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Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA.

ABSTRACT: Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

SUBMITTER: Earp MA

PROVIDER: S-EPMC4063682 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA.

Earp Madalene A MA Kelemen Linda E LE Magliocco Anthony M AM Swenerton Kenneth D KD Chenevix-Trench Georgia G Lu Yi Y Hein Alexander A Ekici Arif B AB Beckmann Matthias W MW Fasching Peter A PA Lambrechts Diether D Despierre Evelyn E Vergote Ignace I Lambrechts Sandrina S Doherty Jennifer A JA Rossing Mary Anne MA Chang-Claude Jenny J Rudolph Anja A Friel Grace G Moysich Kirsten B KB Odunsi Kunle K Sucheston-Campbell Lara L Lurie Galina G Goodman Marc T MT Carney Michael E ME Thompson Pamela J PJ Runnebaum Ingo B IB Dürst Matthias M Hillemanns Peter P Dörk Thilo T Antonenkova Natalia N Bogdanova Natalia N Leminen Arto A Nevanlinna Heli H Pelttari Liisa M LM Butzow Ralf R Bunker Clareann H CH Modugno Francesmary F Edwards Robert P RP Ness Roberta B RB du Bois Andreas A Heitz Florian F Schwaab Ira I Harter Philipp P Karlan Beth Y BY Walsh Christine C Lester Jenny J Jensen Allan A Kjær Susanne K SK Høgdall Claus K CK Høgdall Estrid E Lundvall Lene L Sellers Thomas A TA Fridley Brooke L BL Goode Ellen L EL Cunningham Julie M JM Vierkant Robert A RA Giles Graham G GG Baglietto Laura L Severi Gianluca G Southey Melissa C MC Liang Dong D Wu Xifeng X Lu Karen K Hildebrandt Michelle A T MA Levine Douglas A DA Bisogna Maria M Schildkraut Joellen M JM Iversen Edwin S ES Weber Rachel Palmieri RP Berchuck Andrew A Cramer Daniel W DW Terry Kathryn L KL Poole Elizabeth M EM Tworoger Shelley S SS Bandera Elisa V EV Chandran Urmila U Orlow Irene I Olson Sara H SH Wik Elisabeth E Salvesen Helga B HB Bjorge Line L Halle Mari K MK van Altena Anne M AM Aben Katja K H KK Kiemeney Lambertus A LA Massuger Leon F A G LF Pejovic Tanja T Bean Yukie T YT Cybulski Cezary C Gronwald Jacek J Lubinski Jan J Wentzensen Nicolas N Brinton Louise A LA Lissowska Jolanta J Garcia-Closas Montserrat M Dicks Ed E Dennis Joe J Easton Douglas F DF Song Honglin H Tyrer Jonathan P JP Pharoah Paul D P PD Eccles Diana D Campbell Ian G IG Whittemore Alice S AS McGuire Valerie V Sieh Weiva W Rothstein Joseph H JH Flanagan James M JM Paul James J Brown Robert R Phelan Catherine M CM Risch Harvey A HA McLaughlin John R JR Narod Steven A SA Ziogas Argyrios A Anton-Culver Hoda H Gentry-Maharaj Aleksandra A Menon Usha U Gayther Simon A SA Ramus Susan J SJ Wu Anna H AH Pearce Celeste L CL Pike Malcolm C MC Dansonka-Mieszkowska Agnieszka A Rzepecka Iwona K IK Szafron Lukasz M LM Kupryjanczyk Jolanta J Cook Linda S LS Le Nhu D ND Brooks-Wilson Angela A

Human genetics 20131105 5

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for e ...[more]

PMID: 24190013

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Project description:BACKGROUND:Recently, we witnessed great progress in the discovery of genetic variants associated with obesity and type 2 diabetes (T2D), especially in adults. Much less is known regarding genetic variants associated with insulin resistance (IR). We hypothesized that novel IR genes could be efficiently detected in a population of obese children and adolescents who may not exhibit comorbidities and other confounding factors. OBJECTIVES:This study aimed to determine whether a genome-wide association study (GWAS), using a DNA-pooling approach, could identify novel genes associated with IR. SUBJECTS:The pooled-DNA GWAS analysis included Slovenian obese children and adolescents with and without IR matched for body mass index, gender and age. A replication study was conducted in another independent cohort with or without IR. METHODS:For the pooled-DNA GWAS, we used HumanOmni5-Quad SNP array (Illumina). Allele frequency distributions were compared with modified t-tests and χ2-tests and ranked using PLINK. Top single nucleotide polymorphisms (SNPs) were validated using individual genotyping by high-resolution melting analysis and TaqMan assay. RESULTS:We identified five top-ranking SNPs from the pooled-DNA GWAS analysis within the ECE1, IL1R2, GNPDA1, HLA-J and PYGB loci. All except SNP rs9261108 (HLA-J locus) were confirmed in the validation phase using individual genotyping. The SNP rs2258617 within PYGB remained statistically significant for both recessive and additive models in both cohorts and in a merged analysis of both cohorts and present the strongest novel candidate gene for IR. CONCLUSION:We report for the first time a pooled-DNA GWAS approach to identify five novel SNPs or genes for IR in a paediatric population. The four loci confirmed in the second validation phase study warrant further studies, especially the strongest SNP rs2258617 within PYGB, and provide targets for further basic research of IR mechanisms and for the development of potential new IR and T2D therapies.

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Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA.

Publications

Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA.

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