Abstract 2855: Estrogen transport, metabolism, binding and signalling related single nucleotide polymorphisms modulate menopausal hormone therapy effect on risk of colorectal cancer
Authors: Rudolph Anja , Sainz Juan P. , Hein Rebecca , Hoffmeister Michael , Frank Bernd , Försti Asta , Hemminki Kari , Brenner Hermann , Chang-Claude Jenny 
Published: February 2011

Colorectal cancer (CRC) is the third most common cancer type worldwide and its incidence varies among different populations and among genders. Exogenous hormone use has been associated with reduced CRC risk [1]; therefore sex steroids may play an important role in colon carcinogenesis [2]. We hypothesized that polymorphisms in estrogen metabolism and cellular binding genes influence the level of hormone exposure and therefore modify associated CRC risk. Thus we aim to explore effect modification of menopausal hormone therapy by polymorphisms in selected genes on the risk of CRC in women. We genotyped 46 single nucleotide polymorphisms (SNPs) in estrogen transport, metabolism, binding and signalling genes in study subjects from a German population-based case-control study (DACHS Study) using KASpar assays (KBiosciences). Single SNPs were analysed in 733 female CRC patients (241 rectum cancer cases, 492 colon cancer cases) and 721 healthy controls. Unconditional logistic regression adjusted for matching variables (age, county of residence) and potential confounders (body mass index, ever underwent colonoscopy, diabetes, menopausal hormone therapy (HT), physical activity, regular use of NSAIDs) was performed assuming a log-additive mode of inheritance. The analysis was carried out for binary and nominal responses (cancer site). Multiplicative effect modification was assessed by an interaction term between HT use (ever/never and current/past/never) and SNP encoded according to a log-additive model. SNPs in four estrogen metabolism genes (CYP1B1, CYP2C19, CYP2C9, HSD17B1) and three SNPs in ESR2 gene were significantly associated with risk for CRC in women (p trend &lt;0.05). Polymorphisms in ABCB1, CYP2C9, and ESR1 modified significantly (p interaction &lt;0.05) the effect of ever HT use on overall CRC risk. Genetic variants in ESR2 showed significant effect modification only for colon cancer. Modification of the effect of current HT use was also found for the ABCB1, ESR1 and ESR2 polymorphisms. Similar effect modification of HT use by ESR1 and ESR2 polymorphisms previously reported for breast cancer risk [3] suggest that the genetic modification of reduced risk for CRC associated with HT use may be biologically plausible. Nevertheless, these first observations of effect modification for colorectal cancer risk need to be replicated in further studies.

References:

1. Prentice, R.L. & G.L. Anderson, Annu Rev Public Health, 2008; 29: p. 131-50.

2. Kennelly, R. et al., Lancet Oncol, 2008; 9(4): 385-91

3. Abbas, S. et al., Int J Cancer, 2009; electronically published ahead of print 2009/09/08

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2855.