Recent studies have shown that the G-allele of MDM2 SNP309 (T/G) in the p53 tumour suppressor pathway can accelerate tumorigenesis and alter the risk of various cancers in women and not in men. In this report, data are presented from two independent groups of patients that suggest that the G-allele of SNP309 accelerates colorectal tumour formation only in women, and that lend further support to the model that primarily female-specific hormones, such as oestrogen, could either directly or indirectly allow for the G-allele of SNP309 to accelerate tumour formation in women.T he importance of the p53 stress response pathway in the suppression of tumorigenesis in humans has been shown in many types of cancers. One of the strongest pieces of evidence is the very high rate at which the p53 gene is weakened by somatic mutations in tumours. 4 One of the highest rates of p53 mutation is found in colorectal cancers (CRC), wherein up to 44% of all tumours harbour a p53 mutation.5 Therefore, it is likely, and indeed there is evidence to support, that single-nucleotide polymorphisms that alter the activity of the p53 stress response pathway can result in the development of CRC in humans. [6][7][8] A central node in the p53 pathway is the MDM2 protein, a direct negative regulator of p53.9 A single-nucleotide polymorphism (SNP309 T/G) was found in the promoter of the MDM2 gene, whereby the G-allele resulted in higher levels of MDM2 RNA and protein, and was associated with the attenuation of the p53 pathway both in vitro and in vivo.10 In a survey study of the possible effects of the SNP309 locus in three different cancers, data were presented that suggested a sex difference in the effect of SNP309 in CRC.3 Specifically, it was found that the G-allele of SNP309 was enriched in women diagnosed with CRC compared with the men diagnosed with CRC. Secondly, women with the G-allele of SNP309 showed an earlier average age of diagnosis compared with T/T women, whereas no such observation was made in the male patients. Although these results were separately significant, after adjusting for multiple hypotheses testing, the significance of these observations was lost.Recent studies of the MDM2 SNP309 locus in other cancers have shown that the G-allele of SNP309 is significantly associated with an earlier and greater frequency of tumour formation only in women.1 2 In one report, it was reasoned that, since the SNP309 locus is in a region of the MDM2 promoter, which is regulated by hormonal signalling pathways, and the G-allele of SNP309 increases the affinity of a well-described co-transcriptional activator of nuclear hormone receptors, such as Sp1, the SNP309 locus could alter the effects of hormones on tumorigenesis.1 The results of four independent studies of three different sporadic cancers (diffuse large B cell lymphoma, soft tissue sarcoma and invasive ductal breast carcinoma) supported the model that primarily female-specific hormones, such as oestrogen, could either directly or indirectly allow for the G-allele of SNP309 to accelera...