONCLUSION: Screening adenomas from patients younger than 40 yr of age for MSI was ineffective in identifying potentially new cases of HNPCC. New strategies that improve on the current clinical and molecular screening methods should be developed so that at-risk individuals can be identified and referred for germline testing before developing their first cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Accuracy of liver fat quantification at MR imaging: comparison of out-of-phase gradient-echo and fat-saturated fast spin-echo techniques--initial experience.

PURPOSE: To retrospectively determine the relative accuracy of liver fat quantification with out-of-phase gradient-echo magnetic resonance (MR) imaging and fat-saturated fast spin-echo MR imaging in patients with and without cirrhosis, with histologic analysis as the reference standard. MATERIALS AND METHODS: Committee on Human Research approval was obtained. Patient consent was not required. Data collection ended before HIPAA regulations were implemented, but patient anonymity was maintained. Twenty-seven patients, 16 with cirrhosis, were retrospectively identified who underwent MR imaging before histopathologic evaluation of liver fat at biopsy or surgery. The patient population consisted of 15 male and 12 female patients (mean age, 55 years; range, 16-75 years). One radiologist blinded to the histopathologic results recorded mean signal intensity derived from three regions of interest placed in the right and left lobes of the liver on three sections and signal intensity of the spleen from one region of interest within the same section. Liver fat was quantified with the relative loss of signal intensity on out-of-phase images compared with that on in-phase T1-weighted gradient-echo images and with relative loss of signal intensity on T2-weighted fast spin-echo MR images obtained with fat saturation compared with those obtained without fat saturation. Hotelling t test was used to compare correlation coefficients between relative signal intensity differences and histopathologically determined percentage of fat. RESULTS: In patients without cirrhosis, liver fat quantification with fat-saturated fast spin-echo MR imaging was significantly better than it was with out-of-phase gradient-echo MR imaging (r = 0.92 vs 0.69, P < .01). In patients with cirrhosis, liver fat quantification was correlated only with fat-saturated fast spin-echo MR imaging (r = 0.76, P < .01); the relative signal intensity loss on out-of-phase gradient-echo MR images was not correlated with histopathologically determined percentage of fat (r = 0.25, P = .36). CONCLUSION: Preliminary results suggest liver fat may be more accurately quantified with fat-saturated fast spin-echo MR imaging than with out-of-phase gradient-echo MR imaging, especially in patients with cirrhosis.

Adolescent↗
PubMed2005

Mucinous carcinomas of the colorectum have distinct molecular genetic characteristics.

We compared the frequency of CpG island methylation phenotype (CIMP), inactivation of APC, p53 and DCC genes and K-ras and BRAF mutations in 39 mucinous carcinomas (MC) and 34 non-mucinous carcinomas (NMC) of the colorectum with different microsatellite instability (MSI) status. The higher incidence of MSI (36% vs. 18%) was observed in MC compared with NMC. APC inactivation and K-ras mutations occurred more frequently in NMC (APC, 88%, p<0.001; K-ras, 58%, p=0.01) than in MC (APC, 24%; K-ras, 28%) regardless of MSI status. BRAF mutation occurred at a higher frequency in MC (18%, p=0.01) than in NMC (0%). However, with respect to inactivation of p53 and DCC, MSI status did matter and in both NMC and MC, more frequent inactivation of p53 and DCC was observed in MSS tumors than in MSI tumors. MSS tumors of NMC had a higher frequency of p53 (58% by IHC, p=0.03 and 83% by LOH, p=0.02) and DCC inactivation (83%, p=0.02) compared to MSI tumors of NMC (p53, 33% by IHC and 20% by LOH; DCC, 20%). MSS tumors of MC also showed a higher frequency of p53 and DCC inactivation (p53, 45% by IHC, p=0.02 and 53% by LOH, p=0.005; DCC, 82%, p=0.001) compared to MSI tumors of MC (p53, 0% by IHC and 0% for LOH; DCC, 17%). MC showed a higher frequency of CIMP compared with NMC (41% vs. 11%, p=0.01). These results indicate that mucinous carcinomas of the colorectum exhibit distinct molecular genetic characteristics and may arise from distinct pathogenic pathways.

Adenocarcinoma, Mucinous↗
PubMed2005

Expression of mucin core proteins, trefoil factors, APC and p21 in subsets of colorectal polyps and cancers suggests a distinct pathway of pathogenesis of mucinous carcinoma of the colorectum.

Mucin core proteins are expressed in a tissue and cell type specific manner in the normal gastrointestinal tract. Aberrant expression of mucin core proteins have been reported in colorectal neoplasms. To examine the relationship between subsets of colorectal polyps and non-mucinous and mucinous adenocarcinomas of the colorectum, we evaluated the frequency of the expression of cell lineage associated mucin core proteins (MUC5AC and MUC2), trefoil factors (TFF1 and TFF3), and APC and p21 in these tissues. An immunohistochemical study was performed in 10 normal rectal mucosa samples (NM) 21 hyperplastic polyps (HP), 20 serrated adenomas (SA), 25 tubular adenomas (TA), 13 tubulovillous adenomas (TVA), 7 villous adenomas (VA), 42 non-mucinous colorectal cancers (NMC), and 19 mucinous colorectal cancers (MC). A higher frequency of ectopic expression of gastric foveolar mucin, MUC5AC, and the expression of intestinal goblet cell mucins, MUC2, was observed respectively in HP (100%, 100%), SA (85%, 85%), TVA (85%, 85%), and VA (100%, 100%), compared to TA (32%, p<0.002; 36%, p<0.01). MC (68%, 100%) also showed a higher frequency of the expression of MUC5AC and MUC2 compared to NMC (31%, p=0.001; 38%, p<0.001), and TFF1 showed similar patterns of expression. APC protein and p21 were also expressed at a higher frequency in HP (100%, 100%), and SA (67%, 83%), than in TA (29%, p<0.03; 46%, p<0.05). MC (68%, 100%) showed a higher frequency of expression of APC protein and p21 than NMC (19%, p<0.001; 45%, p<0.01). Our results showed that MUC2 expression and de novo ectopic expression of MUC5AC and TFF1 are more frequent in HP, SA, TVA, VA, and MC than in TA and NMC. These results suggest that simultaneous activation of differentiation pathways of goblet cells and gastric foveolar cells may occur predominantly in the pathogenesis of HP, SA, TVA, VA, and MC, while the pathogenesis of TA and NMC are less likely to involve these processes.

Adenocarcinoma↗
PubMed2004

Histologic changes mimicking biliary disease in liver biopsies with venous outflow impairment.

Impairment of venous outflow from the liver manifests as zone 3 sinusoidal dilatation and congestion (SDC) in liver biopsy. The spectrum of histologic changes in portal tracts has not been described. We studied liver biopsies from 34 patients with a confirmed diagnosis of venous outflow impairment (VOI). Liver transplant recipients and biopsies with cirrhosis and hepatic neoplasms were excluded. Clinical records were reviewed for laboratory tests and radiographic findings. In all, 19 patients had right heart disease, 13 had classic Budd-Chiari syndrome and two had veno-occlusive disease. Liver chemistry tests showed elevated liver transaminases (n=21; 61.8%), elevated alkaline phosphatase (n=31; 91.2%) and GGT (all 13 cases tested). The elevation in ALT and AST was mild (below 200 U/l in all cases), while alkaline phosphatase (ALP) was elevated above 500 U/l in nine (26.5%) patients and above 1000 U/l in three cases. On biopsy, all cases showed SDC. The portal tracts showed (a) portal expansion with bile ductular proliferation (n=16; 47.1%) accompanied by lymphoplasmacytic infiltrate (n=10), lymphocytic cholangitis (n=3) and portal or periportal fibrosis (n=11), (b) Portal and/or periportal fibrosis without ductular proliferation (n=3; 8.8%) or (c) Normal portal tracts (n=15; 44.1%). The combination of elevated ALP and bile ductular changes on biopsy suggested chronic bile duct disease. Ultrasound/CT scan evaluation of bile ducts in 26 patients showed no biliary tree abnormality. Antimitochondrial antibody testing in eight cases also yielded negative results. In conclusion, bile ductular proliferation, portal inflammation and portal-based fibrosis are commonly seen in liver biopsies of patients with VOI even in the absence of bile duct disease. These changes are often accompanied by elevated ALP and GGT and can lead to the suspicion of chronic biliary disease. In the absence of demonstrable abnormalities in the biliary tree, these changes can be attributed to venous outflow impairment.

Biliary Tract Diseases↗