Biomedical subjects

Arndt Hartmann

Publications and source records attributed to Arndt Hartmann.

At least 55 records · Page 3Linked to original sources

PubMed2005

A large, erosive intraspinal and paravertebral gout tophus. Case report.

Symptomatic gout tophi of the spine are a rare but well-characterized complication of tophaceous gout. The authors report the case of a 29-year-old previously healthy man who presented with L-5 radiculopathy. Lumbar magnetic resonance (MR) imaging revealed a 4.5 x 4.5 x 2.8-cm large gout tophus mimicking a malignant spinal tumor or abscess. The tophus completely destroyed both L-4 and L-5 facet joints and the left L-4 lamina and spread epidurally from L-3 to L-5, compressing the left L-5 nerve root. There has been no similar case reported so far with respect to the extent of bone destruction. The authors describe the case history and present intraoperative, MR imaging, and histological findings.

Abscess↗

PubMed2005

Lack of association between the functional CX3CR1 polymorphism V249I and hepatocellular carcinoma.

Chemokine production by cancer cells constitutes a duality. Leukocyte recruitment under the pressure of chemokines may be beneficial for the host or for the tumor. Recently, the chemokine fractalkine and its receptor CX3CR1 have been shown to be expressed in hepatocytes in vivo and in a human hepatocarcinoma cell line in vitro. Therefore, the aim of this study was to analyze the expression of CX3CR1 in hepatocellular carcinoma (HCC) in vivo and to investigate the prevalence of the genetic CX3CR1 polymorphism V249I in HCC patients since this polymorphism has been associated with reduced number of fractalkine binding sites, reduced cell-cell adhesion and decreased signaling and chemotaxis. Genotyping was performed in 183 patients with histologically proven HCC and 99 healthy controls by RFLP-analysis. The frequency of the individual genotypes was similar in HCC patients and controls. The V249I polymorphism revealed no association with tumor grade and stage, the presence of extrahepatic metastasis or the degree of fibrosis in non-tumorous tissue. In addition to genotyping, CX3CR1 mRNA expression was analyzed by quantitative PCR in 9 HCC specimens and in 6 cases in corresponding non-tumorous liver tissues. CX3CR1 mRNA expression levels in HCC showed high variation between individual patients. Similarly, expression in HCC compared to non-tumorous liver varied, from strong downregulation to remarkable upregulation. CX3CR1 mRNA expression levels showed no correlation to the V249I polymorphism. In summary, these results suggest that the patho-physiological role of individual chemokines in carcinogenesis may vary and that the functional CX3CR1 polymorphism V249I is no genetic risk factor for HCC. However, additional independent studies in HCC patients with different ethnic background will be needed to confirm the present study and to elucidate the functional role of CX3CR1 and its polymorphism V249I in chronic liver disease and hepatocarcinogenesis.

Aged↗

PubMed2005

Multitarget FISH and LOH analyses at chromosome 3p in non-small cell lung cancer and adjacent bronchial epithelium.

Multitarget fluorescence in situ hybridization (FISH; LAVysion, Vysis, Downers Grove, IL) targeting chromosomes 6p11-q11, 7p12, 8q24, and 5p15.2 was compared with results of microsatellite studies at chromosome 3p to identify molecular changes associated with tobacco use and tumor development in non-small cell lung cancer (NSCLC). Analyses were performed on 26 NSCLCs and matched benign bronchial epithelium; samples from 10 patients without NSCLC served as control samples. Significant molecular differences between tumor tissue and corresponding benign bronchi were found using FISH (P = .001) and loss of heterozygosity (LOH) analysis (P = .031). Bronchial epithelium from patients with NSCLC was genetically different from epithelium from patients without NSCLC in FISH analysis (P = .025). Receiver operating characteristic curve analysis revealed an optimal cutoff value of 5% atypical cells for bronchial epithelium. There was no statistical correlation with the patient's smoking history, and LOH analysis of bronchi did not differentiate between patients with and without NSCLC. Multicolor FISH analysis is able to detect a tumor-associated molecular field effect in bronchi adjacent to NSCLC.

Adult↗

PubMed2005

High-throughput tissue microarray analysis of COX2 expression in urinary bladder cancer.

To investigate whether protein expression of cyclooxygenase 2 (COX2) is associated with tumor phenotype, immunohistochemical alterations, and clinical outcome in urinary bladder cancer (BC). Tissue microarrays (n = 776) were used to analyze COX2, P53 and the Ki-67 labeling index immunohistochemically. A monoclonal mouse antibody was used after heat-induced antigen retrieval. COX2 expression was scored semiquantitatively (0-3+). COX2 expression was detected in 60% (368/617) of urothelial BC. Positive COX2 staining was seen in 77.8% (140/182) of muscle invasive urothelial BC, compared to 35% (7/20) of muscle invasive squamous cell carcinomas (p < 0.001). COX2 protein expression was associated with advanced tumor stage (p < 0.0001), high-grade histology (p < 0.0001), solid growth pattern in invasive BC (pT1-4, p = 0.02), high Ki-67 labeling index (p < 0.0001), and positive P53 IHC (p < 0.001). COX2 expression was not associated with survival, recurrence, and progression in clinically relevant subgroups (pTa, pT1, pT2-4). Expression of COX2 is common in advanced BC with poor prognostic characteristics, supporting efforts to initiate clinical trials on the efficacy of COX2 inhibitors in the adjuvant treatment of high-risk urinary BC.

Aged↗

PubMed2005

Deletions at chromosome 2q and 12p are early and frequent molecular alterations in bronchial epithelium and NSCLC of long-term smokers.

Most lung cancer is attributed to long-term smoking. In order to define chromosomal regions with an accumulation of smoking-related early molecular damage, we applied 15 microsatellite markers at 8 chromosomal regions (2q35-q36, 3p21.3, 3p14.2, 3p25, 10q11.2, 11p14-15, 12p13.1-p12.3 and 12q14) in an allelotyping study. We studied samples of 42 patients with primary non-small cell lung cancer (NSCLC) (25 squamous cell carcinomas, 13 adenocarcinomas, 2 large cell and 2 bronchioalveolar carcinomas) to compare the frequency of allelic loss in cancer tissue of smokers with matched bronchial epithelium. As a control group we used 11 samples of non-smokers. In NSCLC we found significantly higher frequencies of loss of heterozygosity (LOH) than in matched tumor free bronchial epithelium (p = 0.007). Most frequently, allelic loss was detected in NSCLC at chromosome 3p [3p25 (46%), 3p21.3 (45%), 3p14 (40%)], at 2q35 (24%), 12p12 (29%) and 12q14 (13%), but infrequently at 10q11 (7%) and 11p14-15 (5%). In corresponding histological normal bronchial epithelium, the highest percentage of LOH was found at chromosome 3p [3p21 (17%), 3p25 (12%), 3p14 (9%)] and chromosome 2q (2q35-q36) (17%) and 12p (12p12-p13) (12%). LOH in histologically normal bronchial epithelium was significantly associated with long-term smoking (p = 0.048), especially at chromosome 12p12 (p = 0.018). Our results demonstrate two further deletion hot spots at the chromosomal region 2q35-q36 and 12p12-p13 in tumor tissue of NSCLC and matched histological normal bronchial epithelium of long-term smokers, reflecting a phenomenon referred to as 'field cancerization'. These chromosomal regions represent interesting loci for potential NSCLC associated tumor suppressor genes and could be useful as screening markers for molecular risk assessment of smokers.

Adult↗

PubMed2004

Different types of microsatellite instability in ovarian carcinoma.

Microsatellite instability at mono- and dinucleotide repeats is the hallmark of the hereditary non-polyposis cancer syndrome (HNPCC) and is related to deficient DNA mismatch repair. In contrast, a distinct form of microsatellite instability at selective tetranucleotide repeats (EMAST or elevated microsatellite alterations at selected tetranucleotides) was described in several non-HNPCC cancer types. EMAST is probably unrelated to mismatch repair defects. We investigated the frequency of microsatellite instability at mononucleotide, dinucleotide and tetranucleotide repeats in a series of 75 ovarian carcinomas (53 serous and 22 non-serous). Microsatellite analysis was carried out using 5 mono- and dinucleotide markers from the National Cancer Institute Consensus Panel and 6 tetranucleotide markers, which have been reported as frequently unstable in the literature. High frequency of microsatellite instability (MSI-H) at mono- and dinucleotide repeats was observed in 9% and a low frequency (MSI-L) in 21% of serous carcinomas. MSI-H was detected in 4% and MSI-L in 18% of non-serous carcinomas. Nine percent of serous carcinomas showed instability at multiple and 9% at single tetranucleotide loci. All non-serous carcinomas were stable at tetranucleotide loci. In summary, EMAST (e.g., tumors with tetranucleotide instability without concomitant MSI-H) was observed in 13% of ovarian serous carcinomas. All EMAST positive tumors were of advanced stage. We conclude that EMAST occurs as a distinct form of microsatellite instability in ovarian cancer. EMAST seems to be particularly frequent in advanced serous carcinomas. Its clinical significance needs to be investigated.

Carcinoma↗

PubMed2004

Microsatellite instability predicts poor short-term survival in patients with advanced breast cancer after high-dose chemotherapy and autologous stem-cell transplantation.

PURPOSE: The purpose is to define molecular prognostic factors in patients with advanced breast cancer treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). EXPERIMENTAL DESIGN: Thirty-nine patients with breast cancer and extensive lymph node (level III) and/or systemic metastases from a prospective single-center study of sequential HDCT/ASCT were studied. Microsatellite analysis was performed after laser microdissection using 15 markers selected for sensitive detection of microsatellite instability (MSI) in breast cancer. Exons 5-9 of the P53 gene were directly sequenced. Expression of P53, HER-2/neu, and the mismatch repair proteins hMSH2 and hMLH1 was evaluated by immunohistochemistry. RESULTS: MSI of at least three markers was detected in 13 of 39 patients (33%) and was predominantly found at tetranucleotide markers. All MSI-positive tumors showed normal expression of hMSH2 and hMLH1. Complete sequence analysis of exons 5-9 of the P53 gene was successful in 34 cases; 18% (n = 6) revealed a mutation. Overexpression of HER-2/neu and P53 was observed in 7 (22%) and 12 (46%) of 26 evaluated cases, respectively. The presence of MSI strongly correlated with shorter overall survival (OS; P = 0.0004) and progression-free survival (PFS; P = 0.02). None of the other investigated clinical or molecular factors correlated with OS in univariate analyses, with the exception of menopausal status and previous adjuvant chemotherapy. Testing various multivariate Cox regression models, MSI remained a highly significant, independent, and adverse risk factor for OS. CONCLUSIONS: MSI is frequent in advanced breast cancer and could be an indicator of chemotherapy resistance and poor prognosis in breast cancer patients treated with HDCT/ASCT.

Adult↗

PubMed2004

Gene expression profiling of colorectal cancer and metastases divides tumours according to their clinicopathological stage.

Gene expression profiling of matched colorectal carcinomas and metastases could reveal key molecular events involved in tumour progression and metastasis. Expression profiles have been created from 25 colorectal carcinomas (CRCs, pT1-4), corresponding normal colonic mucosa, and 14 liver metastases using cDNA arrays containing 1176 cancer-related genes (Clontech). Hierarchical clustering clearly distinguished carcinomas from non-cancerous tissues, separated tumours into high-stage (pT4 and extensive lymph node or distant metastases) and low-stage (< or =pT3) groups, and correlated with the histopathological classification in 87% (33/38 cases). Most primary tumours and matched liver metastases clustered on terminal branches of the dendrogram. Statistical analysis (Mann-Whitney U-test) revealed 40 tumour-specific genes (29 up-regulated, 11 down-regulated) which allowed identification of malignant tissue samples by cluster analysis. A specific expression signature in matching metastases was not found, but a set of 23 classifier genes with statistically significant expression patterns in high- and low-stage tumours was identified. These genes may represent important targets in colorectal carcinogenesis and might provide useful clinicopathological tools in the management of colorectal cancer.

Adenocarcinoma↗

PubMed2004

Deletions of chromosome 8p and loss of sFRP1 expression are progression markers of papillary bladder cancer.

Many molecular alterations are known to occur in urothelial carcinoma of the bladder, but their significance for tumor progression is poorly understood. Deletions of chromosome 8p are frequently found in several tumor types and are often associated with progressive disease. In all, 99 bladder tumors were screened for deletions at 8p using loss of heterozygosity (LOH) and multicolor fluorescence in situ hybridization FISH analyses. Allelic loss on chromosome 8p in at least one marker was found in 25/99 (25%) tumors. There was a significant correlation of 8p deletions with invasive tumor growth and a highly significant association with papillary growth pattern in patients with invasive disease. cDNA array analyses revealed that secreted Frizzled-related protein 1 (sFRP1), an antagonist of Frizzled receptors and Wnt pathway activation on chromosome 8p12-11.1, is frequently downregulated in bladder cancer. To investigate sFRP1 as a candidate for a putative progression-related gene on 8p, urothelial cell lines and primary urothelial carcinomas were screened for sFRP1 expression using quantitative real-time PCR, Northern blot, immunofluorescence and immunohistochemistry (IHC). Of the investigated bladder cancers, 38% showed loss of sFRP1 expression by quantitative RT-PCR. Evaluation of the protein expression by IHC using tissue microarrays containing 776 bladder cancers revealed loss or strong reduction of sFRP1 expression in 66% of cases. SFRP1 loss was associated with higher tumor stage and grade and shorter overall survival. In addition, loss of sFRP1 was an independent indicator of poor survival in patients with papillary but not with muscle invasive bladder cancer. There were neither mutations in the coding region of sFRP1 nor homozygous deletions at 8p12-11.21. However, promoter methylation was detected using methylation-specific PCR in 29% of cases. In conclusion, we could show a close correlation of chromosome 8p deletions and progression of papillary bladder tumors. The sFRP1 gene on chromosome 8p12-11.1 could be a candidate gene for the predicted, progression-related tumor suppressor gene in bladder cancer and could contribute to urothelial carcinogenesis.

Biomarkers, Tumor↗

PubMed2004

Distinct secreted Frizzled receptor protein 1 staining pattern in patients with hyperplastic polyposis coli syndrome.

CONTEXT: Patients with hyperplastic polyposis coli syndrome are thought to harbor precursor lesions of a proposed hyperplasia-carcinoma pathway in colorectal cancer, but morphologic recognition of such lesions remains difficult. Hypermethylation of the secreted Frizzled receptor protein 1 gene on chromosome 8p12 is one of the earliest molecular alterations in colorectal carcinogenesis, potentially disrupting the Wnt signaling cascade of cellular growth control. OBJECTIVE: To determine if hyperplastic polyps from patients with hyperplastic polyposis coli syndrome show a distinct immunohistochemical expression pattern for mismatch repair proteins and secreted Frizzled receptor protein 1 compared to their sporadic counterparts. DESIGN: Immunohistochemical studies (secreted Frizzled receptor protein 1, 3 mismatch repair proteins, and p53) were performed on 23 hyperplastic polyps, 6 synchronous colon cancers, and normal colonic mucosa from 6 patients with hyperplastic polyposis coli syndrome and were compared with studies of sporadic hyperplastic polyps obtained from 13 matched control subjects. RESULTS: The staining pattern for the mismatch repair proteins MLH-1, MSH-2, and MSH-6 did not differ between sporadic and syndromic hyperplastic polyps. In contrast, 52% of syndromic hyperplastic polyps showed a reproducible and distinct staining pattern for secreted Frizzled receptor protein 1 that was not seen in control specimens and that was associated with larger polyp size (P =.002) and location in the proximal colon (P =.01). CONCLUSIONS: Some hyperplastic polyps from patients with hyperplastic polyposis coli syndrome show a secreted Frizzled receptor protein 1 immunophenotype that could indicate alterations of cellular growth control. These findings may help identify precursor lesions in the proposed hyperplasia-carcinoma pathway of colorectal carcinogenesis.

Adaptor Proteins, Signal Transducing↗

PubMed2004

No evidence for mutation of B-RAF in urothelial carcinomas of the bladder and upper urinary tract.

Mutational activation of the MAP kinase pathway is frequently found in various cancers. Recently, activating mutations in the B-RAF gene, an important activator of this pathway, have been described in several tumor types including melanoma, colorectal and papillary thyroid cancer. The most frequent mutation in exon 15 (V599E), as well as several other mutations within exons 11 and 15 result in constitutive activation of the oncoprotein. In addition, a significant association between mismatch-repair (MMR) deficiency and the V599E mutation in colorectal tumors has been found. The aim of our study was to investigate B-RAF mutations in 121 urothelial carcinomas of the urinary bladder (ranging from pTaG1 to pT4aG3) and 27 tumors from the upper urinary tract (UUT), including 16 tumors of the renal pelvis and 11 tumors of the ureter). Twelve of 27 UUT tumors were MMR-deficient and showed microsatellite instability. The V599E mutation was screened for by allele-specific PCR (PASA) and exons 11 and 15 of B-RAF including intron-exon-boundaries were sequenced. Overall, 116/121 bladder tumors and 23/27 tumors of the UUT were successfully investigated by PASA. None of the tumors showed the V599E mutation. Sequence analysis of exons 11 and 15 was successful in 46 urothelial tumors (bladder, n=31; UUT, n=15). No mutations within the coding region of exons 11 and 15 and the intron-exon junctions were found. The most frequent alterations in the B-RAF gene do not seem to be involved in urothelial carcinogenesis, and there is no correlation between MMR-deficiency and B-RAF mutations in urothelial tumors.

Aged↗

PubMed2004

Fluorescence in situ hybridization detects frequent chromosome 9 deletions and aneuploidy in histologically normal urothelium of bladder cancer patients.

Investigation of early urothelial lesions is essential to gain insight into the development of bladder cancer. In order to evaluate if deletions of chromosome arms 9p and 9q are preceding histomorphological changes in the urothelium, histologically normal urothelial samples of patients with previous and/or simultaneous (pre)malignant urothelial lesions were investigated. Dual colour fluorescence in situ hybridization (FISH) was performed on 96 histologically inconspicuous urothelial biopsies from 41 patients. Centromeric probes for chromosomes 9 and 17 were combined with gene locus specific probes for 9p21 (p16/CDKI2), 9q22 (FACC) and 17p (p53). Deletions of chromosome 9 (defined as presence of only one copy of centromere 9 or fewer gene-specific than centromeric signals in at least 40% of evaluated cells) were found in 21% of the samples (18/87). Deletions of chromosome 9p were present in 16% of cases (14/89), whereas deletions of chromosome 9q were encountered in 10% of specimens (9/93). A hemizygous deletion of p53 was found only once. Polysomy in more than 10% of cells was encountered in 16% of cases for both chromosome 9 and chromosome 17. Non-diploidy (defined as polysomy of both chromosomes) was found in 6% of samples (5/80). In summary, chromosome 9 deletions are frequently found in histologically normal urothelium of patients with bladder cancer, although less frequently than in hyperplasias and dysplasias. These findings support the hypothesis of multi-focal development of bladder cancer from histologically inconspicuous but already genetically altered urothelium. FISH analysis of chromosome 9 regions could provide a useful tool to detect potentially premalignant lesions in the follow-up care of patients with bladder cancer.

Aneuploidy↗

PubMed2004

Loss of SFRP1 is associated with breast cancer progression and poor prognosis in early stage tumors.

Aberrant activation of the Wnt signaling pathway plays an important role in the development of solid tumors such as breast and colon cancer. Secreted Frizzled-related protein 1 (SFRP1) is a negative regulator of the Wnt pathway. It has been described that SFRP1 mRNA is strongly down-regulated in breast cancer and a putative tumor suppressor function has been postulated. We have generated and characterized an SFRP1 specific antibody to analyze its expression on protein level and to investigate the association of SFRP1 expression with clinicopathological parameters and patient survival. Analysis of >2000 invasive breast tumors and 56 carcinoma in situ revealed similar frequencies of SFRP1 loss in these tumors (46% and 43% respectively). Therefore, we propose that loss of SFRP1 expression is an early event in breast tumorigenesis. SFRP1 expression was inversely correlated with tumor stage (p<0.001) but not with tumor grade (p=0.14) or lymph node status (p=0.84). Performing a multivariate analysis we could confirm the association between tumor stage and SFRP1 expression (p=0.029). In particular, loss of SFRP1 expression in early stage breast tumors (pT1) was associated with poor prognosis (p=0.04). In conclusion, expression of SFRP1 is commonly lost in breast cancer. SFRP1 expression might be useful as a novel prognostic marker in early stage breast cancer.

Biomarkers, Tumor↗

PubMed2003

WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer.

To detect novel Wnt-pathway genes involved in tumourigenesis, this study analysed the RNA expression levels of 40 genes of the Wnt pathway by chip hybridization of microdissected matched pairs of 54 primary prostate carcinomas. Eleven genes showed greater than two-fold differential expression in at least 10% of prostate cancers. Three of these genes encode extracellular components of the Wnt pathway (WNT2, WIF1, SFRP4); two are receptors (FZD4, FZD6); two belong to the intracellular signal cascade (DVL1, PPP2CB); one regulates transcription (TCF4); and three represent genes regulated by this pathway (CCND2, CD44, MYC). While SFRP4, FZD4, FZD6, DVL1, TCF4, and MYC are up-regulated, WIF1, WNT2, PPP2CB, CCND2, and CD44 are down-regulated in certain prostate cancer patients. Wnt inhibitory factor 1 (WIF1) and secreted frizzled related protein (SFRP4) showed the most significant aberrant expression at the RNA level. WIF1 was down-regulated in 64% of primary prostate cancers, while SFRP4 was up-regulated in 81% of the patients. Immunohistochemical analysis using a polyclonal antibody revealed strong cytoplasmic perinuclear WIF1 expression in normal epithelial cells of the prostate, breast, lung, and urinary bladder. Strong reduction of WIF1 protein expression was found in 23% of prostate carcinomas, but also in 60% of breast, 75% of non-small cell lung (NSCLC), and 26% of bladder cancers analysed. No significant association between WIF1 down-regulation and tumour stage or grade was observed for prostate, breast or non-small cell lung carcinomas, indicating that loss of WIF1 expression may be an early event in tumourigenesis in these tissues. However, down-regulation of WIF1 correlated with higher tumour stage in urinary bladder tumours (pTa versus pT1-pT4; p = 0.038).

Adaptor Proteins, Signal Transducing↗

PubMed2003

A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease.

BACKGROUND AND AIMS: Factors influencing the progression of chronic hepatitis C virus (HCV) infection are poorly understood. Monocyte chemotactic protein-1 (MCP-1) is a potent chemokine, and its hepatic expression is up-regulated during chronic HCV infection mainly in activated hepatic stellate cells (HSC). In this study, we investigated the correlation of the functional -2518 MCP-1 promoter polymorphism with hepatic MCP-1 expression and the disease outcome in patients with HCV. METHODS: MCP-1 genotyping was performed in 206 patients and 139 healthy controls. Hepatic MCP-1 messenger RNA (mRNA) expression was quantified by real-time PCR in 58 HCV patients. Cytokine-induced MCP-1 secretion of activated human HSC (n = 13) was determined by enzyme-linked immunosorbent assay (ELISA). Mobility-shift assays were performed using probes corresponding to the MCP-1 promoter sequence (-2511 to -2528) with or without the A to G mutation at -2518. RESULTS: Frequency of MCP-1 genotypes did not differ between HCV patients and controls. However, carriers of the G allele were significantly more frequent in HCV patients with more advanced fibrosis and severe inflammation. In accordance, hepatic MCP-1 mRNA levels were significantly higher in patients with more advanced fibrosis and in patients carrying the G allele. Furthermore, cytokine-induced MCP-1 secretion of HSC isolated from carriers of the G allele was significantly higher, and there was binding activity in nuclear extracts from activated HSC specifically to the G allele, providing a potential mechanism for the differences seen. CONCLUSIONS: Inheritance of the -2518 MCP-1 G allele, which appears to affect hepatic MCP-1 expression, may predispose HCV patients to more severe hepatic inflammation and fibrosis.

Adult↗

PubMed2003

HFE C282Y heterozygosity in hepatocellular carcinoma: evidence for an increased prevalence.

BACKGROUND & AIMS: Iron overload is observed frequently in chronic liver disease, and some studies have suggested that chronic iron overload may contribute to the pathogenesis of hepatocellular carcinoma (HCC). Heterozygosity for hereditary hemochromatosis (HH) is associated with increased body iron stores. The discovery of the HH gene HFE has enabled identification of the heterozygote status. The aim of this study was to evaluate if heterozygosity for HH is a risk factor for HCC. METHODS: The C282Y and the H63D mutation of the HFE gene were analyzed in 137 patients with HCC and no history of HH, 107 patients with cirrhosis without HCC and 126 healthy controls. Hepatic iron content was measured by using a semiquantitative histologic score. RESULTS: Seventeen of 137 HCC patients (12.4%) were C282Y heterozygote, compared with only 4 of 107 (3.7%) cirrhotic patients without HCC and 6 of 126 (4.8%) healthy controls (P < 0.05). The frequency of the H63D mutation showed no significant differences. C282Y heterozygote HCC patients had significantly higher levels of serum ferritin and transferrin saturation than C282Y wild-type patients (793 +/- 122 vs. 355 +/- 23 ng/mL, and 42.3% +/- 7.3% vs. 29.2% +/- 1.7%, respectively), and significantly higher iron deposition in HCC as well as in nontumorous liver tissue. CONCLUSIONS: The C282Y heterozygous genotype is significantly more common in HCC patients and is associated with significantly increased intrahepatic iron deposition and systemic iron stores. These results suggest that C282Y heterozygosity plays a role in liver iron deposition and could contribute to hepatocarcinogenesis via the accumulation of potentially carcinogenic iron. These findings may have implications for HCC screening and prevention strategies.

Biomarkers, Tumor↗

PubMed2003

Urothelial carcinoma of the upper urinary tract: inverted growth pattern is predictive of microsatellite instability.

Urothelial carcinoma of the renal pelvis and ureter may develop as a manifestation of hereditary nonpolyposis colorectal cancer syndrome (HNPCC), a disorder characterized by mutation or inactivation of a number of DNA mismatch repair genes and detectable as microsatellite instability (MSI). Some urothelial carcinomas display areas of endophytic, or inverted, growth. In this study, urothelial cancers of the upper urinary tract (n = 132) from patients treated at 2 tertiary care centers were studied to identify an association between growth pattern and MSI. Thirty-five neoplasms were microsatellite unstable (26.5%), and MSI was more frequent in papillary lesions than in sessile urothelial cancers (P = .033). The amount of inverted growth was estimated as a percentage of the total tumor. The interobserver and intraobserver concordance in recognizing inverted growth was good, and 65.7% of microsatellite-unstable tumors exhibited at least 20% of an inverted growth component, compared with only 17.5% of microsatellite-stable tumors (P < .0001). In this series, inverted growth predicted MSI with a sensitivity and specificity of .82. Inverted growth in urothelial carcinomas of the upper urinary tract may serve as a marker lesion for MSI and may help identify patients who should be offered testing for HNPCC.

Adult↗

PubMed2003

Lasermicrodissection--an important prerequisite for the molecular-genetic analysis of bladder cancer.

The past 10 years have shown that a crucial point in the molecular-genetic analysis of malignant tumors is the exact histopathological definition and separation of the investigated lesions. Laser microdissection has become an important tool allowing for the study of specific histological entities and defined preneoplastic lesions. Reliable detection of tumor-specific alterations can be compromised by the presence of normal cells. This requires microdissection of pure tumor cell populations (>80%), necessary for detecting chromosomal alterations by loss of heterozygosity analysis (LOH) and fluorescence in situ hybridization (FISH). The combination of microdissection and molecular methods could also be useful for studying multifocal lesions of the urothelial tract. This article describes in detail the use of laser microdissection, whole genome amplification by Improved Primer Extension Preamplification (I-PEP)-PCR and subsequent LOH, FISH, and sequencing analyses for the investigation of urothelial tumors and their precursors, e.g. dysplasias and hyperplasias. The combination of the described methods allows for a wide spectrum of molecular investigations in lesions with a limited number of tumor cells, and might help to understand the fundamental alterations involved in urothelial carcinogenesis.

Chromosome Aberrations↗