Germline mutations in the TGF-beta and Wnt signalling pathways are a rare cause of the "multiple" adenoma phenotype.
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Activin Receptors, Type I↗
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Microsatellite instability and expression of hMLH-1 and hMSH-2 in sebaceous gland carcinomas as markers for Muir-Torre syndrome.
Sebaceous gland carcinomas (SGCs) are rare malignant skin tumors occurring sporadically or as a phenotypic feature of the Muir-Torre syndrome (MTS). A subset of patients with MTS have a variant of the hereditary nonpolyposis colorectal cancer syndrome caused by mutations in mismatch repair (MMR) genes, which lead to microsatellite instability (MSI). We evaluated the value of MSI and loss of expression of the MMR genes, hMLH-1 and hMSH-2, as a marker to identify and distinguish MTS from sporadic SGC. Using a nationwide pathology report database system, we identified patients with the MTS phenotype. SGCs from 10 MTS patients and the colorectal carcinomas from 3 additional MTS patients were collected. In addition, SGCs from eight patients without a history of visceral neoplasm were collected. MSI was detected in 9 of 13 MTS-associated tumors (69%) versus 0 of 8 sporadic SGCs (P = 0.002). Except for the age of onset of colorectal carcinoma [58 years in the MSI-positive group versus 69.8 years in the MSI-negative group (P = 0.17)], no differences were seen between the MSI-negative and the MSI-positive MTS patients. Loss of expression of hMLH-1 (n = 4) or hMSH-2 (n = 4) was found in MSI-positive patients only. MSI and loss of expression of MMR genes can be used as markers for MTS in patients with SGC. Consequently, MSI and loss of MMR gene expression in a patient presenting with SGC as the initial malignancy have important consequences for the patient and family. There are at least two variants of MTS with different molecular genetic mechanisms because 31% of the patients with the MTS phenotype had no MSI.
Adaptor Proteins, Signal Transducing↗
Adrenocortical adenocarcinoma in an MSH2 carrier: coincidence or causal relation?
A woman is described who developed an ovarian adenocarcinoma, 3 metachronous colorectal adenocarcinomas, and a primary adrenocortical adenocarcinoma. Genetic investigation of the mismatch repair genes MLH1 and MSH2 showed a germline mutation in MSH2. Colorectal and ovarian carcinoma belong to the tumor spectrum of hereditary nonpolyposis colorectal cancer (HNPCC). Adrenocortical adenocarcinoma, however, has never been described as 1 of the HNPCC-associated tumors. To investigate whether the adrenocortical adenocarcinoma in this patient was caused by the MSH2 germline mutation, determination of microsatellite instability (MSI) and immunohistochemical analysis were performed on 1 of the colorectal tumors and the adrenocortical adenocarcinoma. MSI and general loss of MSH2 protein expression could be seen in the colorectal tumor but not in the adrenocortical adenocarcinoma. Therefore, it is highly unlikely that the adrenocortical adenocarcinoma found in this patient was due to her genetic predisposition for HNPCC. HUM PATHOL 31:1522-1527.
Adenocarcinoma↗
Sporadic colorectal cancers with defective mismatch repair display a number of specific morphological characteristics: relationship between the expression of hMLH1 and hMSH2 proteins and clinicopathological features of 273 adenocarcinomas.
AIMS: The aim of this study was to assess the independent value of pathological criteria in the diagnosis of mismatch repair (MMR)-defective sporadic colorectal cancers. METHODS AND RESULTS: Resected colorectal adenocarcinomas (n = 273) were reviewed in order to identify a number of specific morphological features of MMR-defective carcinomas. Of the 273 cases, 35.2% were right-sided and 5.9% were poorly differentiated. Focal extracellular mucin secretion was seen in 5.1% of cases and a stromal follicular reaction in 4.6%. The expression of the two major MMR proteins hMLH1 and hMSH2 was studied by immunohistochemistry. Carcinomas were considered deficient in the MMR system when a loss of nuclear signal in neoplastic cells was observed for one of the proteins. Such an extinction was seen in 37 of the cases (13.6%). The hMLH1 protein was the one most frequently altered (86.5%). After multivariate analysis, three independent factors were significantly associated with MMR deficiency: proximal location [odds ratio (OR) = 9.30; 95% confidence interval (CI) 2.79, 30.98], the presence of a true stromal follicular reaction (OR = 13.60; 95% CI 2.98, 62.00) and poor differentiation (OR = 8.33; 95% CI 1.63, 40.32). CONCLUSIONS: These results confirm that sporadic colorectal MMR-defective adenocarcinomas display certain specific morphological characteristics. However, these pathological features are not sufficiently predictive and immunohistochemistry is needed to identify such tumours accurately.
Adaptor Proteins, Signal Transducing↗
p73 overexpression is a prognostic factor in patients with colorectal adenocarcinoma.
PURPOSE: To examine the expression of p73 in the different stages of colorectal cancer development and the association of p73 expression with patient survival. EXPERIMENTAL DESIGN: Expression of p73 protein was evaluated by immunohistochemistry in 221 primary colorectal cancer patients, including 58 patients with matched normal mucosa and metastases in the regional lymph nodes. RESULTS: Frequency and intensity of p73 expression were markedly increased from the normal samples (19%) to primary tumors (67%) and to metastases (95%). Overexpression of p73 predicted poor outcome in the whole group of patients (P = 0.014) and the subgroups with left-sided (P = 0.002) or ras-positive tumors (P = 0.019). The prognostic significance remained in the whole group (P = 0.008) and the subgroup with left-sided tumors (P = 0.019) after adjustment for the patient's sex, age, tumor stage, growth pattern, and differentiation. The p73 expression was positively correlated with ras expression (P = 0.006). The 5-year survival rates were 37, 53, 72, and 74% for the patients with p73+/ras+, p73+/ras-, p73-/ras+, and p73-/ras- tumors, respectively (P = 0.007). CONCLUSION: Our data indicate that overexpression of p73 independently predicted poor prognosis in the patients with colorectal cancer.
Adenocarcinoma↗
Inhibitory effects of costunolide on the telomerase activity in human breast carcinoma cells.
Costunolide, a natural sesquiterpene compound, has been known having cytotoxic and chemopreventive effects on various human cancer cells. In the present study, we examined the effects of costunolide on telomerase activity and on the components of telomerase in MCF-7 (wild-type p53) and MDA-MB-231 (mutant p53) cells. We found that costunolide inhibited the growth and telomerase activity of MCF-7 and MDA-MB-231 cells in a concentration- and time-dependent manner. The expression of hTERT mRNA was also inhibited but hTR mRNA was not. In addition, the bindings of transcription factors in hTERT promoters were significantly decreased in both cells by the treatment of costunolide. These results suggest that costunolide inhibited the growth of both MCF-7 and MDA-MB-231 cells and this effect was mediated at least in part by a significant reduction in telomerase activity.
Antineoplastic Agents, Phytogenic↗
Expression of hMSH2 and hMLH1 in colorectal carcinomas with microsatellite instability.
Microsatellite instability (MIN) due to defective mismatch repair (MMR) genes has been reported in a subset of sporadic colorectal carcinomas and in the majority of tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Among the known MMR genes, hMSH2 and hMLH1 genes are known to be predominantly altered in HNPCC patients and MIN-positive tumors. In this study, we examined MIN and the protein expression pattern of the hMSH2 and hMLH1 by Western blot and immunohistochemistry from 32 sporadic colorectal carcinomas. MIN was observed in 6 (18%) colorectal carcinomas. Of the 6 MIN-positive tumors, one case showed no expression of either protein, 3 cases showed an absence of hMSH2 protein expression, one case showed an absence of hMLH1 protein expression and one case showed no altered expression of either protein by immunohistochemistry. The decreased expression of the hMSH2 protein in a tumor compared to the normal mucosa was also observed in 5 of the 6 MIN-positive cases by Western blot analysis. All of the MIN-negative tumors showed expression of both proteins by immunohistochemistry. Thus most of the MIN-positive tumors appear to be directly related to the altered expression of these two genes and can be diagnosed by the examination of protein expression.
Adaptor Proteins, Signal Transducing↗
Mutation of FADD gene is rare in human colon and stomach cancers.
Failure of apoptosis is one of the hallmarks of cancer. As an adaptor, FADD plays a crucial role during death receptor-mediated apoptosis. We previously reported that the FADD gene is somatically mutated in non-small cell lung cancers. To explore the possibility that the genetic alterations of the FADD gene might be involved in the development of other human cancers, we analyzed the entire coding region and all splice sites of the human FADD gene to detect somatic mutations in 116 stomach cancers and 98 colon cancers. Overall, we detected a somatic missense mutation of the FADD gene in a colon carcinoma, which was predicted to change an amino acid (R140H) in the death domain (DD) of the FADD protein. This is the first report of FADD gene mutation in gastrointestinal cancers, and our data suggest that the FADD gene is rarely mutated in human colon and stomach cancers.
Adaptor Proteins, Signal Transducing↗
Associations between family history of colorectal cancer and genetic alterations in tumors.
A family history of colorectal cancer has been consistently associated with an increased risk of developing colon cancer. However, there is limited information on the association between family history of colorectal cancer and genetic alterations that occur in colon tumors. In this study, we evaluate the association among genetic alterations of Ki-ras and p53, microsatellite instability and having a family history of colorectal cancer in a study of incident colon cancer cases (n = 1993) and population-based controls (n = 2,410). Although there was a slight nonsignificant increase in risk of having an unstable tumor among those with a family history of colorectal cancer, this increase in risk disappeared after excluding those people with a known mutation in either of the mismatch repair genes hMLH1 or hMSH2. A family history of colorectal cancer was not associated with Ki-ras mutations overall, although those with a G to T mutation of the second base of codon 12 were more likely to have a family history of colorectal cancer than were those without this specific type of Ki-ras mutation. Cases with p53 mutations were less likely to have a family history of colorectal cancer than were cases without a p53 mutation. We believe that, given the general lack of association between having a family history of colorectal cancer and genetic alterations in tumors, these alterations are acquired through disease pathways that involve exposure from diet, lifestyle or other environmental factors.
Adaptor Proteins, Signal Transducing↗
Possible alternative carcinogenesis pathway featuring microsatellite instability in colorectal cancer stroma.
Differential microsatellite instability (MSI) in tumour epithelial and stromal compartments has not been well examined for colorectal cancers. Using laser-captured microdissection, separate specimens of these compartments of 40 sporadic colorectal cancers were sampled and MSI was tested with four markers. To examine the relation between the MSI phenotype in the stroma and other genetic events and histopathological features, p53 and K-ras gene mutations were analysed, and the expression of p53, hMLH1, and hMSH2 protein was determined by immunohistochemistry. Microsatellite instability positive results were obtained for both epithelium (34%) and stromal tissue (41%). While MSI in epithelium correlated with differentiation and Dukes' stage, that in stroma demonstrated an inverse relation, being particularly frequent in well-differentiated adenocarcinomas (54%) and Dukes' A lesions (55%). Further, a significant inverse correlation between p53 protein overexpression in the epithelium and MSI in the stroma was found (P=0.02475). The results suggest an alternative pathway of carcinogenesis involving stromal genetic instability in the development of colorectal cancers.
Adaptor Proteins, Signal Transducing↗
Is reduced expression of mismatch repair genes MLH1 and MSH2 in patients with sporadic colorectal cancer related to their prognosis?
The majority of mutations in hereditary nonpolyposis colon carcinoma (HNPCC) patients affect the mismatch-repair genes (MMRG) MLHI and MSH2. In addition, mutations of these genes were found in about 15% of sporadic colorectal carcinomas which appear to be related to microsatellite instability (MSI). However, mutations in MMRG were not found in all MSI-positive carcinomas, but MMRG mutations may be relevant for the assessment of tumor characteristics and patients' prognosis. Therefore, we investigated the relationship between expression of MMRG, tumor biology and patients' survival. In 127 patients with sporadic colorectal carcinomas and a minimum of 5 years follow-up after curative surgery immunohistochemical detection of MLHI and MSH2 was analyzed semiquantitatively. Lost expression of MLHI has been found in tumor specimens from 10 patients, whereas MSH2 expression was missing in 5 patients. This reduced expression did not correlate with tumor stage, lymph node involvement, grading or tumor invasion into blood vessels. However, a significant correlation was found for lymphovascular invasion (P = 0.02) and localization within the colorectum (P = 0.003) in MLH1-negative carcinomas. In addition, although there was a clear tendency for longer overall survival (72 vs. 63 months) for patients with MLH1-negative carcinomas, significant differences for overall and recurrence-free survival were not seen. In conclusion of our results and a critical review of literature, the prognostic importance of the MMR genes in sporadic colorectal carcinomas remains controversial.
Adaptor Proteins, Signal Transducing↗
Identification of MARCKS, FLJ11383 and TAF1B as putative novel target genes in colorectal carcinomas with microsatellite instability.
Somatic frameshift mutations in some genes containing coding mononucleotide repeats (cMNRs) are well known characteristics of tumors with high microsatellite instability (MSI-H). We identified 22 novel and 11 known target genes containing cMNRs with a length of 10 or more nucleotides by using a systematic database search. Frameshift mutation analysis was performed with these 33 genes in 39 MSI-H and 24 microsatellite stable (MSS) colorectal carcinomas by assessing the mobility shifts of PCR products in gel electrophoresis and by sequencing. All the 39 MSI-H colorectal carcinomas, except one, showed mutations in more than one gene, while no mutations were found in 24 MSS colorectal carcinomas. Of these MSI-H tumors, 11 genes were mutated in more than 40%. The most frequently mutated novel genes were MARCKS (72%), FLJ11383 (74%) and TAF1B (82%). Biallelic inactivation in MARCKS and FLJ11383 was also frequent in MSI-H tumors. The observed mutation frequency of the 11 known target genes was compatible with that found by previous studies. The very high frequency of mutations, biallelic mutations and the predicted truncation of protein products suggests that mutations of MARCKS, FLJ11383 and TAF1B are selected, and play a role in the tumorigenesis of MSI-H colorectal carcinomas.
Base Sequence↗
Microsatellite instability in double primary cancers of the colorectum and stomach.
Little is known about genetic alterations of patients who present multiple primary cancers. We hypothesized that microsatellite instability (MSI) is one of the underlying genetic factors in the development of double primary cancers in colorectal cancer patients. We examined for MSI in 41 colorectal cancer patients who presented with extra-colonic primary cancers consisted of 17 gastric and 24 non-gastric cancers. Coincident MSI+ in tumors of two organs were observed in 3 (17.7%) of 17 patients with colon and stomach cancers and 0 of 24 patients with colon and non-gastric cancers (P =.03). In 17 patients with colon and stomach cancers, 6 (31.6%) of 19 colon cancers and 3 (17.7%) of 17 gastric cancers exhibited MSI+. Among four patients with metachronous colon cancers who were identified within the 41 double primary cancer patients, two patients were associated with the MSI+ phenotype. In summary, the prevalent coincidence of MSI suggests that genetic defect of mismatch repair deficiency may be responsible for a small subset of double primary cancers of the colorectum and stomach.
Aged↗
Molecular evidence of viral-like biochemical activities in human genitourinary malignancies.
We have demonstrated previously that core structures of urine samples from patients with genitourinary malignancies contain ribonucleic acid-directed deoxyribonucleic acid polymerase and a high molecular weight ribonucleic acid. If these particles originated from the existing genitourinary malignancies then the malignancies should contain similar characteristics. We examined 13 prostatic carcinomas, 4 bladder carcinomas, 1 urethral carcinoma and 1 hypernephroma. Positive reactions were noted in 10 of the 13 prostatic carcinomas (77 per cent), all 4 bladder carcinomas, the 1 urethral carcinoma and the hypernephroma with the simultaneous detection assay. The control samples consisted of 7 tissues of benign prostatic hypertrophy, and tissue from 2 normal bladders and 1 normal kidney. None of these tissues showed a positive response. Tritium labeled deoxyribonucleic acid probes synthesized from the malignant tissues hybridized to the polysomal ribonucleic acids but not to the corresponding normal tissues. Particles derived from the probes have a density of 1,1620 in sucrose gradient. No sequence homology could be demonstrated with various known oncogenic ribonucleic acid viruses nor with malignancies arising from other organs.
Adenocarcinoma↗
DNA topoisomerase IIalpha and Her-2/neu gene dosages in pediatric malignant gliomas.
Pediatric malignant non-brainstem glioma (PMNBG) is a rare tumor that accounts for only about five percent of childhood intracranial neoplasms. DNA topoisomerase IIalpha (TIIalpha) is a novel marker of cell-cycle turnover and a target of high-risk chemotherapy in PMNBG. We have shown that TIIalpha protein expression strongly correlates with event-free and overall survival in these malignancies. The molecular mechanism causing the varying TIIalpha protein expression in PMNBG remains unknown. Utilizing a combined approach of immunocytochemistry-based morphology guidance, laser-assisted microdissection and quantitative real-time PCR, we report a low-level co-amplification of the neighboring TIIalpha and Her-2/neu gene loci on chromosome 17q11-q22 in one of seventeen examined PMNBGs. Analysis of both genes by real-time PCR in the crude tumor samples without prior tissue heterogeneity reduction via laser microdissection, resulted in loss of detection of amplification of the syngeneic Her-2/neu locus. Gene dosage assessment in a microscopically distant tumor area revealed no amplification of either gene. Our results suggest that low-level amplification of the TIIalpha gene locus may be a sporadic mechanism of increased TIIalpha protein expression in PMNBG, which can coincide with low-level amplification of Her-2/neu. The observed intratumor genetic heterogeneity for TIIalpha in PMNBGs may have an impact on the relevance of TIIalpha as a biological constituent of outcome in these neoplasms.
Antigens, Neoplasm↗
Expression and sequence analyses of p33(ING1) gene in myeloid leukemia.
p33(ING1) is a novel candidate tumor suppressor gene which is involved in the regulation of apoptosis. p33(ING1) interacts with p53 signaling pathway and regulates cellular growth. It has reported that the expression of p33(ING1) mRNA was decreased in lymphoid malignancies. We thus investigated the potential involvement of p33(ING1) abnormalities in myeloid leukemias. However, the levels of p33(ING1) transcript were almost equal in 3 AML cell lines and 10 fresh AML samples. In addition, neither point mutations nor deletions in p33(ING1) gene were found in myeloid leukemias. These results suggest that p33(ING1) may not be a major candidate tumor suppressor gene in myeloid leukemias.
Adenocarcinoma↗
Intronic deletion affecting a negative regulatory region of TP73 is related to breast and colorectal carcinomas.
The TP73 gene encodes a nuclear protein that has high homology with TP53. TP73 is rarely mutated in human cancer. The presence of a 1-kb regulatory fragment within the first intron of TP73 was recently reported. This fragment exerts silencer activity on TP73 mediated by ZEB. We searched for possible mutations in this negative regulatory region in 45 colorectal and 43 breast cancer patients and in 34 healthy donors. The study was carried out using the SSCP method, and the allelic variants detected were sequenced. The expression of TP73 was analyzed by quantitative RT-PCR, and loss of heterozygosity (LOH) was assessed by microsatellite study. In several samples, we identified an allele variant that corresponds to a deletion of 73 bp in tumor tissues and normal counterparts, localized between -489 and -417 from the ATG start site of exon 2. Among the 88 tumor samples, 35 (40%) showed at least 1 allele with the cited deletion, versus 7 of the 34 (21%) healthy donors (P = 0.045). When we classified the patients according to the number of variations into homozygous or heterozygous groups, the significance was clearer (P = 0.03). No LOH was detected in the heterozygous cases. There was a positive quantitative correlation between the expression of TP73 and the presence of the allelic variant (P = 0.029). These data suggest that this allelic variant is common in breast and colorectal cancers and that it could alter the expression of the TP73 gene with an additive effect.
Base Sequence↗
Mismatch repair polymorphisms and the risk of colorectal cancer.
Rare germline variants in mismatch repair genes have been linked to hereditary nonpolyposis colorectal cancer; however, it is unknown whether common polymorphisms in these genes alter the risk of colorectal cancer. To examine the association between common variants in mismatch repair genes and colorectal cancer, we conducted a case-cohort study within the CLUE II cohort. Four single nucleotide polymorphisms in 3 mismatch repair genes (MSH3 R940Q, MSH3 T1036A, MSH6 G39E and MLH1 I219V) were genotyped in 237 colorectal cancer cases and a subcohort of 2,189 participants. Incidence rate ratios (RRs) and 95% confidence intervals (95% CIs) for each polymorphism were estimated. The MSH3 1036A variant was found to be associated with an increased risk of colorectal cancer (RR=1.28, 95% CI: 0.94-1.74 and RR=1.65, 95% CI: 1.01-2.70 for the AT and TT genotypes, respectively, with p(trend)=0.02), particularly proximal colon cancer. Although the MSH3 940Q variant was only weakly associated with colorectal cancer overall (p(trend)=0.07), it was associated with a significant increased risk of proximal colon cancer (RR=1.69, 95% CI: 1.10-2.61 and RR=2.68, 95% CI: 0.96-7.47 for the RQ and QQ genotypes, respectively with p(trend)=0.005). Processed meat intake appeared to modify the association between the MSH3 polymorphisms and colorectal cancer (p(interaction) < 0.10 for both). No association was observed with the MSH6 and MLH1 polymorphisms overall. This study suggests that common polymorphisms in the mismatch repair gene, MSH3, may increase the risk of colorectal cancer, especially proximal colon cancer.
Adaptor Proteins, Signal Transducing↗