Oklahoma City, OK, United States
Oklahoma City, OK, United States

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Jupe E.R.,InterGenetics Incorporated | Dalessandri K.M.,Surgeon Scientist | Mulvihill J.J.,University of Oklahoma | Miike R.,University of California at San Francisco | And 11 more authors.
BBA Clinical | Year: 2014

Background: We have combined functional gene polymorphisms with clinical factors to improve prediction and understanding of sporadic breast cancer risk, particularly within a high incidence Caucasian population. Methods: A polyfactorial risk model (PFRM) was built from both clinical data and functional single nucleotide polymorphism (SNP) gene candidates using multivariate logistic regression analysis on data from 5022 US Caucasian females (1671 breast cancer cases, 3351 controls), validated in an independent set of 1193 women (400 cases, 793 controls), and reassessed in a unique high incidence breast cancer population (165 cases, 173 controls) from Marin County, CA. Results: The optimized PFRM consisted of 22 SNPs (19 genes, 6 regulating steroid metabolism) and 5 clinical risk factors, and its 5-year and lifetime risk prediction performance proved significantly superior (~. 2-fold) over the Gail model (Breast Cancer Risk Assessment Tool, BCRAT), whether assessed by odds (OR) or positive likelihood (PLR) ratios over increasing model risk levels. Improved performance of the PFRM in high risk Marin women was due in part to genotype enrichment by a CYP11B2 (-344T/C) variant. Conclusions and general significance: Since the optimized PFRM consistently outperformed BCRAT in all Caucasian study populations, it represents an improved personalized risk assessment tool. The finding of higher Marin County risk linked to a CYP11B2 aldosterone synthase SNP associated with essential hypertension offers a new genetic clue to sporadic breast cancer predisposition. © 2014.

Dalessandri K.M.,PO Box 1173 | Miike R.,University of California at San Francisco | Wiencke J.K.,University of California at San Francisco | Farren G.,Marin Community Clinic | And 4 more authors.
Journal of the American College of Surgeons | Year: 2012

Background: Marin County, CA has very high incidence of breast cancer. Traditional risk factors, such as those included in the Gail model, do not effectively stratify breast cancer in this population. This retrospective case-control pilot study evaluates DNA from volunteers from a previous Marin County breast cancer epidemiology study. A polyfactorial risk model (OncoVue; InterGenetics Incorporated) that incorporates 22 polymorphisms in 19 genes and 5 clinical risk factors was used to stratify risk in Marin County women. Study Design: DNA genotyping was performed on 164 Caucasian women diagnosed with primary breast cancer in Marin County from 1997 to 1999 and 174 age- and ethnicity-matched control subjects. Individual lifetime risks were determined using the polyfactorial risk model and genotype frequencies in women at elevated risk were compared with the overall genotypes. Results: The vitamin D receptor VDR ApaI A2/A2 (rs7975232) homozygous polymorphism was present in high frequency in elevated-risk women. Sixty-four percent of elevated-risk women had the VDR Apa1 A2/A2 genotype compared with only 34% in the overall study, a statistically significant 1.9-fold difference (p = 0.0003). VDR Apa1 A2/a1 and a1/a1 genotypes were also present, but in lower frequencies. Conclusions: The high frequency of the VDR Apa1 A2/A2 homozygous polymorphism in women designated as elevated risk for breast cancer by the polyfactorial risk model might be related to the high incidence rates of breast cancer in Marin County, CA. Vitamin D supplementation could modify risk of breast cancer in this population. © 2012 American College of Surgeons.

Yue W.,University of Virginia | Yager J.D.,University of Virginia | Yager J.D.,Johns Hopkins University | Wang J.-P.,University of Virginia | And 3 more authors.
Steroids | Year: 2013

Long term exposure to estrogens is associated with an increased risk of breast cancer. The precise mechanisms responsible for estrogen mediated carcinogenesis are not well understood. The most widely accepted theory holds that estradiol (E2), acting through estrogen receptor alpha (ERα), stimulates cell proliferation and initiates mutations arising from replicative errors occurring during pre-mitotic DNA synthesis. The promotional effects of E2 then support the growth of cells harboring mutations. Over a period of time, sufficient numbers of mutations accumulate to induce neoplastic transformation. Laboratory and epidemiological data also suggest that non-receptor mediated mechanisms resulting from the genotoxic effects of estrogen metabolites are involved in breast cancer development. This manuscript critically reviews existing data implicating both ER-dependent and -independent mechanisms. The weight of evidence supports the possibility that both mechanisms are involved in the carcinogenic process. In addition, estrogen metabolites likely modulate stem cell functionality and cancer progression. The roles of ER dependent and independent actions in the carcinogenic process are pertinent to the consideration of breast cancer preventative agents as anti-estrogens block only receptor mediated pathways whereas the aromatase inhibitors block both. © 2012 Elsevier Inc. All rights reserved.

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