SummaryResearchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras incolorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer. © 2001 Cancer Research Campaign http://www.bjcancer.comIt is widely accepted that mutations in the Kirsten ras (Ki-ras) gene in patients with colorectal cancer develop early in the progression from adenoma to carcinoma. Our first collaborative study including 2721 patients, clarified that Ki-ras mutations are not only 692

Cell-in-cell (CIC) structures are commonly seen in tumours. Their biological significance remains unclear, although they have been associated with more aggressive tumours. Here we report that mutant p53 promotes CIC via live cell engulfment. Engulfed cells physically interfere in cell divisions of host cells and for cells without p53 this leads to host cell death. In contrast, mutant p53 host cells survive, display aberrant divisions, multinucleation and tripolar mitoses. In xenograft studies, CIC-rich p53 mutant/null co-cultures show enhanced tumour growth. Furthermore, our results show that CIC is common within lung adenocarcinomas, is an independent predictor of poor outcome and disease recurrence, is associated with mutant p53 expression and correlated to measures of heterogeneity and genomic instability. These findings suggest that pro-tumorigenic entotic engulfment activity is associated with mutant p53 expression, and the two combined are a key factor in genomic instability.

Summary Damage arising from putative environmental sources has been found in the DNA of the gastric and colorectal mucosae of patients presenting with gastrointestinal disorders from the South Manchester area.06-Methylguanine (06-MeG) in the range 0.010->0.300timolesmole-' adenine was heterogeneously distributed both between and within individuals. The pattern of alkylation of tissue DNA appears to differ when comparison is made between gastric and colorectal samples. Most of the gastric tumour DNA samples were alkylated (5/6; 0.087 + 0.097), whereas the DNA of the associated mucosa was alkylated less frequently (2/7) and to a lesser extent; (0.017 ± 0.030; P = 0.07). Conversely, colorectal tumour DNA was alkylated infrequently (1/7) and to a lower extent (0.003 ± 0.007) than the DNA of the adjacent mucosa (8/10 samples alkylated with a mean of 0.083 + 0.106; P = <0.01), or indeed of any other tissue. Although increased levels of DNA damage in tissue associated with malignant disease have been indicated by independent studies of DNA damage at other cancer sites, significant differences were not observed in the present report, neither was there any suggestion of a relationship with smoking or alcohol consumption.The data provided by this report indicate that exposure to putative environmental alkylating agents occurs in the UK at levels comparable to those previously detected in areas of higher cancer risk. Although we cannot determine the extent to which this DNA damage is attributable to normal background exposures, it is evident that the alkylation of tissue DNA occurs and is not uniform. In conjunction with other reports, therefore these differences may begin to provide indications of mechanisms that could be of relevance in the aetiology of gastrointestinal cancers.

SUMMARY Of 5018 patients who had undergone gastric surgery at St James Hospital, Balham, at least 25 years ago, death certificates have been received for 2768, whilst 1746 patients are still alive and are flagged (Office of Populations, Censuses and Surveys (OPCS) will notify us of their death and its cause) and only 504 could not be traced. Mortality from cancers of various organs has been determined using a 'years at risk' calculation in five year bands. There was no increase in mortality risk from any cancers during the first 15 postoperative years, but from 20 years after operation there was a significant excess risk not only of cancer of the stomach (4.5-fold), but also of the large bowel (1-6-fold), bronchus (3.9-fold), pancreas (4-0-fold), biliary tract (9-1-fold), oesophagus (2.3-fold), bladder (2-4-fold), breast (4-0-fold), and cancer of all sites (3-3-fold). These findings are consistent with the production in the operated-upon stomach of circulating carcinogens with a 20 year latency period.There have been a number of studies relating surgery for peptic ulcer to the subsequent risk of gastric cancer, some showing an association'-4 and some not."7 Many possible explanations for this have been suggested, but our large study' of 2577 duodenal ulcer patients and 1385 gastric ulcer patients showed that whereas more than 20 years postsurgery both groups of patients had an excess risk of gastric cancer, during the first 20 postoperative years there was an excess risk in the gastric ulcer patients but a decreased risk in duodenal ulcer patients. Thus, an association between gastric surgery and gastric cancer in either direction or no association at all could be expected depending solely on the relative proportion of duodenal ulcer and gastric ulcer patients, and on the length of follow up.A possible mechanism for this increased carcinogenesis is that surgery results in gastric hypoacidity leading to bacterial overgrowth with consequent production of carcinogens. A hypothesis involving nitrite and N-nitroso compounds has been sug-

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