Contribution of the CHEK2 1100delC variant to risk of multiple colorectal adenoma and carcinoma
Introduction
A recent twin study has indicated that ∼30% of all colorectal cancer can be ascribed to inherited susceptibility [1]. However, fewer than 5% of cases can be ascribed to dominant syndromes for which mutations have been found to be causative [2], [3]—including APC, DNA mismatch repair genes, ALK3, SMAD4, LKB1/STK11. The remaining inherited susceptibility is likely to be composed of a combination of dominantly inherited genes with moderate penetrance and variants, such as APC1307K [4], that act as a low penetrance susceptibility allele.
Since the effects of low penetrance variants are undetectable through linkage analysis for most practical purposes, their identification is reliant upon allelic population and/or candidate genes studies [5]. Importantly, such studies have shown to be greatly empowered by analysing cases with a family history of colorectal cancer or multiple adenomas.
Aneuploidy is a characteristic of a subset of colorectal cancers and recent work has suggested that mitotic checkpoint defects play a role in its development. CHEK2 is one of the cell cycle checkpoint genes coding for a family of proteins that sense damage in eukaryotic cells. Failure of checkpoint function results in genomic instability, predisposing cells to neoplastic transformation and tumour progression [6], [7], [8]. Mammalian cells adopt checkpoint regulation by phosphorylation and stabilisation of TP53, to delay cell cycle progression. CHEK2 acts upstream of TP53 in response to DNA damage by phosphorylation and thus stabilisation of TP53 leading to cell cycle arrest in G1 phase [7].
Germline variation in CHEK2 has been shown to confer cancer susceptibility. Heterozygous mutations have been identified in patients with TP53-negative Li–Fraumeni syndrome [9]. Furthermore, the CHEK2 1100delC variant carried by 1% of the population has been shown to act as a low penetrance allele for breast cancer [10], [11]. The recent observation that this variant confers an increased risk of prostate cancer [12] suggests that the CHEK2 1100delC allele has pleiotropic effects on cancer risk. To further our knowledge about the contribution of CHEK2 1100delC to cancer incidence we have analysed a series of 149 patients with multiple colorectal adenomas, some of whom developed colorectal cancer.
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Materials and methods
Patients. One-hundred and forty-nine patients who had multiple adenomas were studied. Patients were ascertained through genetics departments in the United Kingdom (St Mark's Hospital, Harrow; Churchill Hospital, Oxford; and Guy's Hospital, London) with multiple (5–100) synchronous or metachronous colorectal adenomas. Patients had been referred to these centres either because of a family history of colorectal tumours or because they had presented with symptoms and multiple polyps, suggesting the
Results and discussion
Three of the patients (2%; 95% CI: 0.4–5.7) carried the CHEK2 1100delC variant (Table 1). Using a series of microsatellite markers that included the monosatellite marker BAT26, tumours and adenomas from all three patients were evaluated for miss-match repair deficiency. All tumours were shown to be microsatellite stable.
Previously we have shown that the prevalence of CHEK2 1100delC in the population is 1.1% (18/1620) [10]. On the basis of this carrier frequency there is no significant
Acknowledgments
This work was undertaken with support from Cancer Research UK.
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