In 1994 we described a list of approximately 2500 point mutations in the p53 gene of human tumors and cell lines which we had compiled from the published literature and made available electronically through the file server at the EMBL Data Library. This database, updated twice a year, now contains records on 4496 published mutations (July 1995 release) and can be obtained from the EMBL Outstation-the European Bioinformatics Institute (EBI) through the network or on CD-ROM. This report describes the criteria for inclusion of data in this database, a description of the current format and a brief discussion of the current relevance of p53 mutation analysis to clinical and biological questions.

Since 1989, about 570 different p53 mutations have been identified in more than 8000 human cancers. A database of these mutations was initiated by M. Hollstein and C. C. Harris in 1990. This database originally consisted of a list of somatic point mutations in the p 53 gene of human tumors and cell lines, compiled from the published literature and made available in a standard electronic form. The database is maintained at the International Agency for Research on Cancer (IARC) and updated versions are released twice a year (January and July). The current version (July 1997) contains records on 6800 published mutations and will surpass the 8000 mark in the January 1998 release. The database now contains information on somatic and germline mutations in a new format to facilitate data retrieval. In addition, new tools are constructed to improve data analysis, such as a Mutation Viewer Java applet developed at the European Bioinformatics Institute (EBI) to visualise the location and impact of mutations on p53 protein structure. The database is available in different electronic formats at IARC (http://www.iarc. fr/p53/homepage.htm ) or from the EBI server (http://www.ebi.ac.uk ). The IARC p53 website also provides reports on database analysis and links with other p53 sites as well as with related databases. In this report, we describe the criteria for inclusion of data, the revised format and the new visualisation tools. We also briefly discuss the relevance of p 53 mutations to clinical and biological questions.

We have examined DNA from four human esophageal carcinoma cell lines and 50 primary esophageal carcinomas obtained from China, Italy, and France for amplification of the cyclin Dl gene. We also examined 36 of these 50 carcinomas for expression of the cydin Dl and retinoblastoma (RB) proteins by immunohistochemistry. We found a 3-to 10-fold amplification of the cyclin Dl INT2,, and loss of heterozygosity of the tumor suppressor genes RB (9), p53 (10-12), MCC (13) and APC (13). Point mutations in the p53 gene occur in about 40% of esophageal cancers (10-12). However, activation of RAS oncogenes by point mutation appears to be a very rare event in this type of cancer (12,(14)(15)(16). Despite the fact that amplification of the HSTI and INT2 genes on chromosome 11q13 has been found in about 20-50% ofesophageal cancers, little or no expression of these two genes has been detected in the corresponding cells (6)(7)(8). These findings suggest that an additional gene(s) at the chromosome 11q13 locus is involved in the development of esophageal cancer. These considerations attracted our interest in a recent report thatThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. the cyclin Dl gene had been mapped to the chromosome 11q13 locus close to the INT2 and HSTI genes (17).Cyclins form a family of proteins that complex with cyclindependent protein kinases (CDKs) to govern key transitions in the cell cycle (for review, see refs. 18 and 19) Cyclin Dl was isolated as a gene that is rearranged in parathyroid adenomas (PRADI) and certain B-cell leukemias (BCL-J) (17,20). It also complements a Saccharomyces cerevisiae strain that is mutant in three known Gl cyclins (21, 22) and is induced in the late G1 phase following the treatment of a growth-arrested macrophage cell line with colony-stimulating factor 1 (23). The product of the cyclin Dl gene is expressed at high levels and forms a complex with a CDK during the G1 phase of the cell cycle in sychronized cells (23). In a recent study we detected amplification of the cyclin Dl gene in about 25% of primary esophageal tumors from China (24).The RB gene, which is located on chromosome 13q14, was the first tumor suppressor gene to be isolated. Loss of heterozygosity and loss ofexpression ofthe RB gene are seen during the development of retinoblastoma (RB) and several other types of human cancers (25). The product of the RB gene is a 110-kDa nuclear phosphoprotein. This protein is hypophosphorylated during the G1 phase and hyperphosphorylated in the S, G2, and M phases of the cell cycle. It is thought that this phosphorylation blocks an inhibitory function ofthe RB protein on progression through the later phases of the cell cycle (26). Alternatively, oncoproteins encoded by certain DNA tumor viruses can bind to the RB protein and block its inhibitory function (26). In vitro studies demonstrate that several serine and th...

Hepatocellular carcinoma (HCC) is the most common cancer in The Gambia. Hepatitis B virus (HBV) infection is endemic, with 15% to 20% of the population being chronic carriers, whereas hepatitis C virus (HCV) prevalence is low. We recruited 216 incident cases of HCC and 408 controls from three sites. HBV carriage was present in 61% (129/211) of HCC patients and 16% (64/402) of controls, whereas 19% (36/191) of HCC patients were HCV seropositive compared with 3% (11/382) of controls. HCC patients with HCV were notably older and were more likely to be female than those with HBV. Increased HCC risk was strongly associated with chronic HBV (odds ratio, 16.7; 95% CI, 9.7-28.7), HCV (16.7; 6.9 -40.1), and dual infection (35.3; 3.9 -323). We interpret the additive nature of risk with coinfection as representative of HBV and HCV acting primarily through shared steps in the multistage process of hepatocarcinogenesis. HCV infection was not observed among younger participants, suggesting a possible cohort effect. Reasons for the striking age and gender differences in HCC associated with HBV compared with HCV are unclear, but transmission patterns and age at exposure may be factors. In conclusion, in a standardized evaluation of well-characterized study participants from The Gambia, most cases of HCC are attributable to HBV (57%), but HCV adds a significant fraction (20%), especially among older patients and females. If HCV transmission is not perpetuated in future cohorts, focusing available resources on HB vaccination efforts could greatly ameliorate a major cause of cancer death in sub-Saharan Africa. (HEPATOLOGY 2004;39:211-219.) H epatitis B virus (HBV) and hepatitis C virus (HCV) infections are established causes of hepatocellular carcinoma (HCC). 1 Despite decades of experimental and epidemiologic investigation and widespread acceptance of their carcinogenicity, the specific mechanisms by which they lead to HCC and the effect of coinfection with HBV and HCV remain poorly understood.Geography plays an important role, whereby variation in the epidemiologic patterns of infection and the corresponding HBV and HCV prevalence crudely reflects HCC incidence patterns. 2,3 The greatest burden of HCC is in sub-Saharan Africa and parts of Asia, where HCC is the most frequent cause of cancer death among men. 2 Chronic HBV infection is highly prevalent and is the predominant risk factor for HCC in these high-incidence regions. [2][3][4] The United States and Europe have much lower HCC rates, with increases in recent years attributed to HCV infection. 5,6 The age of onset of HCC is much younger in Africa and Asia, with a median of 40 to 50 years compared with 55 to 65 years in the United States (see Fig. 1). The male-to-female ratio of HCC cases is

In recent years, there has been an exponential increase in the number of p53 mutations identified in human cancers. The p53 mutation database consists of a list of point mutations in thep53 gene of human tumors and cell lines, compiled from the published literature and made available through electronic media. The database is now maintained at the International Agency for Research on Cancer (IARC) and is updated twice a year. The current version contains records on 5091 published mutations and is expected to surpass the 6000 mark in the January 1997 release. The database is available in various formats through the European Bioinformatics Institute (EBI) ftp server at: ftp://ftp.ebi.ac.uk/pub/databases/p53/ or by request from IARC (p53database@iarc.fr) and will be searchable through the SRS system in the near future. This report provides a description of the criteria for inclusion of data and of the current formats, a summary of the relevance ofp53 mutation analysis to clinical and biological questions, and a brief discussion of the prospects for future developments.