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Hereditary Cancer in Clinical Practice
Published in: Hereditary Cancer in Clinical Practice 1/2013

Open Access 01-12-2013 | Research

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

Authors: Bente A Talseth-Palmer, Juul T Wijnen, Eva K Andreassen, Daniel Barker, Shantie Jagmohan-Changur, Carli M Tops, Cliff Meldrum, Allan Spigelman, Frederik J Hes, Tom Van Wezel, Hans FA Vasen, Rodney J Scott, The Dutch Cancer Genetics Group

Published in: Hereditary Cancer in Clinical Practice | Issue 1/2013

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Abstract

Background

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. 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.

Methods

Genomic 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.

Results

An 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.

Conclusion

These 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.
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Metadata
Title
The importance of a large sample cohort for studies on modifier genes influencing disease severity in FAP patients
Authors
Bente A Talseth-Palmer
Juul T Wijnen
Eva K Andreassen
Daniel Barker
Shantie Jagmohan-Changur
Carli M Tops
Cliff Meldrum
Allan Spigelman
Frederik J Hes
Tom Van Wezel
Hans FA Vasen
Rodney J Scott
The Dutch Cancer Genetics Group
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Hereditary Cancer in Clinical Practice / Issue 1/2013
Electronic ISSN: 1897-4287
DOI
https://doi.org/10.1186/1897-4287-11-20

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