In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3182-3182
Abstract:
While endometriosis is a known risk factor for endometrioid and clear-cell ovarian cancer subtypes, a convincing link between endometriosis and endometrial cancer has been difficult to establish epidemiologically. Such a link has been speculated as both are hormonally regulated diseases of abnormal endometrium growth and they share a number of risk factors (e.g. early menarche, low parity) and pathological features (e.g. progesterone resistance). To investigate the genetic relationship between endometriosis and endometrial cancer, we recently applied a cross-disease analysis approach utilizing genome-wide association study (GWAS) data1,2. Genetic prediction analyses revealed significant (P=7.8 × 10-10) shared genetic architecture underlying endometriosis and endometrial cancer, indicating the existence of genetic loci that influence the risk of both diseases. We then performed a cross-disease meta-analysis which revealed 102 SNPs at 65 independent genetic loci with good support (P-values & lt; 10-5) for association with risk of both diseases. To date, we have validation for two of these loci in an independent sample of 4,400 endometrial cancer cases and 28,000 controls. A gene at one locus, the protein tyrosine phosphatase receptor type D gene (PTPRD: best SNP P-value =8.8 × 10-8, Odds Ratio=1.08±0.03) has been suggested as a tumour suppressor in neuroblastoma, and as a type II diabetes candidate. The second locus is in the region of the transcription factor A-P 2 beta-like 1 (TFAP2D) and beta (TFAP2B) genes (best SNP P-value 8.2 × 10-7, Odds Ratio 1.07±0.03), the latter of which has been recently associated with metabolic syndrome, BMI and overweight. These genes are entirely plausible candidates for involvement in endometrial cancer aetiology given the increased risk of endometrial cancer with increasing BMI. Imputation to the April 2012 release of the 1000 Genomes project data has revealed additional SNPs in both regions with equal or better evidence of statistical support, and we are currently performing bioinformatic analyses to search for potentially functional SNPs in both regions for genotyping in additional endometrial cancer samples. In summary, our results from prediction analysis indicate that genetic loci contribute to both endometriosis and endometrial cancer susceptibility, and case-control association analyses suggest two plausible candidate genes for further study. These findings support the value of cross-disease meta-analyses for finding new genes contributing to cancer susceptibility. Citation Format: Jodie N. Painter, Stuart Macgregor, Ian Tomlinson, Dale R. Nyholt, Krina Zondervan, Deborah Thompson, Alison Dunning, Douglas Easton, Grant W. Montgomery, Amanda B. Spurdle. A GWAS-based cross-disease approach suggests genes predisposing to risk of endometriosis and endometrial cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3182. doi:10.1158/1538-7445.AM2013-3182
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-3182
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
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