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Articles by I. J Jacobs
Total Records ( 2 ) for I. J Jacobs
  A. E Teschendorff , U Menon , A Gentry Maharaj , S. J Ramus , D. J Weisenberger , H Shen , M Campan , H Noushmehr , C. G Bell , A. P Maxwell , D. A Savage , E Mueller Holzner , C Marth , G Kocjan , S. A Gayther , A Jones , S Beck , W Wagner , P. W Laird , I. J Jacobs and M. Widschwendter
 

Polycomb group proteins (PCGs) are involved in repression of genes that are required for stem cell differentiation. Recently, it was shown that promoters of PCG target genes (PCGTs) are 12-fold more likely to be methylated in cancer than non-PCGTs. Age is the most important demographic risk factor for cancer, and we hypothesized that its carcinogenic potential may be referred by irreversibly stabilizing stem cell features. To test this, we analyzed the methylation status of over 27,000 CpGs mapping to promoters of ~14,000 genes in whole blood samples from 261 postmenopausal women. We demonstrate that stem cell PCGTs are far more likely to become methylated with age than non-targets (odds ratio = 5.3 [3.8–7.4], P < 10–10), independently of sex, tissue type, disease state, and methylation platform. We identified a specific subset of 69 PCGT CpGs that undergo hypermethylation with age and validated this methylation signature in seven independent data sets encompassing over 900 samples, including normal and cancer solid tissues and a population of bone marrow mesenchymal stem/stromal cells (P < 10–5). We find that the age-PCGT methylation signature is present in preneoplastic conditions and may drive gene expression changes associated with carcinogenesis. These findings shed substantial novel insights into the epigenetic effects of aging and support the view that age may predispose to malignant transformation by irreversibly stabilizing stem cell features.

  H Song , S. J Ramus , S. K Kjaer , R. A DiCioccio , G Chenevix Trench , C. L Pearce , E Hogdall , A. S Whittemore , V McGuire , C Hogdall , J Blaakaer , A. H Wu , D. J Van Den Berg , D. O Stram , U Menon , A Gentry Maharaj , I. J Jacobs , P. M Webb , J Beesley , X Chen , The Australian Ovarian Cancer Study Group the Australian Cancer (Ovarian) Study , J. A Doherty , J Chang Claude , S Wang Gohrke , M. T Goodman , G Lurie , P. J Thompson , M. E Carney , R. B Ness , K Moysich , E. L Goode , R. A Vierkant , J. M Cunningham , S Anderson , J. M Schildkraut , A Berchuck , E. S Iversen , P. G Moorman , M Garcia Closas , S Chanock , J Lissowska , L Brinton , H Anton Culver , A Ziogas , W. R Brewster , B. A.J Ponder , D. F Easton , S. A Gayther , P. D.P Pharoah and on behalf of the Ovarian Cancer Association Consortium (OCAC)
 

Because both ovarian and breast cancer are hormone-related and are known to have some predisposition genes in common, we evaluated 11 of the most significant hits (six with confirmed associations with breast cancer) from the breast cancer genome-wide association study for association with invasive ovarian cancer. Eleven SNPs were initially genotyped in 2927 invasive ovarian cancer cases and 4143 controls from six ovarian cancer case–control studies. Genotype frequencies in cases and controls were compared using a likelihood ratio test in a logistic regression model stratified by study. Initially, three SNPs (rs2107425 in MRPL23, rs7313833 in PTHLH, rs3803662 in TNRC9) were weakly associated with ovarian cancer risk and one SNP (rs4954956 in NXPH2) was associated with serous ovarian cancer in non-Hispanic white subjects (P-trend < 0.1). These four SNPs were then genotyped in an additional 4060 cases and 6308 controls from eight independent studies. Only rs4954956 was significantly associated with ovarian cancer risk both in the replication study and in combined analyses. This association was stronger for the serous histological subtype [per minor allele odds ratio (OR) 1.07 95% CI 1.01–1.13, P-trend = 0.02 for all types of ovarian cancer and OR 1.14 95% CI 1.07–1.22, P-trend = 0.00017 for serous ovarian cancer]. In conclusion, we found that rs4954956 was associated with increased ovarian cancer risk, particularly for serous ovarian cancer. However, none of the six confirmed breast cancer susceptibility variants we tested was associated with ovarian cancer risk. Further work will be needed to identify the causal variant associated with rs4954956 or elucidate its function.

 
 
 
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