No abstract

Summary Alterations of microsatellites have been found at relatively high frequency in hereditary and sporadic colorectal cancer and gastric and pancreatic cancers and at lower frequency in some other cancers. We determined the frequency of instability at 39 poly-CA microsatellite loci in 20 squamous cell carcinomas and 26 Barrett's adenocarcinomas of the oesophagus. None of the tumours presented instability for a high percentage of the tested loci. Four squamous cell carcinomas and six Barrett's adenocarcinomas showed microsatellite instability at one locus, and three Barrett's adenocarcinomas showed microsatellite instability at two loci. The presence of few loci showing microsatellite instability could be due to an instability background. We conclude that genetic defects in the DNA mismatch repair system do not play an important role in oesophageal cancers.Keywords: microsatellite instability; cancer of the oesophagus; squamous cell carcinoma of the oesophagus; Barrett's adenocarcinoma; DNA mismatch repair system Recently a new class of genetic alterations in human tumours has been described Thibodeau et al, 1993). These appear at microsatellite loci that are short, repeated nucleotide sequences distributed within the normal genome. Alterations of microsatellites consist of the loss or gain of one or more repeat units in tumours compared with matched normal DNA and have been termed microsatellite instability (MI). MI was first described in colorectal cancer, in both hereditary non-polyposis colorectal cancer (HNPCC) and sporadic colorectal cancer cases Thibodeau et al, 1993), as a result of a deficient DNA mismatch repair system (Fishel et al, 1993;Leach et al, 1993;Parsons et al, 1993;Bronner et al, 1994;Papadopoulos et al, 1994). MI has also been observed in a variety of sporadic cancers, such as endometrium, stomach, kidney, ovary and pancreas cancers, belonging to the HNPCC tumour spectrum (Han et al, 1993;Peltomaki et al, 1993;Risinger et al, 1993). In bladder, breast and lung cancers, MI has been reported with variable frequency (Gonzalez-Zulueta et al, 1993;Merlo et al, 1994; Schridar et al, 1994). There are conflicting reports concerning the presence of MI in oesophageal cancers (Meltzer et al, 1994;Keller et al, 1995;Mironov et al, 1995;Nakashima et al, 1995;Gleeson et al, 1996). Cancer of the oesophagus is among the most common and severe malignant neoplasms in the world (Muller et al, 1990;Parkin et al, 1993). There are two main histological types of oesophageal cancer, squamous cell carcinoma (SCC) and Barrett's adenocarcinoma (BA). SCC is more frequent and is associated with alcohol and tobacco consumption in Western countries (Tomatis et al, 1990

Background. An important marker for hepatocellular carcinoma is the presence of des‐γ‐carboxy (abnormal) prothrombin. However, the molecular basis for the reduced carboxylation of prothrombin is unknown. Methods. Two groups of patients were defined according to the absence (Group I, n = 7) or presence (Group II, n = 8) of des‐γ‐carboxy prothrombin. The enzymatic activity of y‐carboxylase and the total microsomal prothrombin concentration were determined in all tumors. The kinetic parameters for the synthetic peptide Phe‐Leu‐Glu‐Glu‐Leu (FLEEI.) were measured in eight tumors. The γ‐carboxylase mRNA expression was evaluated by Northern blot analysis in 12 of 15 tumors. In addition, the total vitamin K content (K, K, epoxide, and menaquinones 4‐10) in 10 tumors was investigated by high performance liquid chromatography. Results. Concentrations of menaquinones 4‐10 were normal in the nontumorous part of the liver but significantly decreased (P = 0.02) in all the tumors (Groups I and II). This decrease was more severe in Group II (P = 0.02). The tumors in Group I had normal or increased γ‐carboxylase activity and increased mRNA expression (P < 0.02) as compared with their nontumorous counterparts. The tumors in Group II were heterogeneous. Five tumors displayed low y‐carboxylase activity, associated with low mRNA expression in two, whereas two others had high γ carboxylase activity and mRNA expression. The concentration of FLEEL at half‐maximal velocity was normal in all the tumors examined (Groups I and II), and a relation was found between the level of expression of γ‐carboxylase and the maximal velocity for FLEEL carboxylation in the tumors in Group II (r = 0.98; P < 0.01). The microsomal content of normal prothrombin was within normal limits in all tumors (Groups I and II). Conclusions. Tumor vitamin K content has a critical role in the synthesis of des‐γ‐carboxy prothrombin. Furthermore, the γ‐carboxylase defect, which is observed in some secreting tumors, is the result of the defective gene expression of a normal enzyme and not the consequence of the presence of a competitive inhibitor. It is possible that a 75% reduction in γ‐carboxylase gene expression could take a part in the secretion of des‐γ‐carboxy prothrombin, but this mechanism is not predominant.

No abstract

No abstract