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1. eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

Author

Wang, Xiaoyu, Gharahkhani, Puya, Levine, David M., Fitzgerald, Rebecca C., Gockel, Ines, Corley, Douglas A., Risch, Harvey A., Bernstein, Leslie, Chow, Wong-Ho, Onstad, Lynn, Shaheen, Nicholas J., Lagergren, Jesper, Hardie, Laura J., Wu, Anna H., Pharoah, Paul D.P., Liu, Geoffrey, Anderson, Lesley A., Iyer, Prasad G., Gammon, Marilie D., Caldas, Carlos, Ye, Weimin, Barr, Hugh, Moayyedi, Paul, Harrison, Rebecca, Watson, R.G. Peter, Attwood, Stephen, Chegwidden, Laura, Love, Sharon B., MacDonald, David, deCaestecker, John, Prenen, Hans, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismüller, Josef, Reeh, Matthias, Nöthen, Markus, Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Rösch, Thomas, Böhmer, Anne C., Hölscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Tomlinson, Ian, Palles, Claire, Jankowski, Janusz A., Whiteman, David C., MacGregor, Stuart, Schumacher, Johannes, Vaughan, Thomas L., Buas, Matthew F., Dai, James Y., DeCaestecker, John, Weismueller, Josef, Noethen, Markus M., Roesch, Thomas, Boehmer, Anne C., and Hoelscher, Arnulf H.

Subjects
Barrett Esophagus, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Oncology, Esophageal Neoplasms, Epidemiology, Quantitative Trait Loci, Medizin, Humans, Genetic Predisposition to Disease, Human medicine, Adenocarcinoma, Biology, Article
Abstract

Background: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: Although the standard approach did not identify significant signals, the eQTL set–based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set–based genetic association approach. Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set–based genetic association approach as an alternative method for TWAS analysis.

Published
2022

2. Multi-Tissue Transcriptome-Wide Association Study Identifies 26 Novel Candidate Susceptibility Genes for High Grade Serous Epithelial Ovarian Cancer

Author

Gusev, Alexander, Lawrenson, Kate, Segato, Felipe, Fonseca, Marcos A.S., Kar, Siddhartha, Vavra, Kevin C., Lee, Janet M, Pejovic, Tanya, Karlan, Beth Y., Freedman, Matthew L., Noushmehr, Houtan, Pharoah, Paul D.P., Pasaniuc, Bogdan, and Gayther, Simon A.

Subjects
Genetics, 0303 health sciences, Biology, 3. Good health, Transcriptome, 03 medical and health sciences, Exon, 0302 clinical medicine, 030220 oncology & carcinogenesis, Expression quantitative trait loci, Gene expression, RNA splicing, Gene, Genotyping, 030304 developmental biology, Genetic association
Abstract

Genome-wide association studies (GWASs) have identified about 30 different susceptibility loci associated with high grade serous ovarian cancer (HGSOC) risk. We sought to identify potential susceptibility genes by integrating the risk variants at these regions with genetic variants impacting gene expression and splicing of nearby genes. We compiled gene expression and genotyping data from 2,169 samples for 6 different HGSOC-relevant tissue types. We integrated these data with GWAS data from 13,037 HGSOC cases and 40,941 controls, and performed a transcriptome-wide association study (TWAS) across >70,000 significantly heritable gene/exon features. We identified 24 transcriptome-wide significant associations for 14 unique genes, plus 90 significant exon-level associations in 20 unique genes. We implicated multiple novel genes at risk loci, e.g.LRRC46at 19q21.32 (TWASP=1×10−9) and aPRC1splicing event (TWASP=9×10−8) which was splice-variant specific and exhibited no eQTL signal. Functional analyses in HGSOC cell lines found evidence of essentiality forGOSR2, INTS1, KANSL1andPRC1; with the latter gene showing levels of essentiality comparable to that ofMYC. Overall, gene expression and splicing events explained 41% of SNP-heritability for HGSOC (s.e. 11%,P=2.5×10−4), implicated at least one target gene for 6/13 distinct genome-wide significant regions and revealed 2 known and 26 novel candidate susceptibility genes for HGSOC.STATEMENT OF SIGNIFICANCEFor many ovarian cancer risk regions, the target genes regulated by germline genetic variants are unknown. Using expression data from >2,100 individuals, this study identified novel associations of genes and splicing variants with ovarian cancer risk; with transcriptional variation now explaining over one-third of the SNP-heritability for this disease.

Published
2018
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3. phip - a novel candidate breast cancer susceptibility locus on 6q14.1

Author

Jiao, Xiang, Aravidis, Christos, Marikkannu, Rajeshwari, Rantala, Johanna, Picelli, Simone, Adamovic, Tatjana, Liu, Tao, Maguire, Paula, Kremeyer, Barbara, Luo, Liping, von Holst, Susanna, Kontham, Vinaykumar, Thutkawkorapin, Jessada, Margolin, Sara, Du, Quan, Lundin, Johanna, Michailidou, Kyriaki, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Lush, Michael, Ambrosone, Christine B., Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Beckmann, Matthias W., Blomqvist, Carl, Blot, William, Boeckx, Bram, Bojesen, Stig E., Bonanni, Bernardo, Brand, Judith S., Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Chang-Claude, Jenny, Collaborators, NBCS, Couch, Fergus J., Cox, Angela, Cross, Simon S., Deming-Halverson, Sandra L., Devilee, Peter, dos-Santos-Silva, Isabel, Dörk, Thilo, Eriksson, Mikael, Fasching, Peter A., Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gabrielson, Marike, García-Closas, Montserrat, Giles, Graham G., González-Neira, Anna, Guénel, Pascal, Guo, Qi, Gündert, Melanie, Haiman, Christopher A., Hallberg, Emily, Hamann, Ute, Harrington, Patricia, Hooning, Maartje J., Hopper, John L., Huang, Guanmengqian, Jakubowska, Anna, Jones, Michael E., Kerin, Michael J., Kosma, Veli-Matti, Kristensen, Vessela N., Lambrechts, Diether, Marchand, Loic Le, Lubinski, Jan, Mannermaa, Arto, Martens, John W.M., Meindl, Alfons, Milne, Roger L., Mulligan, Anna Marie, Neuhausen, Susan L., Nevanlinna, Heli, Peto, Julian, Pylkas, Katri, Radice, Paolo, Rhenius, Valerie, Sawyer, Elinor J., Schmidt, Marjanka K., Schmutzler, Rita K., Seynaeve, Caroline, Shah, Mitul, Simard, Jacques, Southey, Melissa C., Swerdlow, Anthony J., Truong, Therese, Wendt, Camilla, Winqvist, Robert, Zheng, Wei, Investigators, kConFab/AOCS, Benitez, Javier, Dunning, Alison M., Pharoah, Paul D.P., Easton, Douglas F., Czene, Kamila, Hall, Per, and Lindblom, Annika

Subjects
DNA-sequencing data, wide linkage scan, familial breast cancer, association, sequencing, families, mutations, localization, risk haplotype, expression, linkage analysis, gene, genome, discovery
Abstract

Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.

Published
2017

4. Development and Validation of a New Walking Pace Function Using Crowd-Sourced GPS Data

Author

Pharoah, Paul D.P.

Subjects
Preferred walking speed, Computer science, business.industry, Gps data, Computer graphics (images), Global Positioning System, Elevation, Computer vision, Function (mathematics), Artificial intelligence, business
Abstract

There are several functions that hikers can use to predict walking time based on elevation change or slope of the ground. The most commonly used is the Naismith function that was first published over 100 years ago. The availability of GPS devices to record tracks now make it possible to evaluate the performance of walking time functions. Four data sources were used: 98 tracks downloaded from the Wikiloc web site; 55 tracks recorded by the author; 19 tracks recorded by the blogger Iron Hiker; and 20 tracks recorded by the blogger Hiking Guy. The ․gpx files were processed to generate segements of ~100m in length, with the associated segment duration and elevation change. The association between walking pace and elevation change was assessed in the Wikiloc data using linear spline regression. The performance of the linear spline function was then compared with the Naismith, Tobler and Laingmuir functions. The linear spline performed the best, but all four performed reasonably well. While the linear spline function could easily be programmed into the software of standard GPS devices, the Naismith function provides a simple-to-use rule-of-thumb for estimating walking time for a typical hike in the mountains.FundingNoneAcknowledgementsI thank Chris Hazzard and Keith Wilson for sharing their hiking records and for helpful comments on the manuscript.Disclosure of interestsThe authors have no interest to disclose

Published
2017
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5. Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene

Author

Dicks, Ed, Song, Honglin, Ramus, Susan J., Van Oudenhove, Elke, Tyrer, Jonathan P., Intermaggio, Maria P., Kar, Siddhartha, Harrington, Patricia, Bowtell, David D., Study Group, Aocs, Cicek, Mine S., Cunningham, Julie M., Fridley, Brooke L., Alsop, Jennifer, Jimenez-Linan, Mercedes, Piskorz, Anna, Goranova, Teodora, Kent, Emma, Siddiqui, Nadeem, Paul, James, Crawford, Robin, Poblete, Samantha, Lele, Shashi, Sucheston-Campbell, Lara, Moysich, Kirsten B., Sieh, Weiva, McGuire, Valerie, Lester, Jenny, Odunsi, Kunle, Whittemore, Alice S., Bogdanova, Natalia, Dürst, Matthias, Hillemanns, Peter, Karlan, Beth Y., Gentry-Maharaj, Aleksandra, Menon, Usha, Tischkowitz, Marc, Levine, Douglas, Brenton, James D., Dörk, Thilo, Goode, Ellen L., Gayther, Simon A., Pharoah, Paul D.P., Dicks, Ed [0000-0002-0617-0401], Song, Honglin [0000-0001-5076-7371], Tyrer, Jonathan [0000-0003-3724-4757], Tischkowitz, Marc [0000-0002-7880-0628], Brenton, James [0000-0002-5738-6683], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, DNA repair, Oncology and Carcinogenesis, Genome-wide association study, VARIANTS, Biology, BREAST, Germline, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, Clinical Research, Medicine and Health Sciences, LOCUS, Genetics, CONFER SUSCEPTIBILITY, 2.1 Biological and endogenous factors, FANCL, susceptibility genes, FANCM, Genetic Testing, GENOME-WIDE ASSOCIATION, Mutation frequency, Aetiology, Exome sequencing, Cancer, next generation sequencing, RAD51C, MUTATIONS, Prevention, Human Genome, BRCA2, RISKS, 3. Good health, 030104 developmental biology, Good Health and Well Being, ovarian cancer, Oncology, 030220 oncology & carcinogenesis, Cancer research
Abstract

We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8x10(-3)). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 - were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin. We estimated mutation prevalence for each gene and tested for associations with disease risk. Mutations were identified in both cases and controls in all genes except MAD2L2, where we found no evidence of mutations in controls. In FANCM we observed a higher mutation frequency in HGSOC cases compared to controls (29/3,107 cases, 0.96 percent; 13/3,368 controls, 0.38 percent; P = 0.008) with little evidence for association with other subtypes (6/1,491, 0.40 percent; P = 0.82). The relative risk of HGSOC associated with deleterious FANCM mutations was estimated to be 2.5 (95% CI 1.3 - 5.0; P = 0.006). In summary, whole exome sequencing of EOC cases with large-scale replication in case-control studies has identified FANCM as a likely novel susceptibility gene for HGSOC, with mutations associated with a moderate increase in risk. These data may have clinical implications for risk prediction and prevention approaches for high-grade serous ovarian cancer in the future and a significant impact on reducing disease mortality.

Published
2017
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6. Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer

Author

Shi, Jiajun, Zhang, Yanfeng, Zheng, Wei, Michailidou, Kyriaki, Ghoussaini, Maya, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Lush, Michael, Milne, Roger L., Shu, Xiao-Ou, Beesley, Jonathan, Kar, Siddhartha, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W., Zhao, Zhiguo, Guo, Xingyi, Benitez, Javier, Beeghly-Fadiel, Alicia, Blot, William, Bogdanova, Natalia V., Bojesen, Stig E., Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Hui, Canisius, Sander, Chang-Claude, Jenny, Choi, Ji-Yeob, Couch, Fergus J., Cox, Angela, Cross, Simon S., Czene, Kamila, Darabi, Hatef, Devilee, Peter, Droit, Arnaud, Dork, Thilo, Fasching, Peter A., Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gaborieau, Valerie, García-Closas, Montserrat, Giles, Graham G., Guenel, Pascal, Haiman, Christopher A., Hamann, Ute, Hartman, Mikael, Miao, Hui, Hollestelle, Antoinette, Hopper, John L., Hsiung, Chia-Ni, Ito, Hidemi, Jakubowska, Anna, Johnson, Nichola, Torres, Diana, Kabisch, Maria, Kang, Daehee, Khan, Sofia, Knight, Julia A., Kosma, Veli-Matti, Lambrechts, Diether, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Le Marchand, Loic, Margolin, Sara, Marme, Frederik, Matsuo, Keitaro, McLean, Catriona, Meindl, Alfons, Muir, Kenneth, Neuhausen, Susan L., Nevanlinna, Heli, Nord, Silje, Børresen-Dale, Anne-Lise, Olson, Janet E., Orr, Nick, van den Ouweland, Ans M.W., Peterlongo, Paolo, Putti, Thomas Choudary, Rudolph, Anja, Sangrajrang, Suleeporn, Sawyer, Elinor J., Schmidt, Marjanka K., Schmutzler, Rita K., Shen, Chen-Yang, Hou, Ming-Feng, Shrubsole, Matha J, Southey, Melissa C., Swerdlow, Anthony, Teo, Soo Hwang, Thienpont, Bernard, Toland, Amanda E., Tollenaar, Robert A.E.M., Tomlinson, Ian, Truong, Therese, Tseng, Chiu-chen, Wen, Wanqing, Winqvist, Robert, Wu, Anna H., Yip, Cheng Har, Zamora, Pilar M., Zheng, Ying, Floris, Giuseppe, Cheng, Ching-Yu, Hooning, Maartje J., Martens, John W.M., Seynaeve, Caroline, Kristensen, Vessela N., Hall, Per, Pharoah, Paul D.P., Simard, Jacques, Chenevix-Trench, Georgia, Dunning, Alison M., Antoniou, Antonis C., Easton, Douglas F., Cai, Qiuyin, and Long, Jirong

Subjects
Risk, Genotype, European Continental Ancestry Group, Quantitative Trait Loci, Chromosome Mapping, Genetic Variation, 8q24, Breast Neoplasms, Polymorphism, Single Nucleotide, Article, White People, Linkage Disequilibrium, breast cancer, fine-mapping, Haplotypes, single nucleotide polymorphism, Case-Control Studies, Odds Ratio, Humans, Female, Alleles, genetic susceptibility, Chromosomes, Human, Pair 8, Genome-Wide Association Study
Abstract

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.

Published
2016

7. Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

Author

Johnatty, Sharon E., Tyrer, Jonathan P., Kar, Siddhartha, Beesley, Jonathan, Lu, Yi, Gao, Bo, Fasching, Peter A., Hein, Alexander, Ekici, Arif B., Beckmann, Matthias W., Lambrechts, Diether, Nieuwenhuysen, Els Van, Vergote, Ignace, Lambrechts, Sandrina, Rossing, Mary Anne, Doherty, Jennifer A., Chang-Claude, Jenny, Modugno, Francesmary, Ness, Roberta B., Moysich, Kirsten B., Levine, Douglas A., Kiemeney, Lambertus A., Massuger, Leon F.A.G., Gronwald, Jacek, Lubiński, Jan, Jakubowska, Anna, Cybulski, Cezary, Brinton, Louise, Lissowska, Jolanta, Wentzensen, Nicolas, Song, Honglin, Rhenius, Valerie, Campbell, Ian, Eccles, Diana, Sieh, Weiva, Whittemore, Alice S., McGuire, Valerie, Rothstein, Joseph H., Sutphen, Rebecca, Anton-Culver, Hoda, Ziogas, Argyrios, Gayther, Simon A., Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J., Pearce, Celeste L, Pike, Malcolm C, Stram, Daniel O., Wu, Anna H., Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Rzepecka, Iwona K., Spiewankiewicz, Beata, Goodman, Marc T., Wilkens, Lynne R., Carney, Michael E., Thompson, Pamela J, Heitz, Florian, du Bois, Andreas, Schwaab, Ira, Harter, Philipp, Pisterer, Jacobus, Hillemanns, Peter, Karlan, Beth Y., Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Winham, Stacey J, Earp, Madalene, Larson, Melissa C., Fogarty, Zachary C., Høgdall, Estrid, Jensen, Allan, Kjaer, Susanne Kruger, Fridley, Brooke L., Cunningham, Julie M., Vierkant, Robert A., Schildkraut, Joellen M., Iversen, Edwin S., Terry, Kathryn L., Cramer, Daniel W., Bandera, Elisa V., Orlow, Irene, Pejovic, Tanja, Bean, Yukie, Høgdall, Claus, Lundvall, Lene, McNeish, Ian, Paul, James, Carty, Karen, Siddiqui, Nadeem, Glasspool, Rosalind, Sellers, Thomas, Kennedy, Catherine, Chiew, Yoke-Eng, Berchuck, Andrew, MacGregor, Stuart, deFazio, Anna, Pharoah, Paul D.P., Goode, Ellen L., Webb, Penelope M., and Chenevix-Trench, Georgia

Subjects
Oncology, Cancer Research, Genome-wide association study, AGO Study Group, Kaplan-Meier Estimate, Carcinoma, Ovarian Epithelial, Bioinformatics, chemistry.chemical_compound, Neoplasms, Ovarian Epithelial, 2.1 Biological and endogenous factors, Neoplasms, Glandular and Epithelial, Aetiology, Cancer, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Glandular and Epithelial, Single Nucleotide, Prognosis, Ovarian Cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Australian Ovarian Cancer Study Group, medicine.medical_specialty, Genotype, Quantitative Trait Loci, Oncology and Carcinogenesis, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, Rare Diseases, Meta-Analysis as Topic, Clinical Research, Internal medicine, Carcinoma, medicine, Genetics, SNP, Humans, Progression-free survival, Oncology & Carcinogenesis, Polymorphism, Alleles, business.industry, Human Genome, Computational Biology, medicine.disease, Carboplatin, Patient Outcome Assessment, Regimen, Orphan Drug, chemistry, Ovarian cancer, business, Genome-Wide Association Study
Abstract

Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.

Published
2015

8. Common non-synonymous snps associated with breast cancer susceptibility: findings from the breast cancer association consortium

Author

Milne, Roger L., Burwinkel, Barbara, Michailidou, Kyriaki, Arias-Perez, Jose-Ignacio, Zamora, M. Pilar, Menéndez-Rodríguez, Primitiva, Hardisson, David, Mendiola, Marta, González-Neira, Anna, Pita, Guillermo, Alonso, M. Rosario, Dennis, Joe, Wang, Qin, Bolla, Manjeet K., Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Schoemaker, Minouk, Ko, Yon-Dschun, Brauch, Hiltrud, Hamann, Ute, Andrulis, Irene L., Knight, Julia A., Glendon, Gord, Tchatchou, Sandrine, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Tajima, Kazuo, Li, Jingmei, Brand, Judith S., Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Lambrechts, Diether, Peuteman, Gilian, Christiaens, Marie-Rose, Smeets, Ann, Jakubowska, Anna, Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katazyna, Hartman, Mikael, Hui, Miao, Yen Lim, Wei, Wan Chan, Ching, Marme, Federick, Yang, Rongxi, Bugert, Peter, Lindblom, Annika, Margolin, Sara, García-Closas, Montserrat, Chanock, Stephen J., Lissowska, Jolanta, Figueroa, Jonine D., Bojesen, Stig E., Nordestgaard, Børge G., Flyger, Henrik, Hooning, Maartje J., Kriege, Mieke, van den Ouweland, Ans M.W., Koppert, Linetta B., Fletcher, Olivia, Johnson, Nichola, dos-Santos-Silva, Isabel, Peto, Julian, Zheng, Wei, Deming-Halverson, Sandra, Shrubsole, Martha J., Long, Jirong, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Winqvist, Robert, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Grip, Mervi, Cox, Angela, Cross, Simon S., Reed, Malcolm W.R., Schmidt, Marjanka K., Broeks, Annegien, Cornelissen, Sten, Braaf, Linde, Kang, Daehee, Choi, Ji-Yeob, Park, Sue K., Noh, Dong-Young, Simard, Jacques, Dumont, Martine, Goldberg, Mark S., Labrèche, France, Fasching, Peter A., Hein, Alexander, Ekici, Arif B., Beckmann, Matthias W., Radice, Paolo, Peterlongo, Paolo, Azzollini, Jacopo, Barile, Monica, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Miller, Nicola, Hopper, John L., Schmidt, Daniel F., Makalic, Enes, Southey, Melissa C., Hwang Teo, Soo, Har Yip, Cheng, Sivanandan, Kavitta, Tay, Wan-Ting, Shen, Chen-Yang, Hsiung, Chia-Ni, Yu, Jyh-Cherng, Hou, Ming-Feng, Guénel, Pascal, Truong, Therese, Sanchez, Marie, Mulot, Claire, Blot, William, Cai, Qiuyin, Nevanlinna, Heli, Muranen, Taru A., Aittomäki, Kristiina, Blomqvist, Carl, Wu, Anna H., Tseng, Chiu-Chen, Van Den Berg, David, Stram, Daniel O., Bogdanova, Natalia, Dörk, Thilo, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Shu, Xiao-Ou, Lu, Wei, Gao, Yu-Tang, Zhang, Ben, Couch, Fergus J., Toland, Amanda E., Yannoukakos, Drakoulis, Sangrajrang, Suleeporn, McKay, James, Wang, Xianshu, Olson, Janet E., Vachon, Celine, Purrington, Kristen, Severi, Gianluca, Baglietto, Laura, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Devilee, Peter, Tollenaar, Robert A.E.M., Seynaeve, Caroline, Czene, Kamila, Eriksson, Mikael, Humphreys, Keith, Darabi, Hatef, Ahmed, Shahana, Shah, Mitul, Pharoah, Paul D.P., Hall, Per, Giles, Graham G., Benítez, Javier, Dunning, Alison M., Chenevix-Trench, Georgia, Easton, Douglas F., Berchuck, Andrew, Eeles, Rosalind A., Olama, Ali Amin Al, Kote-Jarai, Zsofia, Benlloch, Sara, Antoniou, Antonis, McGuffog, Lesley, Offit, Ken, Lee, Andrew, Dicks, Ed, Luccarini, Craig, Tessier, Daniel C., Bacot, Francois, Vincent, Daniel, LaBoissière, Sylvie, Robidoux, Frederic, Nielsen, Sune F., Cunningham, Julie M., Windebank, Sharon A., Hilker, Christopher A., Meyer, Jeffrey, Angelakos, Maggie, Maskiell, Judi, van der Schoot, Ellen, Rutgers, Emiel, Verhoef, Senno, Hogervorst, Frans, Boonyawongviroj, Prat, Siriwanarungsan, Pornthep, Schrauder, Michael, Rübner, Matthias, Oeser, Sonja, Landrith, Silke, Williams, Eileen, Ryder-Mills, Elaine, Sargus, Kara, McInerney, Niall, Colleran, Gabrielle, Rowan, Andrew, Jones, Angela, Sohn, Christof, Schneeweiß, Andeas, Álvarez, Núria, Lacey, James, Wang, Sophia, Ma, Huiyan, Lu, Yani, Deapen, Dennis, Pinder, Rich, Lee, Eunjung, Schumacher, Fred, Horn-Ross, Pam, Reynolds, Peggy, Nelson, David, Ziegler, Hartwig, Wolf, Sonja, Hermann, Volker, Lo, Wing-Yee, Justenhoven, Christina, Baisch, Christian, Fischer, Hans-Peter, Brüning, Thomas, Pesch, Beate, Rabstein, Sylvia, Lotz, Anne, Harth, Volker, Heikkinen, Tuomas, Erkkilä, Irja, Aaltonen, Kirsimari, von Smitten, Karl, Antonenkova, Natalia, Hillemanns, Peter, Christiansen, Hans, Myöhänen, Eija, Kemiläinen, Helena, Thorne, Heather, Niedermayr, Eveline, Bowtell, D, Chenevix-Trench, G, deFazio, A, Gertig, D, Green, A, Webb, P, Green, A., Parsons, P., Hayward, N., Webb, P., Whiteman, D., Fung, Annie, Yashiki, June, Smeets, Dominiek, Brussel, Thomas Van, Corthouts, Kathleen, Obi, Nadia, Heinz, Judith, Behrens, Sabine, Eilber, Ursula, Celik, Muhabbet, Olchers, Til, Manoukian, Siranoush, Peissel, Bernard, Scuvera, Giulietta, Zaffaroni, Daniela, Bonanni, Bernardo, Feroce, Irene, Maniscalco, Angela, Rossi, Alessandra, Bernard, Loris, Tranchant, Martine, Valois, Marie-France, Turgeon, Annie, Heguy, Lea, Sze Yee, Phuah, Kang, Peter, Nee, Kang In, Mariapun, Shivaani, Sook-Yee, Yoon, Lee, Daphne, Ching, Teh Yew, Taib, Nur Aishah Mohd, Otsukka, Meeri, Mononen, Kari, Selander, Teresa, Weerasooriya, Nayana, staff, OFBCR, Krol-Warmerdam, E., Molenaar, J., Blom, J., Brinton, Louise, Szeszenia-Dabrowska, Neonila, Peplonska, Beata, Zatonski, Witold, Chao, Pei, Stagner, Michael, Bos, Petra, Blom, Jannet, Crepin, Ellen, Nieuwlaat, Anja, Heemskerk, Annette, Higham, Sue, Cross, Simon, Cramp, Helen, Connley, Dan, Balasubramanian, Sabapathy, Brock, Ian, Conroy, Don, Baynes, Caroline, and Chua, Kimberley

Subjects
Adult, A Kinase Anchor Proteins, Alleles, Ataxin-7, Breast Neoplasms, Case-Control Studies, Cytoskeletal Proteins, Female, Genome-Wide Association Study, Humans, Middle Aged, Nerve Tissue Proteins, Protein-Serine-Threonine Kinases, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Molecular Biology, Genetics, Genetics (clinical), Protein Serine-Threonine Kinases, Medizinische Fakultät, NIMA-Related Kinases, ddc:610, Polymorphism, risk, variants, Association Studies Articles, identifies 2, Single Nucleotide, confer susceptibility, 5p12, loci, alleles, genome-wide association, metaanalysis
Abstract

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.

Published
2014

9. Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

Author

Gaudet, Mia M., Kuchenbaecker, Karoline B., Vijai, Joseph, Klein, Robert J., Kirchhoff, Tomas, McGuffog, Lesley, Barrowdale, Daniel, Dunning, Alison M., Lee, Andrew, Dennis, Joe, Healey, Sue, Dicks, Ed, Soucy, Penny, Sinilnikova, Olga M., Pankratz, Vernon S., Wang, Xianshu, Eldridge, Ronald C., Tessier, Daniel C., Vincent, Daniel, Bacot, Francois, Hogervorst, Frans B.L., Peock, Susan, Stoppa-Lyonnet, Dominique, Coulet, Florence, Colas, Chrystelle, Soubrier, Florent, Peterlongo, Paolo, Schmutzler, Rita K., Nathanson, Katherine L., Piedmonte, Marion, Singer, Christian F., Thomassen, Mads, Sokolowska, Johanna, Bronner, Myriam, Hansen, Thomas V.O., Neuhausen, Susan L., Blanco, Ignacio, Greene, Mark H., Garber, Judith, Weitzel, Jeffrey N., Andrulis, Irene L., Goldgar, David E., D'Andrea, Emma, Caldes, Trinidad, Nevanlinna, Heli, Osorio, Ana, van Rensburg, Elizabeth J., Arason, Adalgeir, Rennert, Gad, van den Ouweland, Ans M.W., van der Hout, Annemarie H., Kets, Carolien M., Aalfs, Cora M., Wijnen, Juul T., Ausems, Margreet G.E.M., Frost, Debra, Ellis, Steve, Fineberg, Elena, Platte, Radka, Evans, D. Gareth, Jacobs, Chris, Adlard, Julian, Tischkowitz, Marc, Porteous, Mary, Damiola, Francesca, Golmard, Lisa, Barjhoux, Laure, Longy, Michel, Belotti, Muriel, Ferrer, Sandra Fert, Mazoyer, Sylvie, Spurdle, Amanda B., Manoukian, Siranoush, Barile, Monica, Genuardi, Maurizio, Arnold, Norbert, Meindl, Alfons, Sutter, Christian, Wappenschmidt, Barbara, Domchek, Susan M., Pfeiler, Georg, Friedman, Eitan, Jensen, Uffe Birk, Robson, Mark, Shah, Sohela, Lazaro, Conxi, Mai, Phuong L., Benitez, Javier, Southey, Melissa C., Schmidt, M. K., Fasching, Peter A., Peto, Julian, Humphreys, Manjeet K., Wang, Qin, Michailidou, Kyriaki, Sawyer, Elinor J., Burwinkel, Barbara, Guénel, Pascal, Bojesen, Stig E., Milne, Roger L., Brenner, Hermann, Lochmann, Magdalena, Brauch, Hiltrud, Ko, Yon Dschun, Baisch, Christian, Fischer, Hand Peter, Bruening, Thomas, Pesch, Beate, Rabstein, Sylvia, Spickenheuer, Anne, Aittomäki, Kristiina, Dörk, Thilo, Margolin, Sara, Mannermaa, Arto, Lambrechts, Diether, Chang-Claude, Jenny, Radice, Paolo, Giles, Graham G., Haiman, Christopher A., Winqvist, Robert, Devillee, Peter, García-Closas, Montserrat, Schoof, Nils, Hooning, M. J., Cox, Angela, Pharoah, Paul D.P., Jakubowska, Anna, Orr, Nick, González-Neira, Anna, Pita, Guillermo, Alonso, M. Rosario, Hall, Per, Couch, Fergus J., Simard, Jacques, Altshuler, David, Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., Offit, Kenneth, Rookus, M. A., van Leeuwen, F. E., Verhoef, S., de Lange, J. L., Collée, J. M., Seynaeve, C., van Deurzen, C. H.M., van Asperen, C. J., Tollenaar, R. A., Devilee, P., van Cronenburg, T. C.T.E.F., Mensenkamp, A. R., van der Luijt, R. B., van Os, T. A.M., Gille, J. J.P., Waisfisz, Q., Meijers-Heijboer, H. E.J., Gómez-Garcia, E. B., Blok, M. J., Oosterwijk, J. C., Mourits, M. J., de Bock, G. H., Vasen, H. F., Miedzybrodzka, Zosia, Gregory, Helen, Morrison, Patrick, Jeffers, Lisa, Cole, Trevor, Ong, Kai ren, Hoffman, Jonathan, Donaldson, Alan, James, Margaret, Paterson, Joan, Taylor, Amy, Murray, Alexandra, Rogers, Mark T., McCann, Emma, Kennedy, M. John, Barton, David, Drummond, Sarah, Brewer, Carole, Kivuva, Emma, Searle, Anne, Goodman, Selina, Hill, Kathryn, Davidson, Rosemarie, Murday, Victoria, Bradshaw, Nicola, Snadden, Lesley, Longmuir, Mark, Watt, Catherine, Gibson, Sarah, Haque, Eshika, Tobias, Ed, Duncan, Alexis, Izatt, Louise, Langman, Caroline, Brady, Angela, Dorkins, Huw, Melville, Athalie, Randhawa, Kashmir, Barwell, Julian, Serra-Feliu, Gemma, Ellis, Ian, Houghton, Catherine, Lalloo, Fiona, Taylor, Jane, Side, Lucy, Male, Alison, Berlin, Cheryl, Eason, Jacqueline, Douglas, Fiona, Claber, Oonagh, Collier, Rebecca, Jobson, Irene, Walker, Lisa, McLeod, Diane, Durell, Sarah, Stayner, Barbara, Eeles, Rosalind A., Shanley, Susan, Rahman, Nazneen, Houlston, Richard, Bancroft, Elizabeth, Page, Elizabeth, Ardern-Jones, Audrey, Kohut, Kelly, Wiggins, Jennifer, Castro, Elena, Killick, Emma, Martin, Sue, Rea, Gillian, Kulkarni, Anjana, Cook, Jackie, Quarrell, Oliver, Bardsley, Cathryn, Hodgson, Shirley, Goff, Sheila, Brice, Glen, Winchester, Lizzie, Eddy, Charlotte, Tripathi, Vishakha, Attard, Virginia, Lehmann, Anna, Eccles, Diana, Lucassen, Anneke, Crawford, Gillian, McBride, Donna, Smalley, Sarah, Sinilnikova, Olga, Verny-Pierre, Carole, Giraud, Sophie, Léone, Mélanie, Gauthier-Villars, Marion, Buecher, Bruno, Houdayer, Claude, Moncoutier, Virginie, Tirapo, Carole, de Pauw, Antoine, Bressac-de-Paillerets, Brigitte, Caron, Olivier, Bignon, Yves Jean, Uhrhammer, Nancy, Lasset, Christine, Bonadona, Valérie, Handallou, Sandrine, Hardouin, Agnés, Berthet, Pascaline, Sobol, Hagay, Bourdon, Violaine, Noguchi, Tetsuro, Remenieras, Audrey, Coupier, Isabelle, Pujol, Pascal, Peyrat, Jean Philippe, Fournier, Joëlle, Révillion, Françoise, Vennin, Philippe, Adenis, Claude, Rouleau, Etienne, Lidereau, Rosette, Demange, Liliane, Nogues, Catherine, Muller, Danièle, Fricker, Jean Pierre, Barouk-Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Sevenet, Nicolas, Toulas, Christine, Guimbaud, Rosine, Gladieff, Laurence, Feillel, Viviane, Dreyfus, Hélène, Rebischung, Christine, Peysselon, Magalie, Coron, Fanny, Faivre, Laurence, Prieur, Fabienne, Lebrun, Marine, Kientz, Caroline, Frénay, Marc, Vénat-Bouvet, Laurence, Delnatte, Capucine, Mortemousque, Isabelle, Lynch, Henry T., Snyder, Carrie L., Clinical Genetics, Medical Oncology, Human Genetics, Human genetics, EMGO - Quality of care, Anesthesiology, CCA - Oncogenesis, CCA - Cancer biology and immunology, Epidemiology and Data Science, Department of Obstetrics and Gynecology, Clinicum, and Department of Medical and Clinical Genetics

Subjects
Cancer Research, SUSCEPTIBILITY ALLELES, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], QH426-470, Settore MED/03 - GENETICA MEDICA, Genoma humà, SUBTYPES, Breast cancer, 0302 clinical medicine, Risk Factors, CDKN2A, Genotype, BRCA2 MUTATION CARRIERS, Malalties hereditàries, GWAS, skin and connective tissue diseases, Genetics (clinical), POPULATION, 2. Zero hunger, Genetics, 0303 health sciences, education.field_of_study, BRCA1 Protein, COMMON VARIANTS, genetic modifiers, BRCA2, cancer risk, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 6, Female, Genetic diseases, Adult, Heterozygote, Medizinische Fakultät -ohne weitere Spezifikation, education, Population, Breast Neoplasms, Single-nucleotide polymorphism, Locus (genetics), Human chromosomes, Biology, Polymorphism, Single Nucleotide, OVARIAN-CANCER, BRCA2-specific modifier locus at 6p24, Càncer de mama, 03 medical and health sciences, TRANSCRIPTION FACTOR AP-2, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Allele, GENOME-WIDE ASSOCIATION, Molecular Biology, Alleles, Ecology, Evolution, Behavior and Systematics, Aged, 030304 developmental biology, BRCA2 Protein, Cromosomes humans, Human genome, Hereditary cancer and cancer-related syndromes [ONCOL 1], CONSORTIUM, medicine.disease, Mutation, 3111 Biomedicine, ZNF365, Genome-Wide Association Study
Abstract

Contains fulltext : 118578.pdf (Publisher’s version ) (Open Access) Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9x10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Published
2013
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10. Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome

Author

White, Kristen L., Vierkant, Robert A., Fogarty, Zachary C., Charbonneau, Bridget, Block, Matthew S., Pharoah, Paul D.P., Chenevix-Trench, Georgia, Rossing, Mary Ann, Cramer, Daniel W., Pearce, Celeste Leigh, Schildkraut, Joellen M., Menon, Usha, Kjaer, Sussanne Kruger, Levine, Douglas A., Gronwald, Jacek, Culver, Hoda Anton, Whittemore, Alice S., Karlan, Beth Y., Lambrechts, Diether, Kupryjanczyk, Jolanta, Wentzensen, Nicolas, Chang-Claude, Jenny, Bandera, Elisa V., Hogdall, Estrid, Heitz, Florian, Kaye, Stanley B., Fasching, Peter A., Campbell, Ian, Pejovic, Tanja, Goodman, Marc T., Bean, Yukie, Lurie, Galina, Eccles, Diana, Hein, Alexander, Beckmann, Matthias W., Ekici, Arif B., Paul, James, Brown, Robert, Flanagan, James M., Harter, Philipp, Schwaab, Ira, Du Bois, Andreas, Hogdall, Claus K., Lundvall, Lene, Olson, Sara H., Orlow, Irene, Paddock, Lisa E., Rudolph, Anja, Eilber, Ursula, Dansonka-Mieszkowska, Agnieszka, Rzepecka, Iwona K., Ziolkowska-Seta, Izabela, Brinton, Louise, Yang, Hannah, Garcia-Closas, Montserrat, Despierre, Evelyn, Lambrechts, Sandrina, Vergote, Ignace, Walsh, Christine, Lester, Jenny, Sieh, Weiva, McGuire, Valerie, Rothstein, Joseph H., Ziogas, Argyrios, Lubinksi, Jan, Cybulski, Cezary, Menkiszak, Janusz, Jensen, Allan, Gayther, Simon A., Ramus, Susan J., Gentry-Maharaj, Aleksandra, Berchuck, Andrew, Wu, Anna H., Pike, Malcolm C., Van Den Berg, David, Terry, Kathryn L., Vitonis, Allison F., Doherty, Jennifer A., Johnatty, Sharon E., DeFazio, Anna, Song, Honglin, Tyrer, Jonathan, Sellers, Thomas A., Phelan, Catherine M., Kalli, Kimberly R., Cunningham, Julie M., Fridley, Brooke L., and Goode, Ellen L.

Subjects
Public health, Oncology, 3. Good health
Abstract

Background: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed.

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