Exposure to the sun and sunbeds and the risk of cutaneous melanoma in the UK: a case-control study.

Migration, latitude and case-control studies have clearly established a link between melanoma and sun exposure. This case-control study of melanoma was set up to examine the role of sun exposure and sunbeds in the pathogenesis of melanoma in the United Kingdom (UK), a country with low levels of ultraviolet radiation. The study included 413 cases and 416 controls. More than 10 severe sunburns compared with less than 10 sunburns was associated with an Odds Ratio (OR) of 1.98 (95% Confidence Interval (CI) 1.02-3.86) (P=0.04) when adjusted for age, gender and skin type. Sunburns before the age of 15 years were not associated with melanoma once adjustments for age, gender and skin were made. 31% of women and 16% of the men had used sunbeds. Sunbed users were younger than non-users (40 years versus 51 years, P<0.0001). Ever use of sunbeds gave an adjusted OR of 1.19 (95% CI 0.84-1.68) (P=0.33). The risk of melanoma did not increase with increasing hours or years of sunbed exposure. The risk associated with sunbed use was only significant for young individuals with fair skin for whom there was a significant OR of 2.66 (95% CI 1.66-6.09) (P=0.02) after adjustment for the sun exposure variables. Outdoor occupation and residence in hot countries were not associated with an increased risk of melanoma. The only significant associations in this study were with 10 or more sunburns and the use of a sunbed in young subjects with fair skin. Sunbed use is now becoming more prevalent in Caucasian populations and the results of this study suggest that sunbed usage may moderately affect individuals with sun-sensitive skin types. However, the magnitude of melanoma risk in association with natural and artificial sun exposure is small compared with phenotypic risk factors such as skin type and naevus counts. However, it is possible that the mean lag time of 7 years between exposure to sunbed and melanoma in this study may have led to an under-estimation of the long-term melanoma risk.

APC in the regulation of intestinal crypt fission.

The functional effects of APC (adenomatous polyposis coli gene) germ-line mutations on crypt fission and cell proliferation were investigated in the normal intestine of human familial adenomatous polyposis (FAP) and multiple intestinal neoplasia (MIN) mice. Compared with controls, there was a 19-fold increase in the proportion of crypts in fission in FAP colon [95 per cent confidence interval (CI): 11-32, P < 0.0001], and a 75 and 61 per cent increase in MIN colon (95 per cent CI: 1.08-2.82, P < 0.02) and small bowel, respectively (95 per cent CI: 1.31-1.99, P < 0.001). In marked contrast, no significant differences in intra-cryptal epithelial cell proliferation or mitotic distribution were seen. Furthermore, 10.9 per cent of crypts in FAP were in asymmetrical fission as opposed to only 1 per cent in controls (P = 0.001). The largest relative increases in MIN crypt fission were in the colon (proximal and distal colon:190 per cent, P = 0.02 and 83 per cent, P = 0.01), suggesting that Apc mutations exert their maximal influence site-specifically. However, sites with the highest relative increases were also those with the largest eventual tumour sizes, but not the highest polyp counts. Three-dimensional serial section reconstruction analysis corroborated that FAP adenomas enlarge by crypt fission, which was frequently both asymmetrical and atypical. It is proposed that the absence of an increase in intestinal cell division infers that APC regulates intestinal crypt differentiation, specifically through the crypt cycle. This role appears analogous to the control of axis re-duplication in embryonic development, when downstream targets of APC are over-expressed. It is concluded that in vivo, the major defect in pre-neoplastic intestine harbouring APC mutations is elevated rates of crypt fission, and that this is also the mode by which micro-adenomas enlarge.

Effects of epidermal growth factor and dimethylhydrazine on crypt size, cell proliferation, and crypt fission in the rat colon. Cell proliferation and crypt fission are controlled independently.

Crypt fission is now established as an important mechanism of intestinal growth and regeneration. It has been proposed that increased crypt size is the stimulus for crypt fission, because crypts preparing for fission are generally larger. Consequently, we investigated the effects of epidermal growth factor (EGF) and dimethylhydrazine, which are both known to stimulate crypt cell proliferation, on crypt fission in the rat intestine. We also examined whether the effects of EGF on both proliferation and crypt fission are modified by the pretreatment with dimethylhydrazine for 16 weeks, dimethylhydrazine was then discontinued for 8 weeks, followed by intravenous infusion of EGF for 1 week. There were four groups: vehicle alone, EGF alone, dimethylhydrazine alone, and dimethylhydrazine followed by EGF infusion. The rats were killed at 25 weeks and rates of intestinal crypt cell production, crypt size, and crypt fission were determined. Intravenously infused EGF significantly increased crypt cell production rate, but the magnitude of the effect decreased from the proximal to the distal colon. EGF caused an increase in crypt area, possibly reflecting an increase in crypt size. Importantly dimethylhydrazine had no significant effect on crypt cell production rate nor on crypt area in the distal colon, but it did cause an increase in crypt area in the mid-colon. The crypt fission index was significantly decreased by EGF and increased by dimethylhydrazine. There was no qualitative interaction between EGF and dimethylhydrazine. These results demonstrate the marked proliferative effect of intravenously infused EGF in the colon of orally fed rats, with significant site effects (P = 0.0007); the effect was greatest in the proximal colon and disappeared in the distal colon. The observation that EGF reduced crypt fission indicates that increased cell proliferation, per se, is not a stimulus for crypt fission. This is further supported by the observation that dimethylhydrazine increases crypt fission in crypts of normal size in the distal colon without significantly increasing cell proliferation. These results suggest that increasing crypt cellularity by proliferation is not sufficient to induce crypt fission, and factors other than increased crypt size by proliferation can control crypt fission. It is also probable that cell proliferation and crypt fission are independently regulated. Crypt fission appears to play a considerable role in the intestinal response to carcinogens.

Familial Burkitt's lymphoma in Papua New Guinea.

A study of Burkitt's lymphoma (BL) in Papua New Guinea for the years 1958-87 revealed four instances of familial BL. Incident cases occurred within 1 year of each other in the four families. Personal follow-up was possible for three of these families whose pedigrees showed that two or more siblings were affected. There was no significant variation of the incidence of BL by year of diagnosis or month of onset. There was significant variation in annual average incidence of BL between the three provinces studied, with the highest incidence in the Nuku and Lumi census districts (of the West Sepik Province). This is the first report of familial BL outside Africa.