title: Modification of menopausal hormone therapy-associated colorectal cancer risk by polymorphisms in sex steroid signaling, metabolism and transport related genes.
abstract: The mechanisms underlying the association of menopausal hormone therapy (MHT) with reduced colorectal cancer (CRC) risk are unknown and the identification of genetic modifiers may yield further insight. We explored the effect modification of MHT-associated CRC risk in postmenopausal women by 47 polymorphisms with known or putative functional relevance in 16 candidate genes related to hormone metabolism (COMT, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP3A4, CYP17A1, GSTP, and HSD17B1), transport (ABCB1), and signaling (ESR1, ESR2, SHBG, PGR, and NR1I2). A total of 685 CRC patients and 684 healthy controls from a German population-based case-control study (DACHS) were genotyped. Multiplicative statistical interaction between polymorphisms and ever MHT use as well as duration of use was assessed using multivariate logistic regression. CRC risk associated with ever MHT use as well as with duration was significantly modified by rs1202168 in the transporter gene ABCB1 (P interaction=0.04). The MHT-associated risk reduction was not significant in homozygous non-carriers (odds ratio (OR) ever use=0.84, 95% confidence interval (CI) 0.53-1.34; OR per 5 year duration=0.94, 95% CI 0.83-1.08), while homozygous carriers of the minor T allele had a 57% lower risk with ever use of MHT (95% CI 0.21-0.88) and a 22% lower risk per 5 years of MHT use (95% CI 0.62-0.97). Significant effect modification was also observed for the ESR1_rs910416 polymorphism (P interaction=0.03 for ever use and 0.07 for duration of use), whereby the decreased risk was attenuated in homozygous carriers of the minor C allele (OR ever use=0.87, 95% CI 0.48-1.60, OR per 5 year duration=0.99, 95% CI 0.83-1.18). Results of this exploratory study provide first evidence that polymorphisms in genes related to estrogen transport and signaling may modify MHT-associated CRC risk but warrant replication in an independent population.
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Rudolph
authors.forename: Juan
authors.initials: J
authors.lastname: Sainz
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hein
authors.forename: Michael
authors.initials: M
authors.lastname: Hoffmeister
authors.forename: Bernd
authors.initials: B
authors.lastname: Frank
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001692:Biological Transport / Q000235:genetics; D002277:Carcinoma / Q000209:etiology* / Q000235:genetics; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000235:genetics; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D005260:Female; D056726:Genetic Association Studies; D012739:Gonadal Steroid Hormones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000502:physiology; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D012739:Gonadal Steroid Hormones