Dataset Information

Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.

ABSTRACT:

Background

Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.

Methods

In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.

Results

The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).

Conclusion

These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

SUBMITTER: Chornokur G

PROVIDER: S-EPMC4474865 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.

Chornokur Ganna G Lin Hui-Yi HY Tyrer Jonathan P JP Lawrenson Kate K Dennis Joe J Amankwah Ernest K EK Qu Xiaotao X Tsai Ya-Yu YY Jim Heather S L HS Chen Zhihua Z Chen Ann Y AY Permuth-Wey Jennifer J Aben Katja K H KK Anton-Culver Hoda H Antonenkova Natalia N Bruinsma Fiona F Bandera Elisa V EV Bean Yukie T YT Beckmann Matthias W MW Bisogna Maria M Bjorge Line L Bogdanova Natalia N Brinton Louise A LA Brooks-Wilson Angela A Bunker Clareann H CH Butzow Ralf R Campbell Ian G IG Carty Karen K Chang-Claude Jenny J Cook Linda S LS Cramer Daniel W DW Cunningham Julie M JM Cybulski Cezary C Dansonka-Mieszkowska Agnieszka A du Bois Andreas A Despierre Evelyn E Dicks Ed E Doherty Jennifer A JA Dörk Thilo T Dürst Matthias M Easton Douglas F DF Eccles Diana M DM Edwards Robert P RP Ekici Arif B AB Fasching Peter A PA Fridley Brooke L BL Gao Yu-Tang YT Gentry-Maharaj Aleksandra A Giles Graham G GG Glasspool Rosalind R Goodman Marc T MT Gronwald Jacek J Harrington Patricia P Harter Philipp P Hein Alexander A Heitz Florian F Hildebrandt Michelle A T MA Hillemanns Peter P Hogdall Claus K CK Hogdall Estrid E Hosono Satoyo S Jakubowska Anna A Jensen Allan A Ji Bu-Tian BT Karlan Beth Y BY Kelemen Linda E LE Kellar Mellissa M Kiemeney Lambertus A LA Krakstad Camilla C Kjaer Susanne K SK Kupryjanczyk Jolanta J Lambrechts Diether D Lambrechts Sandrina S Le Nhu D ND Lee Alice W AW Lele Shashi S Leminen Arto A Lester Jenny J Levine Douglas A DA Liang Dong D Lim Boon Kiong BK Lissowska Jolanta J Lu Karen K Lubinski Jan J Lundvall Lene L Massuger Leon F A G LF Matsuo Keitaro K McGuire Valerie V McLaughlin John R JR McNeish Iain I Menon Usha U Milne Roger L RL Modugno Francesmary F Moysich Kirsten B KB Ness Roberta B RB Nevanlinna Heli H Eilber Ursula U Odunsi Kunle K Olson Sara H SH Orlow Irene I Orsulic Sandra S Weber Rachel Palmieri RP Paul James J Pearce Celeste L CL Pejovic Tanja T Pelttari Liisa M LM Pike Malcolm C MC Poole Elizabeth M EM Risch Harvey A HA Rosen Barry B Rossing Mary Anne MA Rothstein Joseph H JH Rudolph Anja A Runnebaum Ingo B IB Rzepecka Iwona K IK Salvesen Helga B HB Schernhammer Eva E Schwaab Ira I Shu Xiao-Ou XO Shvetsov Yurii B YB Siddiqui Nadeem N Sieh Weiva W Song Honglin H Southey Melissa C MC Spiewankiewicz Beata B Sucheston Lara L Teo Soo-Hwang SH Terry Kathryn L KL Thompson Pamela J PJ Thomsen Lotte L Tangen Ingvild L IL Tworoger Shelley S SS van Altena Anne M AM Vierkant Robert A RA Vergote Ignace I Walsh Christine S CS Wang-Gohrke Shan S Wentzensen Nicolas N Whittemore Alice S AS Wicklund Kristine G KG Wilkens Lynne R LR Wu Anna H AH Wu Xifeng X Woo Yin-Ling YL Yang Hannah H Zheng Wei W Ziogas Argyrios A Hasmad Hanis N HN Berchuck Andrew A Iversen Edwin S ES Schildkraut Joellen M JM Ramus Susan J SJ Goode Ellen L EL Monteiro Alvaro N A AN Gayther Simon A SA Narod Steven A SA Pharoah Paul D P PD Sellers Thomas A TA Phelan Catherine M CM

PloS one 20150619 6

<h4>Background</h4>Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contribute ...[more]

PMID: 26091520

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Project description:BACKGROUND:Recent studies have identified several single nucleotide polymorphisms (SNPs) in the population that are associated with variations in the risks of many different diseases including cancers such as breast, prostate and colorectal. For ovarian cancer, the known highly penetrant susceptibility genes (BRCA1 and BRCA2) are probably responsible for only 40% of the excess familial ovarian cancer risks, suggesting that other susceptibility genes of lower penetrance exist. METHODS:We have taken a candidate approach to identifying moderate risk susceptibility alleles for ovarian cancer. To date, we have genotyped 340 SNPs from 94 candidate genes or regions, in up to 1,491 invasive epithelial ovarian cancer cases and 3,145 unaffected controls from three different population based studies from the UK, Denmark and USA. RESULTS:After adjusting for population stratification by genomic control, 18 SNPs (5.3%) were significant at the 5% level, and 5 SNPs (1.5%) were significant at the 1% level. The most significant association was for the SNP rs2107425, located on chromosome 11p15.5, which has previously been identified as a susceptibility allele for breast cancer from a genome wide association study (P-trend = 0.0012). When SNPs/genes were stratified into 7 different pathways or groups of validation SNPs, the breast cancer associated SNPs were the only group of SNPs that were significantly associated with ovarian cancer risk (P-heterogeneity = 0.0003; P-trend = 0.0028; adjusted (for population stratification) P-trend = 0.006). We did not find statistically significant associations when the combined data for all SNPs were analysed using an admixture maximum likelihood (AML) experiment-wise test for association (P-heterogeneity = 0.051; P-trend = 0.068). CONCLUSION:These data suggest that a proportion of the SNPs we evaluated were associated with ovarian cancer risk, but that the effect sizes were too small to detect associations with individual SNPs.

Project description:Background Ovarian cancer is the most lethal tumor of the female reproductive system. Establishing a methodology to screen and diagnose ovarian cancer in the early stage is important. Exosomes have been shown to be loaded with tumor-associated molecules. In this study, we compared the proteins loaded in exosomes from the peripheral circulation of epithelial ovarian carcinoma (EOC) patients and controls. Methods Exosomes were purified via ultracentrifugation plus 0.22 µm filtration from the blood of EOC patients and patients with pelvic floor dysfunction (PFD). Tumor tissues and normal ovarian tissues were also obtained. Proteomic analyses of exosomes and tumor/normal ovarian tissues were performed with isobaric tags for relative and absolute quantitation (iTRAQ) and high-performance liquid chromatography/mass spectrometry (HPLC/MS) analyses. The LocDB (http://www.rostlab.org/services/locDB), PANTHER (http://www.pantherdb.org/) and Vesiclepedia databases were used for biological information analysis. Results We identified 408 differentially expressed proteins in exosomes from EOC patients and noncancer controls. Furthermore, we identified 954 differentially expressed proteins from ovarian cancer tissues and normal ovarian tissues. Thirty-five proteins exhibited upregulation in both cancer patient exosomes and cancer tissues. Among these 35 proteins, eight proteins (chloride intracellular channel protein 4, serine/threonine-protein kinase 1, aminoacyl tRNA synthetase complex-interacting multifunctional protein 1, sorting nexin-3, protein FAM49B, fermitin family homolog 3, tubulin beta-3 chain and lactotransferrin) were confirmed in both exosome databases and other studies. Conclusions We isolated exosomes from the peripheral blood of EOC patients and noncancer controls and identified 35 proteins that were upregulated in both EOC patient exosomes and ovarian cancer tissues. Comparisons with the exosome molecular databases and other studies identified eight proteins as potential tumor markers, which might offer new tools for the early diagnosis of ovarian cancer.

Dataset Information

Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.

Background

Methods

Results

Conclusion

Publications

Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.

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