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1.  Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer 
Andersson, Ulrika | Wibom, Carl | Cederquist, Kristina | Aradottir, Steina | Borg, Åke | Armstrong, Georgina N. | Shete, Sanjay | Lau, Ching C. | Bainbridge, Matthew N. | Claus, Elizabeth B. | Barnholtz-Sloan, Jill | Lai, Rose | Il'yasova, Dora | Houlston, Richard S. | Schildkraut, Joellen | Bernstein, Jonine L. | Olson, Sara H. | Jenkins, Robert B. | Lachance, Daniel H. | Wrensch, Margaret | Davis, Faith G. | Merrell, Ryan | Johansen, Christoffer | Sadetzki, Siegal | Bondy, Melissa L. | Melin, Beatrice S. | Adatto, Phyllis | Morice, Fabian | Payen, Sam | McQuinn, Lacey | McGaha, Rebecca | Guerra, Sandra | Paith, Leslie | Roth, Katherine | Zeng, Dong | Zhang, Hui | Yung, Alfred | Aldape, Kenneth | Gilbert, Mark | Weinberger, Jeffrey | Colman, Howard | Conrad, Charles | de Groot, John | Forman, Arthur | Groves, Morris | Levin, Victor | Loghin, Monica | Puduvalli, Vinay | Sawaya, Raymond | Heimberger, Amy | Lang, Frederick | Levine, Nicholas | Tolentino, Lori | Saunders, Kate | Thach, Thu-Trang | Iacono, Donna Dello | Sloan, Andrew | Gerson, Stanton | Selman, Warren | Bambakidis, Nicholas | Hart, David | Miller, Jonathan | Hoffer, Alan | Cohen, Mark | Rogers, Lisa | Nock, Charles J | Wolinsky, Yingli | Devine, Karen | Fulop, Jordonna | Barrett, Wendi | Shimmel, Kristen | Ostrom, Quinn | Barnett, Gene | Rosenfeld, Steven | Vogelbaum, Michael | Weil, Robert | Ahluwalia, Manmeet | Peereboom, David | Staugaitis, Susan | Schilero, Cathy | Brewer, Cathy | Smolenski, Kathy | McGraw, Mary | Naska, Theresa | Rosenfeld, Steven | Ram, Zvi | Blumenthal, Deborah T. | Bokstein, Felix | Umansky, Felix | Zaaroor, Menashe | Cohen, Avi | Tzuk-Shina, Tzeela | Voldby, Bo | Laursen, René | Andersen, Claus | Brennum, Jannick | Henriksen, Matilde Bille | Marzouk, Maya | Davis, Mary Elizabeth | Boland, Eamon | Smith, Marcel | Eze, Ogechukwu | Way, Mahalia | Lada, Pat | Miedzianowski, Nancy | Frechette, Michelle | Paleologos, Nina | Byström, Gudrun | Svedberg, Eva | Huggert, Sara | Kimdal, Mikael | Sandström, Monica | Brännström, Nikolina | Hayat, Amina | Tihan, Tarik | Zheng, Shichun | Berger, Mitchel | Butowski, Nicholas | Chang, Susan | Clarke, Jennifer | Prados, Michael | Rice, Terri | Sison, Jeannette | Kivett, Valerie | Duo, Xiaoqin | Hansen, Helen | Hsuang, George | Lamela, Rosito | Ramos, Christian | Patoka, Joe | Wagenman, Katherine | Zhou, Mi | Klein, Adam | McGee, Nora | Pfefferle, Jon | Wilson, Callie | Morris, Pagan | Hughes, Mary | Britt-Williams, Marlin | Foft, Jessica | Madsen, Julia | Polony, Csaba | McCarthy, Bridget | Zahora, Candice | Villano, John | Engelhard, Herbert | Borg, Ake | Chanock, Stephen K | Collins, Peter | Elston, Robert | Kleihues, Paul | Kruchko, Carol | Petersen, Gloria | Plon, Sharon | Thompson, Patricia | Johansen, C. | Sadetzki, S. | Melin, B. | Bondy, Melissa L. | Lau, Ching C. | Scheurer, Michael E. | Armstrong, Georgina N. | Liu, Yanhong | Shete, Sanjay | Yu, Robert K. | Aldape, Kenneth D. | Gilbert, Mark R. | Weinberg, Jeffrey | Houlston, Richard S. | Hosking, Fay J. | Robertson, Lindsay | Papaemmanuil, Elli | Claus, Elizabeth B. | Claus, Elizabeth B. | Barnholtz-Sloan, Jill | Sloan, Andrew E. | Barnett, Gene | Devine, Karen | Wolinsky, Yingli | Lai, Rose | McKean-Cowdin, Roberta | Il'yasova, Dora | Schildkraut, Joellen | Sadetzki, Siegal | Yechezkel, Galit Hirsh | Bruchim, Revital Bar-Sade | Aslanov, Lili | Sadetzki, Siegal | Johansen, Christoffer | Kosteljanetz, Michael | Broholm, Helle | Bernstein, Jonine L. | Olson, Sara H. | Schubert, Erica | DeAngelis, Lisa | Jenkins, Robert B. | Yang, Ping | Rynearson, Amanda | Andersson, Ulrika | Wibom, Carl | Henriksson, Roger | Melin, Beatrice S. | Cederquist, Kristina | Aradottir, Steina | Borg, Åke | Merrell, Ryan | Lada, Patricia | Wrensch, Margaret | Wiencke, John | Wiemels, Joe | McCoy, Lucie | McCarthy, Bridget J. | Davis, Faith G.
Neuro-Oncology  2014;16(10):1333-1340.
Background
Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers.
Methods
Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer.The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma.
Results
We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer.
Conclusions
Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes.
doi:10.1093/neuonc/nou052
PMCID: PMC4165415  PMID: 24723567
CDKN2A/B; family history; glioma; MLH1; MSH2; TP53
2.  Targeted Sequencing in Chromosome 17q Linkage Region Identifies Familial Glioma Candidates in the Gliogene Consortium 
Scientific Reports  2015;5:8278.
Glioma is a rare, but highly fatal, cancer that accounts for the majority of malignant primary brain tumors. Inherited predisposition to glioma has been consistently observed within non-syndromic families. Our previous studies, which involved non-parametric and parametric linkage analyses, both yielded significant linkage peaks on chromosome 17q. Here, we use data from next generation and Sanger sequencing to identify familial glioma candidate genes and variants on chromosome 17q for further investigation. We applied a filtering schema to narrow the original list of 4830 annotated variants down to 21 very rare (<0.1% frequency), non-synonymous variants. Our findings implicate the MYO19 and KIF18B genes and rare variants in SPAG9 and RUNDC1 as candidates worthy of further investigation. Burden testing and functional studies are planned.
doi:10.1038/srep08278
PMCID: PMC4317686  PMID: 25652157
3.  Genes-environment interactions in obesity- and diabetes-associated pancreatic cancer: A GWAS data analysis 
Background
Obesity and diabetes are potentially alterable risk factors for pancreatic cancer. Genetic factors that modify the associations of obesity and diabetes with pancreatic cancer have previously not been examined at the genome-wide level.
Methods
Using GWAS genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study of 2,028 cases and 2,109 controls to examine gene-obesity and gene-diabetes interactions in relation to pancreatic cancer risk by employing the likelihood ratio test (LRT) nested in logistic regression models and Ingenuity Pathway Analysis (IPA).
Results
After adjusting for multiple comparisons, a significant interaction of the chemokine signaling pathway with obesity (P = 3.29 × 10−6) and a near significant interaction of calcium signaling pathway with diabetes (P = 1.57 × 10−4) in modifying the risk of pancreatic cancer was observed. These findings were supported by results from IPA analysis of the top genes with nominal interactions. The major contributing genes to the two top pathways include GNGT2, RELA, TIAM1 and GNAS. None of the individual genes or SNPs except one SNP remained significant after adjusting for multiple testing. Notably, SNP rs10818684 of the PTGS1 gene showed an interaction with diabetes (P = 7.91 × 10−7) at a false discovery rate of 6%.
Conclusions
Genetic variations in inflammatory response and insulin resistance may affect the risk of obesity and diabetes-related pancreatic cancer. These observations should be replicated in additional large datasets.
Impact
Gene-environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer.
doi:10.1158/1055-9965.EPI-13-0437-T
PMCID: PMC3947145  PMID: 24136929
GWAS; obesity; diabetes; interaction; pancreatic cancer; genetic susceptibility
4.  Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer 
Block, Matthew S. | Charbonneau, Bridget | Vierkant, Robert A. | Fogarty, Zachary | Bamlet, William R. | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Rossing, Mary Anne | Cramer, Daniel | Pearce, Celeste Leigh | Schildkraut, Joellen | Menon, Usha | Kjaer, Susanne K. | Levine, Douglas A. | Gronwald, Jacek | Culver, Hoda Anton | Whittemore, Alice S. | Karlan, Beth Y. | Lambrechts, Diether | Wentzensen, Nicolas | Kupryjanczyk, Jolanta | Chang-Claude, Jenny | Bandera, Elisa V. | Hogdall, Estrid | Heitz, Florian | Kaye, Stanley B. | Fasching, Peter A. | Campbell, Ian | Goodman, Marc T. | Pejovic, Tanja | Bean, Yukie T. | Hays, Laura E. | Lurie, Galina | Eccles, Diana | Hein, Alexander | Beckmann, Matthias W. | Ekici, Arif B. | Paul, James | Brown, Robert | Flanagan, James M. | Harter, Philipp | du Bois, Andreas | Schwaab, Ira | 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 A. | Yang, Hannah | Garcia-Closas, Montserrat | Despierre, Evelyn | Lambrechts, Sandrina | Vergote, Ignace | Walsh, Christine S. | Lester, Jenny | Sieh, Weiva | McGuire, Valerie | Rothstein, Joseph H. | Ziogas, Argyrios | Lubiński, 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. | Ramirez, Starr M. | Rider, David N. | Knutson, Keith L. | Sellers, Thomas A. | Phelan, Catherine M. | Doherty, Jennifer A. | Johnatty, Sharon E. | deFazio, Anna | Song, Honglin | Tyrer, Jonathan | Kalli, Kimberly R. | Fridley, Brooke L. | Cunningham, Julie M. | Goode, Ellen L.
Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance—p < 2.5×10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with CARD11 (caspase recruitment domain family, member 11) rs41324349 in patients with mucinous EOC (HR 1.82, 95% CI 1.41-2.35, p=4.13×10−6) and TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B) rs7501462 in patients with endometrioid EOC (HR 0.68, 95% CI 0.56-0.82, p=2.33×10−5). Other associations of note included TRAF2 (TNF receptor-associated factor 2) rs17250239 in patients with high-grade serous EOC (HR 0.84, 95% CI 0.77-0.92, p=6.49×10−5) and PLCG1 (phospholipase C, gamma 1) rs11696662 in patients with clear cell EOC (HR 0.43, 95% CI 0.26-0.73, p=4.56×10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.
doi:10.1158/1055-9965.EPI-13-0962
PMCID: PMC4082406  PMID: 24740199
single nucleotide polymorphism; recurrence; survival; ovarian neoplasms
5.  Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer 
Block, Matthew S. | Charbonneau, Bridget | Vierkant, Robert A. | Fogarty, Zachary | Bamlet, William R. | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Rossing, Mary Anne | Cramer, Daniel | Pearce, Celeste Leigh | Schildkraut, Joellen | Menon, Usha | Kjaer, Susanne K. | Levine, Douglas A. | Gronwald, Jacek | Culver, Hoda Anton | Whittemore, Alice S. | Karlan, Beth Y. | Lambrechts, Diether | Wentzensen, Nicolas | Kupryjanczyk, Jolanta | Chang-Claude, Jenny | Bandera, Elisa V. | Hogdall, Estrid | Heitz, Florian | Kaye, Stanley B. | Fasching, Peter A. | Campbell, Ian | Goodman, Marc T. | Pejovic, Tanja | Bean, Yukie T. | Hays, Laura E. | Lurie, Galina | Eccles, Diana | Hein, Alexander | Beckmann, Matthias W. | Ekici, Arif B. | Paul, James | Brown, Robert | Flanagan, James M. | Harter, Philipp | du Bois, Andreas | Schwaab, Ira | 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 A. | Yang, Hannah | Garcia-Closas, Montserrat | Despierre, Evelyn | Lambrechts, Sandrina | Vergote, Ignace | Walsh, Christine S. | Lester, Jenny | Sieh, Weiva | McGuire, Valerie | Rothstein, Joseph H. | Ziogas, Argyrios | Lubiński, 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. | Ramirez, Starr M. | Rider, David N. | Knutson, Keith L. | Sellers, Thomas A. | Phelan, Catherine M. | Doherty, Jennifer A. | Johnatty, Sharon E. | deFazio, Anna | Song, Honglin | Tyrer, Jonathan | Kalli, Kimberly R. | Fridley, Brooke L. | Cunningham, Julie M. | Goode, Ellen L.
Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance—p < 2.5×10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with CARD11 (caspase recruitment domain family, member 11) rs41324349 in patients with mucinous EOC (HR 1.82, 95% CI 1.41–2.35, p=4.13×10−6) and TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B) rs7501462 in patients with endometrioid EOC (HR 0.68, 95% CI 0.56–0.82, p=2.33×10−5). Other associations of note included TRAF2 (TNF receptor-associated factor 2) rs17250239 in patients with high-grade serous EOC (HR 0.84, 95% CI 0.77–0.92, p=6.49×10−5) and PLCG1 (phospholipase C, gamma 1) rs11696662 in patients with clear cell EOC (HR 0.43, 95% CI 0.26–0.73, p=4.56×10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.
doi:10.1158/1055-9965.EPI-13-0962
PMCID: PMC4082406  PMID: 24740199
single nucleotide polymorphism; recurrence; survival; ovarian neoplasms
6.  Large-Scale Evaluation of Common Variation in Regulatory T Cell-Related Genes and Ovarian Cancer Outcome 
Charbonneau, Bridget | Moysich, Kirsten B. | Kalli, Kimberly R. | Oberg, Ann L. | Vierkant, Robert A. | Fogarty, Zachary C. | Block, Matthew S. | Maurer, Matthew J. | Goergen, Krista M. | Fridley, Brooke L. | Cunningham, Julie M. | Rider, David N. | Preston, Claudia | Hartmann, Lynn C. | Lawrenson, Kate | Wang, Chen | Tyrer, Jonathan | Song, Honglin | deFazio, Anna | Johnatty, Sharon E. | Doherty, Jennifer A. | Phelan, Catherine M. | Sellers, Thomas A. | Ramirez, Starr M. | Vitonis, Allison F. | Terry, Kathryn L. | Van Den Berg, David | Pike, Malcolm C. | Wu, Anna H. | Berchuck, Andrew | Gentry-Maharaj, Aleksandra | Ramus, Susan J. | Diergaarde, Brenda | Shen, Howard | Jensen, Allan | Menkiszak, Janusz | Cybulski, Cezary | Lubiński, Jan | Ziogas, Argyrios | Rothstein, Joseph H. | McGuire, Valerie | Sieh, Weiva | Lester, Jenny | Walsh, Christine | Vergote, Ignace | Lambrechts, Sandrina | Despierre, Evelyn | Garcia-Closas, Montserrat | Yang, Hannah | Brinton, Louise A. | Spiewankiewicz, Beata | Rzepecka, Iwona K. | Dansonka-Mieszkowska, Agnieszka | Seibold, Petra | Rudolph, Anja | Paddock, Lisa E. | Orlow, Irene | Lundvall, Lene | Olson, Sara H. | Hogdall, Claus K. | Schwaab, Ira | du Bois, Andreas | Harter, Philipp | Flanagan, James M. | Brown, Robert | Paul, James | Ekici, Arif B. | Beckmann, Matthias W. | Hein, Alexander | Eccles, Diana | Lurie, Galina | Hays, Laura E. | Bean, Yukie T. | Pejovic, Tanja | Goodman, Marc T. | Campbell, Ian | Fasching, Peter A. | Konecny, Gottfried | Kaye, Stanley B. | Heitz, Florian | Hogdall, Estrid | Bandera, Elisa V. | Chang-Claude, Jenny | Kupryjanczyk, Jolanta | Wentzensen, Nicolas | Lambrechts, Diether | Karlan, Beth Y. | Whittemore, Alice S. | Culver, Hoda Anton | Gronwald, Jacek | Levine, Douglas A. | Kjaer, Susanne K. | Menon, Usha | Schildkraut, Joellen M. | Pearce, Celeste Leigh | Cramer, Daniel W. | Rossing, Mary Anne | Chenevix-Trench, Georgia | Pharoah, Paul D.P. | Gayther, Simon A. | Ness, Roberta B. | Odunsi, Kunle | Sucheston, Lara E. | Knutson, Keith L. | Goode, Ellen L.
Cancer immunology research  2014;2(4):332-340.
The presence of regulatory T cells (Tregs) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag SNPs in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR=1.42, 95% CI: 1.22-1.64; p=5.7 × 10−6], rs791587 [HR=1.36, 95% CI:1.17-1.57; p=6.2 × 10−5], rs2476491 [HR=1.40, 95% CI: 1.19-1.64; p=5.6 × 10−5], and rs10795763 [HR=1.35, 95% CI: 1.17-1.57; p=7.9 × 10−5], and for clear cell carcinoma and CTLA4 SNP rs231775 [HR=0.67, 95% CI: 0.54-0.82; p=9.3 × 10−5] after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs appear to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid EOC.
doi:10.1158/2326-6066.CIR-13-0136
PMCID: PMC4000890  PMID: 24764580
clear cell; endometrioid; gynecologic neoplasms; single nucleotide polymorphism
7.  Large-Scale Evaluation of Common Variation in Regulatory T Cell-Related Genes and Ovarian Cancer Outcome 
Charbonneau, Bridget | Moysich, Kirsten B. | Kalli, Kimberly R. | Oberg, Ann L. | Vierkant, Robert A. | Fogarty, Zachary C. | Block, Matthew S. | Maurer, Matthew J. | Goergen, Krista M. | Fridley, Brooke L. | Cunningham, Julie M. | Rider, David N. | Preston, Claudia | Hartmann, Lynn C. | Lawrenson, Kate | Wang, Chen | Tyrer, Jonathan | Song, Honglin | deFazio, Anna | Johnatty, Sharon E. | Doherty, Jennifer A. | Phelan, Catherine M. | Sellers, Thomas A. | Ramirez, Starr M. | Vitonis, Allison F. | Terry, Kathryn L. | Van Den Berg, David | Pike, Malcolm C. | Wu, Anna H. | Berchuck, Andrew | Gentry-Maharaj, Aleksandra | Ramus, Susan J. | Diergaarde, Brenda | Shen, Howard | Jensen, Allan | Menkiszak, Janusz | Cybulski, Cezary | Lubiński, Jan | Ziogas, Argyrios | Rothstein, Joseph H. | McGuire, Valerie | Sieh, Weiva | Lester, Jenny | Walsh, Christine | Vergote, Ignace | Lambrechts, Sandrina | Despierre, Evelyn | Garcia-Closas, Montserrat | Yang, Hannah | Brinton, Louise A. | Spiewankiewicz, Beata | Rzepecka, Iwona K. | Dansonka-Mieszkowska, Agnieszka | Seibold, Petra | Rudolph, Anja | Paddock, Lisa E. | Orlow, Irene | Lundvall, Lene | Olson, Sara H. | Hogdall, Claus K. | Schwaab, Ira | du Bois, Andreas | Harter, Philipp | Flanagan, James M. | Brown, Robert | Paul, James | Ekici, Arif B. | Beckmann, Matthias W. | Hein, Alexander | Eccles, Diana | Lurie, Galina | Hays, Laura E. | Bean, Yukie T. | Pejovic, Tanja | Goodman, Marc T. | Campbell, Ian | Fasching, Peter A. | Konecny, Gottfried | Kaye, Stanley B. | Heitz, Florian | Hogdall, Estrid | Bandera, Elisa V. | Chang-Claude, Jenny | Kupryjanczyk, Jolanta | Wentzensen, Nicolas | Lambrechts, Diether | Karlan, Beth Y. | Whittemore, Alice S. | Culver, Hoda Anton | Gronwald, Jacek | Levine, Douglas A. | Kjaer, Susanne K. | Menon, Usha | Schildkraut, Joellen M. | Pearce, Celeste Leigh | Cramer, Daniel W. | Rossing, Mary Anne | Chenevix-Trench, Georgia | Pharoah, Paul D.P. | Gayther, Simon A. | Ness, Roberta B. | Odunsi, Kunle | Sucheston, Lara E. | Knutson, Keith L. | Goode, Ellen L.
Cancer immunology research  2014;2(4):332-340.
The presence of regulatory T cells (Tregs) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag SNPs in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR=1.42, 95% CI: 1.22–1.64; p=5.7 × 10−6], rs791587 [HR=1.36, 95% CI:1.17–1.57; p=6.2 × 10−5], rs2476491 [HR=1.40, 95% CI: 1.191.64; p=5.6 × 10−5], and rs10795763 [HR=1.35, 95% CI: 1.17–1.57; p=7.9 × 10−5], and for clear cell carcinoma and CTLA4 SNP rs231775 [HR=0.67, 95% CI: 0.54–0.82; p=9.3 × 10−5] after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs appear to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid EOC.
doi:10.1158/2326-6066.CIR-13-0136
PMCID: PMC4000890  PMID: 24764580
clear cell; endometrioid; gynecologic neoplasms; single nucleotide polymorphism
8.  Epidemiology of Pancreatic Cancer and the Role of Family History 
Journal of surgical oncology  2012;107(1):1-7.
Pancreatic cancer is a lethal disease for which only a small number of risk factors have been identified. In addition to older age, male gender, and black race, risk factors include smoking, obesity, long-standing diabetes and pancreatitis, and heavy alcohol use; allergies such as hay fever are related to lowered risk. Several genetic syndromes increase risk of pancreatic cancer. Work on more common genetic variants promises to reveal more potentially important genetic associations.
doi:10.1002/jso.23149
PMCID: PMC4159073  PMID: 22589078
epidemiology; smoking; obesity; diabetes; allergies; genetic syndromes
9.  Allergies and Risk of Pancreatic Cancer: A Pooled Analysis From the Pancreatic Cancer Case-Control Consortium 
American Journal of Epidemiology  2013;178(5):691-700.
In order to quantify the risk of pancreatic cancer associated with history of any allergy and specific allergies, to investigate differences in the association with risk according to age, gender, smoking status, or body mass index, and to study the influence of age at onset, we pooled data from 10 case-control studies. In total, there were 3,567 cases and 9,145 controls. Study-specific odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression adjusted for age, gender, smoking status, and body mass index. Between-study heterogeneity was assessed by using the Cochran Q statistic. Study-specific odds ratios were pooled by using a random-effects model. The odds ratio for any allergy was 0.79 (95% confidence interval (CI): 0.62, 1.00) with heterogeneity among studies (P < 0.001). Heterogeneity was attributable to one study; with that study excluded, the pooled odds ratio was 0.73 (95% CI: 0.64, 0.84) (Pheterogeneity = 0.23). Hay fever (odds ratio = 0.74, 95% CI: 0.56, 0.96) and allergy to animals (odds ratio = 0.62, 95% CI: 0.41, 0.94) were related to lower risk, while there was no statistically significant association with other allergies or asthma. There were no major differences among subgroups defined by age, gender, smoking status, or body mass index. Older age at onset of allergies was slightly more protective than earlier age.
doi:10.1093/aje/kwt052
PMCID: PMC3755648  PMID: 23820785
allergic rhinitis; case-control studies; hypersensitivity; pancreatic neoplasms
10.  Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4 
Cancer causes & control : CCC  2013;24(3):595-602.
Purpose
The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed.
Methods
Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (<0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition.
Results
When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95%CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95%CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95%CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers.
Conclusions
This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.
doi:10.1007/s10552-012-0138-0
PMCID: PMC4127987  PMID: 23334854
Pancreatic cancer; One-carbon metabolism; Polymorphisms; Biomarkers; Epidemiology
11.  Type I and II Endometrial Cancers: Have They Different Risk Factors? 
Journal of Clinical Oncology  2013;31(20):2607-2618.
Purpose
Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors.
Patients and Methods
Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors.
Results
Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m2 increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (Pheterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar.
Conclusion
The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.
doi:10.1200/JCO.2012.48.2596
PMCID: PMC3699726  PMID: 23733771
12.  CONSUMPTION OF SUGARY FOODS AND DRINKS AND RISK OF ENDOMETRIAL CANCER 
Cancer causes & control : CCC  2013;24(7):1427-1436.
Consumption of foods high in sugar promotes insulin production, which has been linked to endometrial carcinogenesis. We evaluated the impact of dietary intake of sugary foods and beverages, as well as added sugar and total sugar on endometrial cancer risk in a population-based case-control study, including 424 cases and 398 controls. Participants completed an interview and food frequency questionnaire, and provided self-recorded waist and hip measurements. Women in the highest quartile of added sugar intake had significantly increased endometrial cancer risk (OR=1.84, 95% CI: 1.16–2.92). Among women with waist-to-hip ratio ≥0.85, risk was significantly higher for the highest vs. lowest tertile of added sugar intakes (OR=2.50, 95% CI: 1.38–4.52). The association with added sugar also became stronger when analyses were restricted to never users of hormone replacement therapy (OR: 2.03; 95% CI: 1.27–3.26, for highest vs. lowest tertile). There was little evidence of effect modification by body mass index or physical activity. Given the high prevalence of intake of sugary foods and drinks in Western populations, additional research is warranted to confirm our findings on endometrial cancer.
doi:10.1007/s10552-013-0222-0
PMCID: PMC3683350  PMID: 23657460
Endometrial neoplasms; diet; sugar; sugary foods; sugary drinks; added sugars
13.  Exome-Wide Association Study of Endometrial Cancer in a Multiethnic Population 
PLoS ONE  2014;9(5):e97045.
Endometrial cancer (EC) contributes substantially to total burden of cancer morbidity and mortality in the United States. Family history is a known risk factor for EC, thus genetic factors may play a role in EC pathogenesis. Three previous genome-wide association studies (GWAS) have found only one locus associated with EC, suggesting that common variants with large effects may not contribute greatly to EC risk. Alternatively, we hypothesize that rare variants may contribute to EC risk. We conducted an exome-wide association study (EXWAS) of EC using the Infinium HumanExome BeadChip in order to identify rare variants associated with EC risk. We successfully genotyped 177,139 variants in a multiethnic population of 1,055 cases and 1,778 controls from four studies that were part of the Epidemiology of Endometrial Cancer Consortium (E2C2). No variants reached global significance in the study, suggesting that more power is needed to detect modest associations between rare genetic variants and risk of EC.
doi:10.1371/journal.pone.0097045
PMCID: PMC4014590  PMID: 24810602
14.  Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case–control studies 
Cancer causes & control : CCC  2013;24(5):10.1007/s10552-013-0174-4.
Purpose
The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology.
Methods
We used data from 21 case–control studies of ovarian cancer (19,066 controls, 11,972 invasive and 2,752 borderline cases). Study-specific odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio using a random effects model.
Results
Current cigarette smoking increased the risk of invasive mucinous (OR = 1.31; 95 % CI: 1.03–1.65) and borderline mucinous ovarian tumors (OR = 1.83; 95 % CI: 1.39–2.41), while former smoking increased the risk of borderline serous ovarian tumors (OR = 1.30; 95 % CI: 1.12–1.50). For these histological types, consistent dose– response associations were observed. No convincing associations between smoking and risk of invasive serous and endometrioid ovarian cancer were observed, while our results provided some evidence of a decreased risk of invasive clear cell ovarian cancer.
Conclusions
Our results revealed marked differences in the risk profiles of histological types of ovarian cancer with regard to cigarette smoking, although the magnitude of the observed associations was modest. Our findings, which may reflect different etiologies of the histological types, add to the fact that ovarian cancer is a heterogeneous disease.
doi:10.1007/s10552-013-0174-4
PMCID: PMC3818570  PMID: 23456270
Case–control studies; Histological type; Ovarian neoplasms; Smoking
15.  Description of selected characteristics of familial glioma patients – Results from the Gliogene Consortium 
Background
While certain inherited syndromes (e.g. Neurofibromatosis or Li-Fraumeni) are associated with an increased risk of glioma, most familial gliomas are non-syndromic. This study describes the demographic and clinical characteristics of the largest series of non-syndromic glioma families ascertained from 14 centres in the United States (US), Europe and Israel as part of the Gliogene Consortium.
Methods
Families with 2 or more verified gliomas were recruited between January 2007 and February 2011. Distributions of demographic characteristics and clinical variables of gliomas in the families were described based on information derived from personal questionnaires.
Findings
The study population comprised 841 glioma patients identified in 376 families (9797 individuals). There were more cases of glioma among males, with a male to female ratio of 1.25. In most families (83%), 2 gliomas were reported, with 3 and 4 gliomas in 13% and 3% of the families, respectively. For families with 2 gliomas, 57% were among 1st-degree relatives, and 31.5% among 2nd-degree relatives. Overall, the mean (±standard deviation [SD]) diagnosis age was 49.4 (±18.7) years. In 48% of families with 2 gliomas, at least one was diagnosed at <40 y, and in 12% both were diagnosed under 40 y of age. Most of these families (76%) had at least one grade IV glioblastoma multiforme (GBM), and in 32% both cases were grade IV gliomas. The most common glioma subtype was GBM (55%), followed by anaplastic astrocytoma (10%) and oligodendroglioma (8%). Individuals with grades I–II were on average 17 y younger than those with grades III–IV.
Interpretation
Familial glioma cases are similar to sporadic cases in terms of gender distribution, age, morphology and grade. Most familial gliomas appear to comprise clusters of two cases suggesting low penetrance, and that the risk of developing additional gliomas is probably low. These results should be useful in the counselling and clinical management of individuals with a family history of glioma.
doi:10.1016/j.ejca.2012.11.009
PMCID: PMC3615132  PMID: 23290425
Glioma; Familial glioma; Clinical characteristics; Genetic counselling
16.  Tubal ligation and risk of ovarian cancer subtypes: a pooled analysis of case-control studies 
Background Tubal ligation is a protective factor for ovarian cancer, but it is unknown whether this protection extends to all invasive histological subtypes or borderline tumors. We undertook an international collaborative study to examine the association between tubal ligation and ovarian cancer subtypes.
Methods We pooled primary data from 13 population-based case-control studies, including 10 157 patients with ovarian cancer (7942 invasive; 2215 borderline) and 13 904 control women. Invasive cases were analysed by histological type, grade and stage, and borderline cases were analysed by histological type. Pooled odds ratios were estimated using conditional logistic regression to match on site, race/ethnicity and age categories, and to adjust for age, oral contraceptive use duration and number of full-term births.
Results Tubal ligation was associated with significantly reduced risks of invasive serous (OR, 0.81; 95% CI, 0.74-0.89; P < 0.001), endometrioid (OR, 0.48; 95% CI, 0.40-0.59; P < 0.001), clear cell (OR, 0.52; 95% CI, 0.40-0.67; P < 0.001) and mucinous (OR, 0.68; 95% CI, 0.52-0.89; P = 0.005) cancers. The magnitude of risk reduction was significantly greater for invasive endometrioid (P < 0.0001) and clear cell (P = 0.0018) than for serous cancer. No significant associations were found with borderline serous or mucinous tumours.
Conclusions We found that the protective effects of tubal ligation on ovarian cancer risk were subtype-specific. These findings provide insights into distinct aetiologies of ovarian cancer subtypes and mechanisms underlying the protective effects of tubal ligation.
doi:10.1093/ije/dyt042
PMCID: PMC3619957  PMID: 23569193
Ovarian cancer; tubal ligation; tubal sterilization
17.  Genome-wide analysis of the role of copy-number variation in pancreatic cancer risk 
Although family history is a risk factor for pancreatic adenocarcinoma, much of the genetic etiology of this disease remains unknown. While genome-wide association studies have identified some common single nucleotide polymorphisms (SNPs) associated with pancreatic cancer risk, these SNPs do not explain all the heritability of this disease. We hypothesized that copy number variation (CNVs) in the genome may play a role in genetic predisposition to pancreatic adenocarcinoma. Here, we report a genome-wide analysis of CNVs in a small hospital-based, European ancestry cohort of pancreatic cancer cases and controls. Germline CNV discovery was performed using the Illumina Human CNV370 platform in 223 pancreatic cancer cases (both sporadic and familial) and 169 controls. Following stringent quality control, we asked if global CNV burden was a risk factor for pancreatic cancer. Finally, we performed in silico CNV genotyping and association testing to discover novel CNV risk loci. When we examined the global CNV burden, we found no strong evidence that CNV burden plays a role in pancreatic cancer risk either overall or specifically in individuals with a family history of the disease. Similarly, we saw no significant evidence that any particular CNV is associated with pancreatic cancer risk. Taken together, these data suggest that CNVs do not contribute substantially to the genetic etiology of pancreatic cancer, though the results are tempered by small sample size and large experimental variability inherent in array-based CNV studies.
doi:10.3389/fgene.2014.00029
PMCID: PMC3923159  PMID: 24592275
pancreatic cancer; copy number variation; cancer risk; SNP microarrays; CNVs
18.  Comorbidites and endometrial cancer survival in Hispanics and non-Hispanic whites 
Cancer causes & control : CCC  2012;24(1):61-69.
Purpose
We investigated comorbidities and endometrial cancer survival by ethnicity because Hispanic whites (HWs) have worse survival than non-Hispanic whites (NHWs).
Methods
An endometrial cancer cohort (1992–2004) established with the Surveillance, Epidemiology and End Results-Medicare linked database (n=3286) was followed through 2007. Endometrial cancer-specific and other cause mortality were evaluated with multivariate hazard ratios (mHRs).
Results
HWs were more likely than NHWs to have regional/distant disease (31.7% vs. 24.8%), diabetes (31.7% vs. 11.0%), and hypertension (49.4% vs. 37.6%). HWs had poorer endometrial cancer-specific survival than NHWs (age-adjusted HR=1.28; 95%CI 1.01–1.61), but not after adjustment for tumor characteristics and treatment (mHR=1.02; 95%CI 0.81–1.29). In contrast, even after adjustment for cancer-related factors, other cause mortality in HWs was elevated (mHR=1.27; 95%CI 1.01–1.59), but not after further adjustment for comorbid conditions (mHR=1.07; 95%CI 0.85–1.35).
Conclusions
Comorbidities, particularly diabetes, were more common in HWs than NHWs and impacted other cause mortality. Improving diabetes management may be an effective means of improving other cause mortality. This may be particularly true for HWs, given their particularly high prevalence of diabetes.
doi:10.1007/s10552-012-0090-z
PMCID: PMC3529816  PMID: 23109171
endometrial neoplasms; comorbidities; survival; SEER; Medicare
19.  Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium 
Endocrine-related cancer  2013;20(2):10.1530/ERC-12-0395.
Whilst previous studies have reported that higher body-mass index (BMI) increases a woman’s risk of developing ovarian cancer, associations for the different histological subtypes have not been well defined. As the prevalence of obesity has increased dramatically, and classification of ovarian histology has improved in the last decade, we sought to examine the association in a pooled analysis of recent studies participating in the Ovarian Cancer Association Consortium. We evaluated the association between BMI (recent, maximum, and in young adulthood) and ovarian cancer risk using original data from 15 case-control studies (13,548 cases, 17,913 controls). We combined study-specific adjusted odds ratios (ORs) using a random–effects model. We further examined the associations by histological subtype, menopausal status and post-menopausal hormone use. High BMI (all time-points) was associated with increased risk. This was most pronounced for borderline serous (recent BMI: pooled OR=1.24 per 5kg/m2; 95%CI 1.18–1.30), invasive endometrioid (1.17; 1.11–1.23) and invasive mucinous (1.19; 1.06–1.32) tumours. There was no association with serous invasive cancer overall (0.98; 0.94–1.02), but increased risks for low grade serous invasive tumours (1.13, 1.03–1.25) and in pre-menopausal women (1.11; 1.04–1.18). Among post–menopausal women, the associations did not differ between HRT users and non–users. Whilst obesity appears to increase risk of the less common histological subtypes of ovarian cancer, it does not increase risk of high grade invasive serous cancers, and reducing BMI is therefore unlikely to prevent the majority of ovarian cancer deaths. Other modifiable factors must be identified to control this disease.
doi:10.1530/ERC-12-0395
PMCID: PMC3857135  PMID: 23404857
ovarian cancer; obesity; body mass index
20.  Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer 
Shen, Hui | Fridley, Brooke L. | Song, Honglin | Lawrenson, Kate | Cunningham, Julie M. | Ramus, Susan J. | Cicek, Mine S. | Tyrer, Jonathan | Stram, Douglas | Larson, Melissa C. | Köbel, Martin | Ziogas, Argyrios | Zheng, Wei | Yang, Hannah P. | Wu, Anna H. | Wozniak, Eva L. | Woo, Yin Ling | Winterhoff, Boris | Wik, Elisabeth | Whittemore, Alice S. | Wentzensen, Nicolas | Weber, Rachel Palmieri | Vitonis, Allison F. | Vincent, Daniel | Vierkant, Robert A. | Vergote, Ignace | Van Den Berg, David | Van Altena, Anne M. | Tworoger, Shelley S. | Thompson, Pamela J. | Tessier, Daniel C. | Terry, Kathryn L. | Teo, Soo-Hwang | Templeman, Claire | Stram, Daniel O. | Southey, Melissa C. | Sieh, Weiva | Siddiqui, Nadeem | Shvetsov, Yurii B. | Shu, Xiao-Ou | Shridhar, Viji | Wang-Gohrke, Shan | Severi, Gianluca | Schwaab, Ira | Salvesen, Helga B. | Rzepecka, Iwona K. | Runnebaum, Ingo B. | Rossing, Mary Anne | Rodriguez-Rodriguez, Lorna | Risch, Harvey A. | Renner, Stefan P. | Poole, Elizabeth M. | Pike, Malcolm C. | Phelan, Catherine M. | Pelttari, Liisa M. | Pejovic, Tanja | Paul, James | Orlow, Irene | Omar, Siti Zawiah | Olson, Sara H. | Odunsi, Kunle | Nickels, Stefan | Nevanlinna, Heli | Ness, Roberta B. | Narod, Steven A. | Nakanishi, Toru | Moysich, Kirsten B. | Monteiro, Alvaro N.A. | Moes-Sosnowska, Joanna | Modugno, Francesmary | Menon, Usha | McLaughlin, John R. | McGuire, Valerie | Matsuo, Keitaro | Adenan, Noor Azmi Mat | Massuger, Leon F.A. G. | Lurie, Galina | Lundvall, Lene | Lubiński, Jan | Lissowska, Jolanta | Levine, Douglas A. | Leminen, Arto | Lee, Alice W. | Le, Nhu D. | Lambrechts, Sandrina | Lambrechts, Diether | Kupryjanczyk, Jolanta | Krakstad, Camilla | Konecny, Gottfried E. | Kjaer, Susanne Krüger | Kiemeney, Lambertus A. | Kelemen, Linda E. | Keeney, Gary L. | Karlan, Beth Y. | Karevan, Rod | Kalli, Kimberly R. | Kajiyama, Hiroaki | Ji, Bu-Tian | Jensen, Allan | Jakubowska, Anna | Iversen, Edwin | Hosono, Satoyo | Høgdall, Claus K. | Høgdall, Estrid | Hoatlin, Maureen | Hillemanns, Peter | Heitz, Florian | Hein, Rebecca | Harter, Philipp | Halle, Mari K. | Hall, Per | Gronwald, Jacek | Gore, Martin | Goodman, Marc T. | Giles, Graham G. | Gentry-Maharaj, Aleksandra | Garcia-Closas, Montserrat | Flanagan, James M. | Fasching, Peter A. | Ekici, Arif B. | Edwards, Robert | Eccles, Diana | Easton, Douglas F. | Dürst, Matthias | du Bois, Andreas | Dörk, Thilo | Doherty, Jennifer A. | Despierre, Evelyn | Dansonka-Mieszkowska, Agnieszka | Cybulski, Cezary | Cramer, Daniel W. | Cook, Linda S. | Chen, Xiaoqing | Charbonneau, Bridget | Chang-Claude, Jenny | Campbell, Ian | Butzow, Ralf | Bunker, Clareann H. | Brueggmann, Doerthe | Brown, Robert | Brooks-Wilson, Angela | Brinton, Louise A. | Bogdanova, Natalia | Block, Matthew S. | Benjamin, Elizabeth | Beesley, Jonathan | Beckmann, Matthias W. | Bandera, Elisa V. | Baglietto, Laura | Bacot, François | Armasu, Sebastian M. | Antonenkova, Natalia | Anton-Culver, Hoda | Aben, Katja K. | Liang, Dong | Wu, Xifeng | Lu, Karen | Hildebrandt, Michelle A.T. | Schildkraut, Joellen M. | Sellers, Thomas A. | Huntsman, David | Berchuck, Andrew | Chenevix-Trench, Georgia | Gayther, Simon A. | Pharoah, Paul D.P. | Laird, Peter W. | Goode, Ellen L. | Pearce, Celeste Leigh
Nature communications  2013;4:10.1038/ncomms2629.
HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR) = 1.13, P = 3.1 × 10−10) and clear cell (rs11651755 OR = 0.77, P = 1.6 × 10−8) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
doi:10.1038/ncomms2629
PMCID: PMC3848248  PMID: 23535649
21.  A variable age of onset segregation model for linkage analysis, with correction for ascertainment, applied to glioma 
Background
We propose a two-step model-based approach, with correction for ascertainment, to linkage analysis of a binary trait with variable age of onset and apply it to a set of multiplex pedigrees segregating for adult glioma.
Methods
First, we fit segregation models by formulating the likelihood for a person to have a bivariate phenotype, affection status and age of onset, along with other covariates, and from these we estimate population trait allele frequencies and penetrance parameters as a function of age (N=281 multiplex glioma pedigrees). Second, the best fitting models are used as trait models in multipoint linkage analysis (N=74 informative multiplex glioma pedigrees). To correct for ascertainment, a prevalence constraint is used in the likelihood of the segregation models for all 281 pedigrees. Then the trait allele frequencies are re-estimated for the pedigree founders of the subset of 74 pedigrees chosen for linkage analysis.
Results
Using the best fitting segregation models in model-based multipoint linkage analysis, we identified two separate peaks on chromosome 17; the first agreed with a region identified by Shete et al. who used model-free affected-only linkage analysis, but with a narrowed peak: and the second agreed with a second region they found but had a larger maximum log of the odds (LOD).
Conclusions/Impact
Our approach has the advantage of not requiring markers to be in linkage equilibrium unless the minor allele frequency is small (markers which tend to be uninformative for linkage), and of using more of the available information for LOD-based linkage analysis.
doi:10.1158/1055-9965.EPI-12-0703
PMCID: PMC3518573  PMID: 22962404
Glioma; model-based linkage; segregation; age of onset; prevalence constraint
22.  Extensive Variation in the Density and Distribution of DNA Polymorphism in Sorghum Genomes 
PLoS ONE  2013;8(11):e79192.
Sorghum genotypes currently used for grain production in the United States were developed from African landraces that were imported starting in the mid-to-late 19th century. Farmers and plant breeders selected genotypes for grain production with reduced plant height, early flowering, increased grain yield, adaptation to drought, and improved resistance to lodging, diseases and pests. DNA polymorphisms that distinguish three historically important grain sorghum genotypes, BTx623, BTx642 and Tx7000, were characterized by genome sequencing, genotyping by sequencing, genetic mapping, and pedigree-based haplotype analysis. The distribution and density of DNA polymorphisms in the sequenced genomes varied widely, in part because the lines were derived through breeding and selection from diverse Kafir, Durra, and Caudatum race accessions. Genomic DNA spanning dw1 (SBI-09) and dw3 (SBI-07) had identical haplotypes due to selection for reduced height. Lower SNP density in genes located in pericentromeric regions compared with genes located in euchromatic regions is consistent with background selection in these regions of low recombination. SNP density was higher in euchromatic DNA and varied >100-fold in contiguous intervals that spanned up to 300 Kbp. The localized variation in DNA polymorphism density occurred throughout euchromatic regions where recombination is elevated, however, polymorphism density was not correlated with gene density or DNA methylation. Overall, sorghum chromosomes contain distal euchromatic regions characterized by extensive, localized variation in DNA polymorphism density, and large pericentromeric regions of low gene density, diversity, and recombination.
doi:10.1371/journal.pone.0079192
PMCID: PMC3827139  PMID: 24265758
23.  Analysis of Over 10,000 Cases Finds No Association between Previously-Reported Candidate Polymorphisms and Ovarian Cancer Outcome 
White, Kristin L. | Vierkant, Robert A. | Fogarty, Zachary C. | Charbonneau, Bridget | Block, Matthew S. | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Rossing, Mary Anne | Cramer, Daniel W. | Pearce, C. Leigh | Schildkraut, Joellen M. | Menon, Usha | Kjaer, Susanne Kruger | Levine, Douglas A. | Gronwald, Jacek | Culver, Hoda Anton | Whittemore, Alice S. | Karlan, Beth Y. | Lambrechts, Diether | Wentzensen, Nicolas | Kupryjanczyk, Jolanta | Chang-Claude, Jenny | Bandera, Elisa V. | Hogdall, Estrid | Heitz, Florian | Kaye, Stanley B. | Fasching, Peter A. | Campbell, Ian | Goodman, Marc T. | Pejovic, Tanja | Bean, Yukie | Lurie, Galina | Eccles, Diana | Hein, Alexander | Beckmann, Matthias W. | Ekici, Arif B. | Paul, James | Brown, Robert | Flanagan, James | Harter, Philipp | du Bois, Andreas | Schwaab, Ira | 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 | Lubiński, 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 | deFazio, Anna | Song, Honglin | Tyrer, Jonathan | Sellers, Thomas A. | Phelan, Catherine M. | Kalli, Kimberly R. | Cunningham, Julie M. | Fridley, Brooke L. | Goode, Ellen L.
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 (SNPs) 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.
doi:10.1158/1055-9965.EPI-13-0028
PMCID: PMC3650102  PMID: 23513043
24.  Genome-wide association study of endometrial cancer in E2C2 
Human Genetics  2013;133(2):211-224.
Endometrial cancer (EC), a neoplasm of the uterine epithelial lining, is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Women with a family history of EC have an increased risk for the disease, suggesting that inherited genetic factors play a role. We conducted a two-stage genome-wide association study of Type I EC. Stage 1 included 5,472 women (2,695 cases and 2,777 controls) of European ancestry from seven studies. We selected independent single-nucleotide polymorphisms (SNPs) that displayed the most significant associations with EC in Stage 1 for replication among 17,948 women (4,382 cases and 13,566 controls) in a multiethnic population (African America, Asian, Latina, Hawaiian and European ancestry), from nine studies. Although no novel variants reached genome-wide significance, we replicated previously identified associations with genetic markers near the HNF1B locus. Our findings suggest that larger studies with specific tumor classification are necessary to identify novel genetic polymorphisms associated with EC susceptibility.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-013-1369-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-013-1369-1
PMCID: PMC3898362  PMID: 24096698
25.  Racial differences in oncogene mutations detected in early stage, low grade endometrial cancers 
Objective
To describe the pattern and frequency of oncogene mutations in white and African American (AA) women with endometrial cancer, and to determine if racial differences in oncogene mutations exist among women with pathologically similar tumors.
Methods
Endometrial cancer patients from a large, urban hospital were identified through medical records, and representative formalin fixed paraffin embedded tumor blocks were retrieved. The study sample included 150 patients (84 AA) who underwent total abdominal hysterectomy for endometrial cancer. The Sequenom MassARRAY system and the OncoCarta Assay v1.0 (Sequenom), were employed to test for 238 mutations in 19 common oncogenes. Chi-square tests and Fisher’s exact tests were used to assess differences in distribution of variables by race and oncogene mutation status.
Results
There were 20 mutations identified in 2 oncogenes (PIK3CA and KRAS) in tumors from 19 women (12.7%). The majority of mutations were found in PIK3CA (16/20). Thirteen percent of endometroid tumors harbored mutations (11 PIK3CA and 2 KRAS), as did 29% of the Malignant Mixed Mullerian tumors (3 PIK3CA and 1 KRAS). There were no observed mutations in serous, clear cell, or mucinous tumor types. Among low grade endometrioid cancers, tumors from AA patients were significantly associated with harboring either a KRAS or PIK3CA mutation (p=0.04), with 7 PIK3CA mutations and all 4 KRAS mutations identified in AA women.
Conclusions
This study provides preliminary evidence that oncogene mutation frequency of some subtypes of histologically similar endometrial carcinoma differ by race. Additional studies are needed to further explore this phenomenon in patients with endometrial carcinoma.
doi:10.1097/IGC.0b013e31826b1110
PMCID: PMC3512561  PMID: 23013731

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