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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  Genome-wide association study of endometrial cancer in E2C2 
Human Genetics  2013;133:211-224.
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
13.  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
14.  Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer 
Bojesen, Stig E | Pooley, Karen A | Johnatty, Sharon E | Beesley, Jonathan | Michailidou, Kyriaki | Tyrer, Jonathan P | Edwards, Stacey L | Pickett, Hilda A | Shen, Howard C | Smart, Chanel E | Hillman, Kristine M | Mai, Phuong L | Lawrenson, Kate | Stutz, Michael D | Lu, Yi | Karevan, Rod | Woods, Nicholas | Johnston, Rebecca L | French, Juliet D | Chen, Xiaoqing | Weischer, Maren | Nielsen, Sune F | Maranian, Melanie J | Ghoussaini, Maya | Ahmed, Shahana | Baynes, Caroline | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | Healey, Sue | Lush, Michael | Tessier, Daniel C | Vincent, Daniel | Bacot, Françis | Vergote, Ignace | Lambrechts, Sandrina | Despierre, Evelyn | Risch, Harvey A | González-Neira, Anna | Rossing, Mary Anne | Pita, Guillermo | Doherty, Jennifer A | Álvarez, Nuria | Larson, Melissa C | Fridley, Brooke L | Schoof, Nils | Chang-Claude, Jenny | Cicek, Mine S | Peto, Julian | Kalli, Kimberly R | Broeks, Annegien | Armasu, Sebastian M | Schmidt, Marjanka K | Braaf, Linde M | Winterhoff, Boris | Nevanlinna, Heli | Konecny, Gottfried E | Lambrechts, Diether | Rogmann, Lisa | Guénel, Pascal | Teoman, Attila | Milne, Roger L | Garcia, Joaquin J | Cox, Angela | Shridhar, Vijayalakshmi | Burwinkel, Barbara | Marme, Frederik | Hein, Rebecca | Sawyer, Elinor J | Haiman, Christopher A | Wang-Gohrke, Shan | Andrulis, Irene L | Moysich, Kirsten B | Hopper, John L | Odunsi, Kunle | Lindblom, Annika | Giles, Graham G | Brenner, Hermann | Simard, Jacques | Lurie, Galina | Fasching, Peter A | Carney, Michael E | Radice, Paolo | Wilkens, Lynne R | Swerdlow, Anthony | Goodman, Marc T | Brauch, Hiltrud | García-Closas, Montserrat | Hillemanns, Peter | Winqvist, Robert | Dürst, Matthias | Devilee, Peter | Runnebaum, Ingo | Jakubowska, Anna | Lubinski, Jan | Mannermaa, Arto | Butzow, Ralf | Bogdanova, Natalia V | Dörk, Thilo | Pelttari, Liisa M | Zheng, Wei | Leminen, Arto | Anton-Culver, Hoda | Bunker, Clareann H | Kristensen, Vessela | Ness, Roberta B | Muir, Kenneth | Edwards, Robert | Meindl, Alfons | Heitz, Florian | Matsuo, Keitaro | du Bois, Andreas | Wu, Anna H | Harter, Philipp | Teo, Soo-Hwang | Schwaab, Ira | Shu, Xiao-Ou | Blot, William | Hosono, Satoyo | Kang, Daehee | Nakanishi, Toru | Hartman, Mikael | Yatabe, Yasushi | Hamann, Ute | Karlan, Beth Y | Sangrajrang, Suleeporn | Kjaer, Susanne Krüger | Gaborieau, Valerie | Jensen, Allan | Eccles, Diana | Høgdall, Estrid | Shen, Chen-Yang | Brown, Judith | Woo, Yin Ling | Shah, Mitul | Azmi, Mat Adenan Noor | Luben, Robert | Omar, Siti Zawiah | Czene, Kamila | Vierkant, Robert A | Nordestgaard, Børge G | Flyger, Henrik | Vachon, Celine | Olson, Janet E | Wang, Xianshu | Levine, Douglas A | Rudolph, Anja | Weber, Rachel Palmieri | Flesch-Janys, Dieter | Iversen, Edwin | Nickels, Stefan | Schildkraut, Joellen M | Silva, Isabel Dos Santos | Cramer, Daniel W | Gibson, Lorna | Terry, Kathryn L | Fletcher, Olivia | Vitonis, Allison F | van der Schoot, C Ellen | Poole, Elizabeth M | Hogervorst, Frans B L | Tworoger, Shelley S | Liu, Jianjun | Bandera, Elisa V | Li, Jingmei | Olson, Sara H | Humphreys, Keith | Orlow, Irene | Blomqvist, Carl | Rodriguez-Rodriguez, Lorna | Aittomäki, Kristiina | Salvesen, Helga B | Muranen, Taru A | Wik, Elisabeth | Brouwers, Barbara | Krakstad, Camilla | Wauters, Els | Halle, Mari K | Wildiers, Hans | Kiemeney, Lambertus A | Mulot, Claire | Aben, Katja K | Laurent-Puig, Pierre | van Altena, Anne M | Truong, Thérèse | Massuger, Leon F A G | Benitez, Javier | Pejovic, Tanja | Perez, Jose Ignacio Arias | Hoatlin, Maureen | Zamora, M Pilar | Cook, Linda S | Balasubramanian, Sabapathy P | Kelemen, Linda E | Schneeweiss, Andreas | Le, Nhu D | Sohn, Christof | Brooks-Wilson, Angela | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Cybulski, Cezary | Henderson, Brian E | Menkiszak, Janusz | Schumacher, Fredrick | Wentzensen, Nicolas | Marchand, Loic Le | Yang, Hannah P | Mulligan, Anna Marie | Glendon, Gord | Engelholm, Svend Aage | Knight, Julia A | Høgdall, Claus K | Apicella, Carmel | Gore, Martin | Tsimiklis, Helen | Song, Honglin | Southey, Melissa C | Jager, Agnes | van den Ouweland, Ans M W | Brown, Robert | Martens, John W M | Flanagan, James M | Kriege, Mieke | Paul, James | Margolin, Sara | Siddiqui, Nadeem | Severi, Gianluca | Whittemore, Alice S | Baglietto, Laura | McGuire, Valerie | Stegmaier, Christa | Sieh, Weiva | Müller, Heiko | Arndt, Volker | Labrèche, France | Gao, Yu-Tang | Goldberg, Mark S | Yang, Gong | Dumont, Martine | McLaughlin, John R | Hartmann, Arndt | Ekici, Arif B | Beckmann, Matthias W | Phelan, Catherine M | Lux, Michael P | Permuth-Wey, Jenny | Peissel, Bernard | Sellers, Thomas A | Ficarazzi, Filomena | Barile, Monica | Ziogas, Argyrios | Ashworth, Alan | Gentry-Maharaj, Aleksandra | Jones, Michael | Ramus, Susan J | Orr, Nick | Menon, Usha | Pearce, Celeste L | Brüning, Thomas | Pike, Malcolm C | Ko, Yon-Dschun | Lissowska, Jolanta | Figueroa, Jonine | Kupryjanczyk, Jolanta | Chanock, Stephen J | Dansonka-Mieszkowska, Agnieszka | Jukkola-Vuorinen, Arja | Rzepecka, Iwona K | Pylkäs, Katri | Bidzinski, Mariusz | Kauppila, Saila | Hollestelle, Antoinette | Seynaeve, Caroline | Tollenaar, Rob A E M | Durda, Katarzyna | Jaworska, Katarzyna | Hartikainen, Jaana M | Kosma, Veli-Matti | Kataja, Vesa | Antonenkova, Natalia N | Long, Jirong | Shrubsole, Martha | Deming-Halverson, Sandra | Lophatananon, Artitaya | Siriwanarangsan, Pornthep | Stewart-Brown, Sarah | Ditsch, Nina | Lichtner, Peter | Schmutzler, Rita K | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Tseng, Chiu-Chen | Stram, Daniel O | van den Berg, David | Yip, Cheng Har | Ikram, M Kamran | Teh, Yew-Ching | Cai, Hui | Lu, Wei | Signorello, Lisa B | Cai, Qiuyin | Noh, Dong-Young | Yoo, Keun-Young | Miao, Hui | Iau, Philip Tsau-Choong | Teo, Yik Ying | McKay, James | Shapiro, Charles | Ademuyiwa, Foluso | Fountzilas, George | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Hou, Ming-Feng | Healey, Catherine S | Luccarini, Craig | Peock, Susan | Stoppa-Lyonnet, Dominique | Peterlongo, Paolo | Rebbeck, Timothy R | Piedmonte, Marion | Singer, Christian F | Friedman, Eitan | Thomassen, Mads | Offit, Kenneth | Hansen, Thomas V O | Neuhausen, Susan L | Szabo, Csilla I | Blanco, Ignacio | Garber, Judy | Narod, Steven A | Weitzel, Jeffrey N | Montagna, Marco | Olah, Edith | Godwin, Andrew K | Yannoukakos, Drakoulis | Goldgar, David E | Caldes, Trinidad | Imyanitov, Evgeny N | Tihomirova, Laima | Arun, Banu K | Campbell, Ian | Mensenkamp, Arjen R | van Asperen, Christi J | van Roozendaal, Kees E P | Meijers-Heijboer, Hanne | Collée, J Margriet | Oosterwijk, Jan C | Hooning, Maartje J | Rookus, Matti A | van der Luijt, Rob B | van Os, Theo A M | Evans, D Gareth | Frost, Debra | Fineberg, Elena | Barwell, Julian | Walker, Lisa | Kennedy, M John | Platte, Radka | Davidson, Rosemarie | Ellis, Steve D | Cole, Trevor | Paillerets, Brigitte Bressac-de | Buecher, Bruno | Damiola, Francesca | Faivre, Laurence | Frenay, Marc | Sinilnikova, Olga M | Caron, Olivier | Giraud, Sophie | Mazoyer, Sylvie | Bonadona, Valérie | Caux-Moncoutier, Virginie | Toloczko-Grabarek, Aleksandra | Gronwald, Jacek | Byrski, Tomasz | Spurdle, Amanda B | Bonanni, Bernardo | Zaffaroni, Daniela | Giannini, Giuseppe | Bernard, Loris | Dolcetti, Riccardo | Manoukian, Siranoush | Arnold, Norbert | Engel, Christoph | Deissler, Helmut | Rhiem, Kerstin | Niederacher, Dieter | Plendl, Hansjoerg | Sutter, Christian | Wappenschmidt, Barbara | Borg, Åke | Melin, Beatrice | Rantala, Johanna | Soller, Maria | Nathanson, Katherine L | Domchek, Susan M | Rodriguez, Gustavo C | Salani, Ritu | Kaulich, Daphne Gschwantler | Tea, Muy-Kheng | Paluch, Shani Shimon | Laitman, Yael | Skytte, Anne-Bine | Kruse, Torben A | Jensen, Uffe Birk | Robson, Mark | Gerdes, Anne-Marie | Ejlertsen, Bent | Foretova, Lenka | Savage, Sharon A | Lester, Jenny | Soucy, Penny | Kuchenbaecker, Karoline B | Olswold, Curtis | Cunningham, Julie M | Slager, Susan | Pankratz, Vernon S | Dicks, Ed | Lakhani, Sunil R | Couch, Fergus J | Hall, Per | Monteiro, Alvaro N A | Gayther, Simon A | Pharoah, Paul D P | Reddel, Roger R | Goode, Ellen L | Greene, Mark H | Easton, Douglas F | Berchuck, Andrew | Antoniou, Antonis C | Chenevix-Trench, Georgia | Dunning, Alison M
Nature genetics  2013;45(4):371-384e2.
TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10−7), reduced estrogen receptor negative (ER-negative) (P=1.0×10−8) and BRCA1 mutation carrier (P=1.1×10−5) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10−14), increased low malignant potential ovarian cancer risk (P=1.3×10−15) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10−12) and BRCA1 mutation carrier (P=1.6×10−14) breast and invasive ovarian (P=1.3×10−11) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splice-variant.
doi:10.1038/ng.2566
PMCID: PMC3670748  PMID: 23535731
15.  GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer 
Pharoah, Paul D. P. | Tsai, Ya-Yu | Ramus, Susan J. | Phelan, Catherine M. | Goode, Ellen L. | Lawrenson, Kate | Price, Melissa | Fridley, Brooke L. | Tyrer, Jonathan P. | Shen, Howard | Weber, Rachel | Karevan, Rod | Larson, Melissa C. | Song, Honglin | Tessier, Daniel C. | Bacot, François | Vincent, Daniel | Cunningham, Julie M. | Dennis, Joe | Dicks, Ed | Aben, Katja K. | Anton-Culver, Hoda | Antonenkova, Natalia | Armasu, Sebastian M. | Baglietto, Laura | Bandera, Elisa V. | Beckmann, Matthias W. | Birrer, Michael J. | Bloom, Greg | Bogdanova, Natalia | Brenton, James D. | Brinton, Louise A. | Brooks-Wilson, Angela | Brown, Robert | Butzow, Ralf | Campbell, Ian | Carney, Michael E | Carvalho, Renato S. | Chang-Claude, Jenny | Chen, Y. Anne | Chen, Zhihua | Chow, Wong-Ho | Cicek, Mine S. | Coetzee, Gerhard | Cook, Linda S. | Cramer, Daniel W. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | Despierre, Evelyn | Doherty, Jennifer A | Dörk, Thilo | du Bois, Andreas | Dürst, Matthias | Eccles, Diana | Edwards, Robert | Ekici, Arif B. | Fasching, Peter A. | Fenstermacher, David | Flanagan, James | Gao, Yu-Tang | Garcia-Closas, Montserrat | Gentry-Maharaj, Aleksandra | Giles, Graham | Gjyshi, Anxhela | Gore, Martin | Gronwald, Jacek | Guo, Qi | Halle, Mari K | Harter, Philipp | Hein, Alexander | Heitz, Florian | Hillemanns, Peter | Hoatlin, Maureen | Høgdall, Estrid | Høgdall, Claus K. | Hosono, Satoyo | Jakubowska, Anna | Jensen, Allan | Kalli, Kimberly R. | Karlan, Beth Y. | Kelemen, Linda E. | Kiemeney, Lambertus A. | Kjaer, Susanne Krüger | Konecny, Gottfried E. | Krakstad, Camilla | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Nathan | Lee, Janet | Leminen, Arto | Lim, Boon Kiong | Lissowska, Jolanta | Lubiński, Jan | Lundvall, Lene | Lurie, Galina | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R | Menon, Usha | Modugno, Francesmary | Moysich, Kirsten B. | Nakanishi, Toru | Narod, Steven A. | Ness, Roberta B. | Nevanlinna, Heli | Nickels, Stefan | Noushmehr, Houtan | Odunsi, Kunle | Olson, Sara | Orlow, Irene | Paul, James | Pejovic, Tanja | Pelttari, Liisa M | Permuth-Wey, Jenny | Pike, Malcolm C | Poole, Elizabeth M | Qu, Xiaotao | Risch, Harvey A. | Rodriguez-Rodriguez, Lorna | Rossing, Mary Anne | Rudolph, Anja | Runnebaum, Ingo | Rzepecka, Iwona K | Salvesen, Helga B. | Schwaab, Ira | Severi, Gianluca | Shen, Hui | Shridhar, Vijayalakshmi | Shu, Xiao-Ou | Sieh, Weiva | Southey, Melissa C. | Spellman, Paul | Tajima, Kazuo | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J | Timorek, Agnieszka | Tworoger, Shelley S. | van Altena, Anne M. | Berg, David Van Den | Vergote, Ignace | Vierkant, Robert A. | Vitonis, Allison F. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wik, Elisabeth | Winterhoff, Boris | Woo, Yin Ling | Wu, Anna H | Yang, Hannah P. | Zheng, Wei | Ziogas, Argyrios | Zulkifli, Famida | Goodman, Marc T. | Hall, Per | Easton, Douglas F | Pearce, Celeste L | Berchuck, Andrew | Chenevix-Trench, Georgia | Iversen, Edwin | Monteiro, Alvaro N.A. | Gayther, Simon A. | Schildkraut, Joellen M. | Sellers, Thomas A.
Nature genetics  2013;45(4):362-370e2.
Genome wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC) with another two loci being close to genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the United Kingdom. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. Follow-up genotyping was carried out in 18,174 cases and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 previously near genome-wide significance and identified three novel loci associated with risk; two loci associated with all EOC subtypes, at 8q21 (rs11782652, P=5.5×10-9) and 10p12 (rs1243180; P=1.8×10-8), and another locus specific to the serous subtype at 17q12 (rs757210; P=8.1×10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility that implicates CHMP4C in the pathogenesis of ovarian cancer.
doi:10.1038/ng.2564
PMCID: PMC3693183  PMID: 23535730
16.  Genome-wide Association Study for Ovarian Cancer Susceptibility using Pooled DNA 
Recent genome-wide association studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate or low penetrance variants exist among the subset of SNPs not well tagged by the genotyping arrays used in the previous studies which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium. Given that most of the top 20 SNPs from pooling were validated in the same samples by individual genotyping, the lack of replication is likely to be due to the relatively small sample size in our stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by the less dense arrays. However our study lacked power to make clear statements on the existence of hitherto untagged small effect variants.
doi:10.1017/thg.2012.38
PMCID: PMC3785301  PMID: 22794196
17.  An Absolute Risk Model to Identify Individuals at Elevated Risk for Pancreatic Cancer in the General Population 
PLoS ONE  2013;8(9):e72311.
Purpose
We developed an absolute risk model to identify individuals in the general population at elevated risk of pancreatic cancer.
Patients and Methods
Using data on 3,349 cases and 3,654 controls from the PanScan Consortium, we developed a relative risk model for men and women of European ancestry based on non-genetic and genetic risk factors for pancreatic cancer. We estimated absolute risks based on these relative risks and population incidence rates.
Results
Our risk model included current smoking (multivariable adjusted odds ratio (OR) and 95% confidence interval: 2.20 [1.84–2.62]), heavy alcohol use (>3 drinks/day) (OR: 1.45 [1.19–1.76]), obesity (body mass index >30 kg/m2) (OR: 1.26 [1.09–1.45]), diabetes >3 years (nested case-control OR: 1.57 [1.13–2.18], case-control OR: 1.80 [1.40–2.32]), family history of pancreatic cancer (OR: 1.60 [1.20–2.12]), non-O ABO genotype (AO vs. OO genotype) (OR: 1.23 [1.10–1.37]) to (BB vs. OO genotype) (OR 1.58 [0.97–2.59]), rs3790844(chr1q32.1) (OR: 1.29 [1.19–1.40]), rs401681(5p15.33) (OR: 1.18 [1.10–1.26]) and rs9543325(13q22.1) (OR: 1.27 [1.18–1.36]). The areas under the ROC curve for risk models including only non-genetic factors, only genetic factors, and both non-genetic and genetic factors were 58%, 57% and 61%, respectively. We estimate that fewer than 3/1,000 U.S. non-Hispanic whites have more than a 5% predicted lifetime absolute risk.
Conclusion
Although absolute risk modeling using established risk factors may help to identify a group of individuals at higher than average risk of pancreatic cancer, the immediate clinical utility of our model is limited. However, a risk model can increase awareness of the various risk factors for pancreatic cancer, including modifiable behaviors.
doi:10.1371/journal.pone.0072311
PMCID: PMC3772857  PMID: 24058443
18.  Insight in glioma susceptibility through an analysis of 6p22.3, 12p13.33-12.1, 17q22-23.2 and 18q23 SNP genotypes in familial and non-familial glioma 
Human genetics  2012;131(9):1507-1517.
Background
The risk of glioma has consistently been shown to be increased two-fold in relatives of patients with primary brain tumors (PBT). A recent genome-wide linkage study of glioma families provided evidence for a disease locus on 17q12-21.32, with the possibility of four additional risk loci at 6p22.3, 12p13.33-12.1, 17q22-23.2, and 18q23.
Methods
To identify the underlying genetic variants responsible for the linkage signals, we compared the genotype frequencies of 5,122 SNPs mapping to these five regions in 88 glioma cases with and 1,100 cases without a family history of PBT (discovery study). An additional series of 84 familial and 903 non-familial cases were used to replicate associations.
Results
In the discovery study, 12 SNPs showed significant associations with family history of PBT (P < 0.001). In the replication study, two of the 12 SNPs were confirmed: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.031) and 17q12-21.32 SPOP rs650461 (P = 0.025). In the combined analysis of discovery and replication studies, the strongest associations were attained at four SNPs: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.0001), SOX5 rs7305773 (P = 0.0001) and STKY1 rs2418087 (P = 0.0003), and 17q12-21.32 SPOP rs6504618 (P = 0.0006). Further, a significant gene-dosage effect was found for increased risk of family history of PBT with these four SNPs in the combined data set (Ptrend < 1.0 ×10−8).
Conclusion
The results support the linkage finding that some loci in the 12p13.33-12.1 and 17q12-q21.32 may contribute to gliomagenesis and suggest potential target genes underscoring linkage signals.
doi:10.1007/s00439-012-1187-x
PMCID: PMC3604903  PMID: 22688887
Association; Polymorphisms; Glioma; Family history of primary brain tumor; Linkage analysis
19.  Age at Last Birth in Relation to Risk of Endometrial Cancer: Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium 
American Journal of Epidemiology  2012;176(4):269-278.
Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. Individual-level data from 4 cohort and 13 case-control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (Ptrend < 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95% confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44% decreased risk compared with women who had their last birth under the age of 25 years (95% confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years.
doi:10.1093/aje/kws129
PMCID: PMC3491967  PMID: 22831825
endometrial neoplasms; parity; reproductive history
20.  A Replication Study and Genome-wide Scan of Single Nucleotide Polymorphisms Associated with Pancreatic Cancer Risk and Overall Survival 
Purpose
To explore the effects of single nucleotide polymorphisms (SNPs) on pancreatic cancer risk and overall survival.
Experimental Design
The germline DNA of 531 pancreatic cancer cases and 305 healthy controls from a hospital-based study was genotyped at SNPs previously reported to be associated with pancreatic cancer risk or clinical outcome. We analyzed putative risk SNPs for replication of their reported effects on risk and tested for novel effects on overall survival (OS). Similarly, we analyzed putative survival-associated SNPs for replication of their reported effects on OS and tested for novel effects on risk. Lastly, we performed a genome-wide association study of OS using a subset of 252 cases, with two subsequent validation sets of 261 and 572 patients, respectively.
Results
Among seven risk SNPs analyzed, two (rs505922, rs9543325) were associated with risk (p<0.05). Among 24 survival-associated SNPs analyzed, one (rs9350) was associated with OS (p<0.05). No putative risk SNPs or putative survival-associated SNPs were found to be associated with OS or risk, respectively. Further, our GWAS identified a novel SNP (rs1482426, combined stage 1 and 2 p = 1.7 ×10−6, per-allele HR = 1.74, 95% CI 1.38–2.18) to be putatively associated with OS.
Conclusions
The effects of SNPs on pancreatic cancer risk and overall survival were replicated in our study, though further work is necessary to understand the functional mechanisms underlying these effects. More importantly, the putative association with OS identified by GWAS suggests that GWAS may be useful in identifying SNPs associated with clinical outcome in pancreatic cancer.
doi:10.1158/1078-0432.CCR-11-2856
PMCID: PMC3568955  PMID: 22665904
pancreatic cancer; susceptibility; overall survival; genome-wide association study (GWAS)
21.  Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31 
Permuth-Wey, Jennifer | Lawrenson, Kate | Shen, Howard C. | Velkova, Aneliya | Tyrer, Jonathan P. | Chen, Zhihua | Lin, Hui-Yi | Chen, Y. Ann | Tsai, Ya-Yu | Qu, Xiaotao | Ramus, Susan J. | Karevan, Rod | Lee, Janet | Lee, Nathan | Larson, Melissa C. | Aben, Katja K. | Anton-Culver, Hoda | Antonenkova, Natalia | Antoniou, Antonis | Armasu, Sebastian M. | Bacot, François | Baglietto, Laura | Bandera, Elisa V. | Barnholtz-Sloan, Jill | Beckmann, Matthias W. | Birrer, Michael J. | Bloom, Greg | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Brown, Robert | Butzow, Ralf | Cai, Qiuyin | Campbell, Ian | Chang-Claude, Jenny | Chanock, Stephen | Chenevix-Trench, Georgia | Cheng, Jin Q. | Cicek, Mine S. | Coetzee, Gerhard A. | Cook, Linda S. | Couch, Fergus J. | Cramer, Daniel W. | Cunningham, Julie M. | Dansonka-Mieszkowska, Agnieszka | Despierre, Evelyn | Doherty, Jennifer A | Dörk, Thilo | du Bois, Andreas | Dürst, Matthias | Easton, Douglas F | Eccles, Diana | Edwards, Robert | Ekici, Arif B. | Fasching, Peter A. | Fenstermacher, David A. | Flanagan, James M. | Garcia-Closas, Montserrat | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind M. | Gonzalez-Bosquet, Jesus | Goodman, Marc T. | Gore, Martin | Górski, Bohdan | Gronwald, Jacek | Hall, Per | Halle, Mari K. | Harter, Philipp | Heitz, Florian | Hillemanns, Peter | Hoatlin, Maureen | Høgdall, Claus K. | Høgdall, Estrid | Hosono, Satoyo | Jakubowska, Anna | Jensen, Allan | Jim, Heather | Kalli, Kimberly R. | Karlan, Beth Y. | Kaye, Stanley B. | Kelemen, Linda E. | Kiemeney, Lambertus A. | Kikkawa, Fumitaka | Konecny, Gottfried E. | Krakstad, Camilla | Kjaer, Susanne Krüger | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Lancaster, Johnathan M. | Le, Nhu D. | Leminen, Arto | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lin, Jie | Lissowska, Jolanta | Lu, Karen H. | Lubiński, Jan | Lurie, Galina | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R | Menon, Usha | Modugno, Francesmary | Moysich, Kirsten B. | Nakanishi, Toru | Narod, Steven A. | Nedergaard, Lotte | Ness, Roberta B. | Nevanlinna, Heli | Nickels, Stefan | Noushmehr, Houtan | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Paul, James | Pearce, Celeste L | Pejovic, Tanja | Pelttari, Liisa M. | Pike, Malcolm C. | Poole, Elizabeth M. | Raska, Paola | Renner, Stefan P. | Risch, Harvey A. | Rodriguez-Rodriguez, Lorna | Rossing, Mary Anne | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schwaab, Ira | Severi, Gianluca | Shridhar, Vijayalakshmi | Shu, Xiao-Ou | Shvetsov, Yurii B. | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Stram, Daniel | Sutphen, Rebecca | Teo, Soo-Hwang | Terry, Kathryn L. | Tessier, Daniel C. | Thompson, Pamela J. | Tworoger, Shelley S. | van Altena, Anne M. | Vergote, Ignace | Vierkant, Robert A. | Vincent, Daniel | Vitonis, Allison F. | Wang-Gohrke, Shan | Weber, Rachel Palmieri | Wentzensen, Nicolas | Whittemore, Alice S. | Wik, Elisabeth | Wilkens, Lynne R. | Winterhoff, Boris | Woo, Yin Ling | Wu, Anna H. | Xiang, Yong-Bing | Yang, Hannah P. | Zheng, Wei | Ziogas, Argyrios | Zulkifli, Famida | Phelan, Catherine M. | Iversen, Edwin | Schildkraut, Joellen M. | Berchuck, Andrew | Fridley, Brooke L. | Goode, Ellen L. | Pharoah, Paul D. P. | Monteiro, Alvaro N.A. | Sellers, Thomas A. | Gayther, Simon A.
Nature communications  2013;4:1627.
Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3′ untranslated region at putative microRNA (miRNA) binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA binding site single nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (OR=1.12, P=10−8) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10−10). Variation at 17q21.31 associates with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
doi:10.1038/ncomms2613
PMCID: PMC3709460  PMID: 23535648
22.  Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer 
Carcinogenesis  2012;33(7):1384-1390.
Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case–control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10−6, 1.6 × 10−5, 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10−5), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H. pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.
doi:10.1093/carcin/bgs151
PMCID: PMC3405651  PMID: 22523087
23.  Studying Cancer in Minorities– A Look at the Numbers 
Cancer  2011;117(12):2762-2769.
Background
Inclusion of minorities is an important but challenging aspect of epidemiologic studies in the US. One aspect of this challenge that has received little attention is the actual number of minorities affected with specific cancers. We aimed to understand how population characteristics affect the numbers of minority cancer cases in Surveillance, Epidemiology and End Results (SEER) regions.
Methods
Using SEER data, we identified 6 cancers with higher incidence in racial and ethnic minorities and reviewed the annual number of cases of those cancers in SEER areas where there are large numbers of blacks, Hispanics, and Asians. We examined the age characteristics of the populations in SEER areas using data from the U.S. Census.
Results
For blacks, while there are substantial numbers of cases for the most common cancers with higher incidence in this group, numbers are quite small for other cancers: <150 cases, and in many areas, <100 per year. Few registries have substantial numbers of Hispanics or Asians. As expected, the proportion of the minority populations is lower in older age groups, while the proportion of non-Hispanics whites is larger.
Conclusion
Because of the sharp decline in minority populations associated with age, and the high age-specific incidence of most cancers, the actual number of minority cases is quite small for several cancers. This is a further challenge to including minority groups in studies of any but the most common cancers.
doi:10.1002/cncr.25871
PMCID: PMC3695699  PMID: 21656755
cancer; minorities; minority recruitment; epidemiology; population characteristics
24.  Feasibility and yield of screening in relatives from familial pancreatic cancer families 
OBJECTIVES
Pancreatic adenocarcinoma is a lethal disease. Over 80% of patients are found to have metastatic disease at the time of diagnosis. Strategies to improve disease-specific outcome include identification and early detection of precursor lesions or early cancers in high risk groups. In this study we investigate whether screening at-risk relatives of familial pancreatic cancer patients is safe and has significant yield.
METHODS
We enrolled 309 asymptomatic at-risk relatives into our Familial Pancreatic Tumor Registry (FPTR) and offered them screening with MRCP followed by endoscopic ultrasound with fine needle aspiration if indicated. Relatives with findings were referred for surgical evaluation.
RESULTS
As of August 1, 2009, 109 relatives had completed at least one cycle of screening. Abnormal radiographic findings were present on initial screening in 18/109 patients (16.5%), 15 of whom underwent EUS. A significant abnormality was confirmed in 9 of 15 patients, 6 of whom ultimately had surgery for an overall diagnostic yield of 8.3% (9/109). Yield was greatest in relatives >65 years old (35% (6/17) when compared with relatives 55–65 (3% (1/31) and relatives<55 (3% (2/61).
CONCLUSIONS
Screening at-risk relatives from familial pancreatic cancer families has a significant diagnostic yield, particularly in relatives >65 years of age, confirming prior studies. MRCP as initial screening modality is safe and effective.
doi:10.1038/ajg.2011.65
PMCID: PMC3683863  PMID: 21468009
25.  TOTAL AND INDIVIDUAL ANTIOXIDANT INTAKE AND ENDOMETRIAL CANCER RISK: RESULTS FROM A POPULATION-BASED CASE-CONTROL STUDY IN NEW JERSEY 
Cancer causes & control : CCC  2012;23(6):887-895.
We evaluated the role of total dietary antioxidant capacity and of individual antioxidants on endometrial cancer risk in a population-based case-control study in New Jersey, including 417 cases and 395 controls. Dietary intake was ascertained using a food frequency questionnaire (FFQ), and total antioxidant capacity (TAC) intake was estimated using the USDA Oxygen Radical Absorbance Capacity (ORAC) Database and the University of Oslo’s Antioxidant Food Database (AFD) and FFQ-derived estimates of intake. Odds ratios and 95% confidence intervals were derived using multivariate logistic regression controlling for major endometrial cancer risk factors. Using the ORAC database, after adjusting for major covariates, we found decreased risks for the highest tertile of total phenolic intake compared to the lowest (OR: 0.62; 95% CI: 0.39–0.98). There was no association for TAC intake based on the AFD, which utilized the ferric reducing ability of plasma (FRAP) assay to assess antioxidant capacity. There was no strong evidence for an association with intake of any of the individual antioxidants. Our findings suggest that total phenolic consumption may decrease endometrial cancer risk.
doi:10.1007/s10552-012-9958-1
PMCID: PMC3658442  PMID: 22527166
Endometrial neoplasms; antioxidants; total antioxidant capacity; vitamin C; vitamin E; beta-carotene; selenium; lutein; lycopene; diet; phenolics

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