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PS2-41: The FTO Gene, Its Variants and Post-menopausal Breast Cancer

ABSTRACT: Background Adiposity is a well-accepted risk factor for post-menopausal breast cancer (PMBC). SNPs of the FTO gene, located on chromosome 16q12.2, have been associated with adiposity by lowering the activity of the enzyme lipase. This gene also encodes for a protein involved in DNA damage repair pathway. The current epidemiologic paradigm associates the risk of PMBC with increased aromatization of androstenedione to estradial in peripheral adipose tissue and increased serum levels of insulin-like growth-factors. The increased systemic inflammation because of adiposity motivates the inquiries for other plausible biochemical mechanism. We are conducting a pilot nested case-controls study to investigate the association between 3 SNPs of FTO gene with the risk of PMBC, adjusted for the major risk factors. Presently data are available from 50 cases and 202 controls from the cohort of MyCode Biobanking Project at Geisinger Health System. Methods We genotyped the 3 SNPs (rs1861868, rs1477196 and rs9939609) of the gene. Generalized linear model was used to evaluate the association between these 3 SNPs. We also conducted analyses of hyplotypes for 2-SNPs and 3-SNPs association, respectively; odds ratios (OR) and 95% confidence intervals (CI) were calculated to estimate the association between haplotypes and PMBC, and between the genotypes of each SNPs (as an ordinal variable) and PMBC applying unconditional logistic regression modeling approach, while controlling for BMI, age, parity status (=3 or <3) and family history for breast cancer. Results Our analyses suggest that 2 of the SNPs (rs1861868 and rs1477196) most likely form a haplotype (P= 0.002) that is exclusive of the third SNP (rs9939609, P>0.3). None of these SNPs or hyplotypes was associated with BMI (p>0.4), diabetes and metabolic syndrome (P>0.15). Results from the multivariate logistic model suggested a trend toward a potential association (OR=1.68, CI=0.67–4.18, P=0.09) between the (rs1861868) SNP and PMBC. Conclusion Our pilot study attempts to evaluate the association between SNPs of the of FTO gene with PMBC, independent of BMI or other risk factors for PMBC. One SNP was found to be likely associated with PMBC, but the present small sample size eclipses the power of identifying a definite association.

SUBMITTER: Yan X

PROVIDER: S-EPMC3251444 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Project description:Chronic internal inflammation secondary to adiposity is a risk factor for sporadic breast cancer and Post-Menopausal Breast Cancer (PMBC) is largely defined as such. Adiposity is one of the clinical criteria for the diagnosis of Metabolic Syndrome (MetS) and is a risk factor for PMBC. We examined SNPs of eight genes implicated in adiposity, inflammation and cell proliferation in a Prospective-specimen-collection, Retrospective-Blinded-Evaluation (PRoBE) design approach. A total of 180 cases and 732 age-matched controls were identified from the MyCode prospective biobank database and then linked to the Clinical Decision Information System, an enterprise-wide data warehouse, to retrieve clinico-demographic data. Samples were analyzed in a core laboratory where the personnel were masked to their status. Results from multivariate logistic regression yielded one SNP (rs2922126) in the GHSR as protective against PMBC among homozygotes for the minor allele (A/A) (OR?=?0.4, 95% CI 0.18-.89, P-value?=?.02); homozygosity for the minor allele (C/C) of the SNP (rs889312) of the gene MAP3K1 was associated with the risk of PMBC (OR?=?2.41, 95% CI 1.25-4.63 P-value?=?.008). Advanced age was protective against PMBC (OR?=?0.98, 95% CI 0.95-0.99, P-value?=?.02). Family history of breast cancer (OR?=?2.22, 95% CI 1.14-4.43. P?=?.02), HRT (OR?=?3.35; 95% CI 2.15-5.21, P?<?.001), and MetS (OR?=?14.83, 95% CI 5.63-39.08, P?<?.001) and interaction between HRT and MetS (OR?=?39.38, 95% CI 15.71-98.70, P?<?.001) were associated with the risk of PMBC. We did not detected significant interactions between SNPs or between the SNPs and the clinico-demographic risk factors. Our study further confirms that MetS increases the risk of PMBC and argues in favor of reducing exposure to HRT. Our findings are another confirmation that low penetrance genes involved in the inflammatory pathway, i.e. MAP3KI gene, may have a plausible causative role in PMBC. Given the fact that genetic constitutionality of individuals cannot be changed, efforts should be focused on life style modification.

Project description:Background: Breast cancer patients present lower 1,25(OH)2D3 or 25(OH)D3 serum levels than unaffected women. Although 1,25(OH)2D3 pharmacological concentrations of 1,25(OH)2D3 may exert antiproliferative effects in breast cancer cell lines, much uncertainty remains about the effects of calcitriol supplementation in tumor specimens in vivo. We have evaluated tumor dimension (ultrassonography), proliferative index (Ki67 expression), 25(OH)D3 serum concentration and gene expression profile, before and after a short term calcitriol supplementation (dose to prevent osteoporosis) to post-menopausal patients. Results: Thirty three patients with operable disease had tumor samples evaluated. Most of them (87.5%) presented 25(OH)D3 insufficiency (<30 ng/mL). Median period of calcitriol supplementation was 30 days. Although tumor dimension did not vary, Ki67 immunoexpression decreased after supplementation. Transcriptional analysis of 15 matched pre/post-supplementation samples using U133 Plus 2.0 GeneChip (Affymetrix) revealed 18 genes over-expressed in post-supplementation tumors. As a technical validation procedure, expression of four genes was also determined by RT-qPCR and a direct correlation was observed between both methods (microarray vs PCR). To further explore the effects of near physiological concentrations of calcitriol on breast cancer samples, an ex vivo model of fresh tumor slices was utilized. Tumor samples from another 12 post-menopausal patients were sliced and treated in vitro with slightly high concentrations of calcitriol (0.5nM), that can be attained in vivo, for 24 hours In this model, expression of PBEF1, EGR1, ATF3, FOS and RGS1 was not induced after a short exposure to calcitriol. Conclusions: In our work, most post-menopausal breast cancer patients presented at least 25(OH)D3 insufficiency. In these patients, a short period of calcitriol supplementation may prevent tumor growth and reduce Ki67 expression, probably associated with discrete transcriptional changes. This observation deserves further investigation to better clarify calcitriol effects in tumor behavior under physiological conditions. Post-menopausal patients with early stage breast cancer, in the absence of distant metastasis, were invited to take part in the study. This protocol was approved by the Institutional Ethics Committee, and a written informed consent was signed by all participants. Patients had blood and tumor samples collected during biopsy, and were prescribed calcitriol supplementation, (Rocaltrol)TM 0.50 μg/day PO, as recommended for osteoporosis prevention. Tumor specimens obtained during biopsy (pre-supplementation) or breast surgery (post-supplementation) were hand dissected and samples with at least 70% tumor cells were further processed. Breast surgery followed in about one month

Project description:BackgroundSeveral observational studies have suggested a protective effect of oral bisphosphonates (BP) on the risk of breast cancer, but no such association has been seen in randomized control trials. The role of oral BP in breast cancer prevention remains unclear.AimTo investigate the association between different levels of BP exposure and breast cancer incidence in a cohort of osteoporotic post-menopausal women.Subjects and methodsThis historical prospective study was conducted using the computerized databases of Maccabi Healthcare Services (MHS) in Israel. Included in the study were osteopenic and osteoporotic women aged 55-75 years who started BP therapy between 1998 and 2012. The subjects were enrolled in MHS for at least 3 years before therapy initiation, and had a minimum follow-up of 5 years in MHS. Women with a previous cancer, and women treated with selective estrogen receptor modulators (SERMs) were excluded. BP exposure was expressed in quintiles of proportion of days covered (PDC) with BP during follow-up period and cancer incidence was ascertained by the Israel National Tumor Registry. Person-years of follow-up began on January 1st, 1998 and ended at the date of cancer diagnosis, death, or December 31st, 2012, whichever occurred first.ResultsA total of 11,717 patients (mean age = 66.87 ± 4.38) were eligible for the analysis. During a total of 130,252 person-years of follow-up, (mean 7.2 years) 173 incident cases of breast cancer were diagnosed. Compared to women with a PDC with BP of 20% or lower, the adjusted hazard ratio for breast cancer were HR = 0.81 (95%CI: 0.48-1.39), HR = 0.82 (95%CI: 0.50-1.33), HR = 0.72 (95%CI:0.45-1.15) and HR = 1.14 (95%CI:0.76-1.70) among women with 20-40%, 40-60%, 60%-80%, and 80% or higher, PDC, respectively.ConclusionIn this study, we did not find a significant association between oral BP therapy for osteoporosis and the risk of breast cancer in postmenopausal women. The discrepancy between our results and the reports of such an association in observational studies might originate from an indication bias.

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PS2-41: The FTO Gene, Its Variants and Post-menopausal Breast Cancer

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