Progesterone receptor gene variants and risk of endometrial cancer.

Prolonged excessive estrogen exposure unopposed by progesterone is widely accepted to be a risk factor for endometrial cancer development. The physiological function of progesterone is dependent upon the presence of its receptor [progesterone receptor (PGR)] and several studies have reported single nucleotide polymorphisms (SNPs) in the PGR gene to be associated with endometrial cancer risk. We sought to confirm the associations with endometrial cancer risk previously reported for four different PGR polymorphisms. A maximum of 2888 endometrial cancer cases and 4483 female control subjects from up to three studies were genotyped for four PGR polymorphisms (rs1042838, rs10895068, rs11224561 and rs471767). Logistic regression with adjustment for age, study, ethnicity and body mass index was performed to calculate odds ratios (ORs) and associated 95% confidence intervals (CIs) and P-values. Of the four SNPs investigated, only rs11224561 in the 3' region of the PGR gene was found to be significantly associated with endometrial cancer risk. The A allele of the rs11224561 SNP was associated with increased risk of endometrial cancer (OR per allele 1.31; 95% CI 1.12-1.53, P = 0.001, adjusted for age and study), an effect of the same magnitude and direction as reported previously. We have validated the endometrial cancer risk association with a tagSNP in the 3' untranslated region of PGR previously reported in an Asian population. Replication studies will be required to refine the risk estimate and to establish if this, or a correlated SNP, is the underlying causative variant.

[1]  B. Henderson,et al.  Genetic variation in the progesterone receptor gene and risk of endometrial cancer: a haplotype-based approach. , 2010, Carcinogenesis.

[2]  J. Long,et al.  Association of the progesterone receptor gene with endometrial cancer risk in a Chinese population , 2009, Cancer.

[3]  A. Spurdle,et al.  Re: Excess of early onset multiple myeloma in endometrial cancer probands and their relatives suggests common susceptibility. , 2008, Gynecologic oncology.

[4]  A. Whittemore,et al.  Association Between Single-Nucleotide Polymorphisms in Hormone Metabolism and DNA Repair Genes and Epithelial Ovarian Cancer: Results from Two Australian Studies and an Additional Validation Set , 2007, Cancer Epidemiology Biomarkers & Prevention.

[5]  H. Sasano,et al.  Biological roles of estrogen and progesterone in human endometrial carcinoma--new developments in potential endocrine therapy for endometrial cancer. , 2007, Endocrine journal.

[6]  Kiyoshi Ito,et al.  Hormone replacement therapy and cancers: the biological roles of estrogen and progestin in tumorigenesis are different between the endometrium and breast. , 2007, The Tohoku journal of experimental medicine.

[7]  T. Rebbeck,et al.  Case-control study of postmenopausal hormone replacement therapy and endometrial cancer. , 2006, American journal of epidemiology.

[8]  I. da Silva,et al.  Progesterone receptor (PROGINS) polymorphism and the risk of endometrial cancer development , 2006, International Journal of Gynecologic Cancer.

[9]  E. Weiderpass,et al.  No Association between Progesterone Receptor Gene +331G/A Polymorphism and Endometrial Cancer , 2006, Cancer Epidemiology Biomarkers & Prevention.

[10]  A. Romano,et al.  Aberrations in the progesterone receptor gene and the risk of recurrent endometrial carcinoma , 2005, The Journal of pathology.

[11]  I. B. Van den Veyver,et al.  Recurrent pregnancy loss due to familial and non‐familial habitual molar pregnancy , 2003, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[12]  P. Boyle,et al.  Cancer control in women. Update 2003 , 2003, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[13]  E. Steiner,et al.  Multivariate independent prognostic factors in endometrial carcinoma: A clinicopathologic study in 181 patients 10 years experience at the Department of Obstetrics and Gynecology of the Mainz University , 2003, International journal of gynecological cancer : official journal of the International Gynecological Cancer Society.

[14]  R. Kaaks,et al.  Obesity , Endogenous Hormones , and Endometrial Cancer Risk : A Synthetic Review 1 , 2002 .

[15]  G. Colditz,et al.  A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[16]  G. Heinze,et al.  Analysis of the human progesterone receptor gene polymorphism progins in Austrian ovarian carcinoma patients , 2001, International journal of cancer.

[17]  I Persson,et al.  Risk of endometrial cancer following estrogen replacement with and without progestins. , 1999, Journal of the National Cancer Institute.

[18]  Caroline Portmann,et al.  The laboratory assistant , 1999 .

[19]  P Chambon,et al.  Two distinct estrogen‐regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. , 1990, The EMBO journal.

[20]  G. Sutton,et al.  Steroid receptors and clinical outcome in patients with adenocarcinoma of the endometrium. , 1988, American journal of obstetrics and gynecology.

[21]  M. Pike,et al.  The dose-effect relationship between 'unopposed' oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk. , 1988, British Journal of Cancer.