The importance of a large sample cohort for studies on modifier genes influencing disease severity in FAP patients

Bente A Talseth-Palmer,Daniel Barker,Carli M Tops,Hans Fa Vasen,Eva K Andreassen,Rodney J Scott,Shantie Jagmohan-Changur,Allan Spigelman,Cliff Meldrum,Frederik J Hes,Juul T Wijnen,Tom Van Wezel

doi:10.1186/1897-4287-11-20

Abstract

BackgroundFamilial adenomatous polyposis (FAP) is usually characterised by the appearance of hundreds-to-thousands of adenomas throughout the colon and rectum and if left untreated the condition will develop into CRC with close to 100% penetrance. Germline mutations in the APC gene, which plays an integral role in the Wnt-signalling pathway, have been found to be responsible for 70-90% of FAP cases. Several studies suggest that modifier genes may play an important role in the development of CRC and possible modifiers for FAP have been suggested. Interestingly, a study has found that SNPs within ATP5A1 is associated with raised levels of ATP5A1 expression and high expression levels may facilitate CRC development. We aimed to determine if SNPs in ATP5A1 modify the risk of developing CRC/adenomas in FAP patients.MethodsGenomic DNA from 139 Australian FAP patients with a germline APC mutation underwent genotyping at the Australian Genome Research Facility (AGRF) utilising iPLEX GOLD chemistry with Sequenom MassArray on an Autoflex Spectrometer for 16 SNPs in the ATP5A1 gene. Association between ages of diagnosis/risk of CRC/adenomas was tested with Kaplan-Meier estimator analysis, logistic regression and cox proportional hazard regression.ResultsAn association between age of diagnosis of CRC and genotypes was observed for SNP rs2578189 (p = 0.0014), with individuals harbouring the variant genotype developing CRC 29 years earlier than individuals harbouring the wildtype genotype. Individuals harbouring the variant genotype of SNP rs2578189 were also at increased risk of CRC (HR = 13.79, 95% CI = 2.36-80.64, p = 0.004). We used an independent Dutch FAP cohort (n = 427) to validate our results; no association between SNP rs2578189 and CRC was observed.ConclusionThese results highlight the difficulties in studying a disease that has a high degree of intervention and also emphasize the importance of large sample sizes when searching for modifier genes in patients with an inherited predisposition to disease. To fully determine if there are genetic modifiers of disease in FAP we would encourage people that are interested in collaborating in future studies into the role of modifier genes in disease expression in FAP to join forces.

Highlights

Familial adenomatous polyposis (FAP) is usually characterised by the appearance of hundreds-to-thousands of adenomas throughout the colon and rectum and if left untreated the condition will develop into Colorectal cancer (CRC) with close to 100% penetrance
As cancer development in general is known to be influenced by both genetic and environmental factors, it is important to explore the possibility of different genes being involved in modifying the expression of disease in FAP patients - as patients harbouring identical mutations in adenomatous polyposis coli (APC) can have very different disease profiles that cannot be explained by environmental factors alone
As it has been suggested that raised levels of ATP5A1 expression have been linked to certain single nucleotide polymorphisms (SNPs) and high expression levels may facilitate CRC development [28], we aimed to study several SNPs in this gene to determine whether they influence the age of diagnosis or risk of developing CRC

Summary

Introduction

Familial adenomatous polyposis (FAP) is usually characterised by the appearance of hundreds-to-thousands of adenomas throughout the colon and rectum and if left untreated the condition will develop into CRC with close to 100% penetrance. Germline mutations in the APC gene, which plays an integral role in the Wnt-signalling pathway, have been found to be responsible for 70-90% of FAP cases. Familial adenomatous polyposis (FAP) accounts for approximately 1% of all CRCs [3] and is an inherited autosomal-dominant condition characterised by the appearance of hundreds to thousands of adenomas throughout the colon and rectum [3]. Considerable variability in disease expression is observed within families and among individuals with identical mutations exist [8] and it has been shown that the greater the number of colorectal adenomas, the greater the CRC risk is [9]. Most severe disease is associated with germline mutations at codon 1309 [14], while milder forms of disease with less than 100 adenomas and later ages of onset (attenuated FAP (AFAP)) is associated with codons 1595 [11,15]

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