Publications by authors named "Laurie Burdette"

52 Publications

Sub-multiplicative interaction between polygenic risk score and household coal use in relation to lung adenocarcinoma among never-smoking women in Asia.

Environ Int 2021 02 29;147:105975. Epub 2020 Dec 29.

Department of Internal Medicine, Kaohsiung Medical University Hospital, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.
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http://dx.doi.org/10.1016/j.envint.2020.105975DOI Listing
February 2021

Using whole-exome sequencing and protein interaction networks to prioritize candidate genes for germline cutaneous melanoma susceptibility.

Sci Rep 2020 10 14;10(1):17198. Epub 2020 Oct 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Although next-generation sequencing has demonstrated great potential for novel gene discovery, confirming disease-causing genes after initial discovery remains challenging. Here, we applied a network analysis approach to prioritize candidate genes identified from whole-exome sequencing analysis of 98 cutaneous melanoma patients from 27 families. Using a network propagation method, we ranked candidate genes by their similarity to known disease genes in protein-protein interaction networks and identified gene clusters with functional connectivity. Using this approach, we identified several new candidate susceptibility genes that warrant future investigations such as NGLY1, IL1RN, FABP2, PRKDC, and PROSER2. The propagated network analysis also allowed us to link families that did not have common underlying genes but that carried variants in genes that interact on protein-protein interaction networks. In conclusion, our study provided an analysis perspective for gene prioritization in the context of genetic heterogeneity across families and prioritized top potential candidate susceptibility genes in our dataset.
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http://dx.doi.org/10.1038/s41598-020-74293-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560829PMC
October 2020

The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

PLoS Med 2019 01 3;16(1):e1002724. Epub 2019 Jan 3.

National Institute of Public Health, Bucharest, Romania.

Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.

Methods And Findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.

Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
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http://dx.doi.org/10.1371/journal.pmed.1002724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317776PMC
January 2019

Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia.

Nat Commun 2018 10 10;9(1):4182. Epub 2018 Oct 10.

Epidemiology Research Program, American Cancer Society, Atlanta, 30303, GA, USA.

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40-31.03, P = 1.36 × 10) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45-6.96, P = 8.75 × 10). Both risk alleles are observed at a low frequency among controls (~2-3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy.
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http://dx.doi.org/10.1038/s41467-018-06541-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180091PMC
October 2018

Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer.

J Natl Cancer Inst 2017 11;109(11)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; Department of Epidemiology and Cancer Control, Division of Cancer Survivorship, Department of Oncology, Department of Biostatistics, Hartwell Center for Bioinformatics and Biotechnology, and Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN; Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD; Departments of Medicine, Pediatrics, and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY; Section of Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, University of Chicago, Chicago, IL; Nationwide Children's Hospital and the Ohio State University School of Medicine, Columbus, OH; Department of Pediatrics, University of Minnesota, Minneapolis, MN; Information Management Services, Inc., Calverton, MD; Cancer Prevention and Clinical Statistics Programs and Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Genetics and Department of Radiation Physics, The University of Texas at MD Anderson Cancer Center, Houston, TX; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, AL.

Background: Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking.

Methods: We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided.

Results: Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8 ; <10 gray: rs17020562, 1q32.3, RPS6KC1 , RAF controls = 0.0005, P = 6.68 × 10 -8 ). Associations were restricted to these dose subgroups, with consistent findings in the two survivor cohorts.

Conclusions: Our study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer.
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http://dx.doi.org/10.1093/jnci/djx058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059172PMC
November 2017

Rare germline variants in known melanoma susceptibility genes in familial melanoma.

Hum Mol Genet 2017 12;26(24):4886-4895

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Known high-risk cutaneous malignant melanoma (CMM) genes account for melanoma risk in <40% of melanoma-prone families, suggesting the existence of additional high-risk genes or perhaps a polygenic mechanism involving multiple genetic modifiers. The goal of this study was to systematically characterize rare germline variants in 42 established melanoma genes among 144 CMM patients in 76 American CMM families without known mutations using data from whole-exome sequencing. We identified 68 rare (<0.1% in public and in-house control datasets) nonsynonymous variants in 25 genes. We technically validated all loss-of-function, inframe insertion/deletion, and missense variants predicted as deleterious, and followed them up in 1, 559 population-based CMM cases and 1, 633 controls. Several of these variants showed disease co-segregation within families. Of particular interest, a stopgain variant in TYR was present in five of six CMM cases/obligate gene carriers in one family and a single population-based CMM case. A start gain variant in the 5'UTR region of PLA2G6 and a missense variant in ATM were each seen in all three affected people in a single family, respectively. Results from rare variant burden tests showed that familial and population-based CMM patients tended to have higher frequencies of rare germline variants in albinism genes such as TYR, TYRP1, and OCA2 (P < 0.05). Our results suggest that rare nonsynonymous variants in low- or intermediate-risk CMM genes may influence familial CMM predisposition, warranting further investigation of both common and rare variants in genes affecting functionally important pathways (such as melanogenesis) in melanoma risk assessment.
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http://dx.doi.org/10.1093/hmg/ddx368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886297PMC
December 2017

Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.

Eur Urol 2017 11 7;72(5):747-754. Epub 2017 Aug 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, MS, USA.

Background: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.

Objective: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.

Design, Setting, And Participants: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.

Outcome Measurements And Statistical Analysis: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.

Results And Limitations: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).

Conclusions: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.

Patient Summary: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.
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http://dx.doi.org/10.1016/j.eururo.2017.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641242PMC
November 2017

Genome-wide association study identifies multiple risk loci for renal cell carcinoma.

Nat Commun 2017 06 9;8:15724. Epub 2017 Jun 9.

Clinical Center of Serbia (KCS), Clinic of Urology, University of Belgrade-Faculty of Medicine, 11000 Belgrade, Serbia.

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10), 3p22.1 (rs67311347, P=2.5 × 10), 3q26.2 (rs10936602, P=8.8 × 10), 8p21.3 (rs2241261, P=5.8 × 10), 10q24.33-q25.1 (rs11813268, P=3.9 × 10), 11q22.3 (rs74911261, P=2.1 × 10) and 14q24.2 (rs4903064, P=2.2 × 10). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.
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http://dx.doi.org/10.1038/ncomms15724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472706PMC
June 2017

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.

Oncotarget 2016 Oct;7(41):66328-66343

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
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http://dx.doi.org/10.18632/oncotarget.11041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340084PMC
October 2016

Rare Germline Copy Number Variations and Disease Susceptibility in Familial Melanoma.

J Invest Dermatol 2016 12 29;136(12):2436-2443. Epub 2016 Jul 29.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA. Electronic address:

Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and single nucleotide polymorphism arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanoma-prone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g., PARP1, CDKN2A) or cosegregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare cosegregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma.
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http://dx.doi.org/10.1016/j.jid.2016.07.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123914PMC
December 2016

Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population.

Lung Cancer 2016 08 13;98:33-42. Epub 2016 May 13.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address:

Objectives: Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping.

Materials And Methods: We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p<1.51×10(-5)) in an independent set of 866 cases and 796 controls in stage 2.

Results And Conclusion: In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 (p=1.3×10(-9); OR=1.32; 95% CI=1.20-1.44) near CHRNA5, and 5p15.33 marked by rs2853677 (p=2.8×10(-9); OR=1.28; 95% CI=1.18-1.39) near TERT. The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer (p=1.3×10(-8); OR=1.37; 95% CI=1.23-1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking - cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT, on 15q25.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans.
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http://dx.doi.org/10.1016/j.lungcan.2016.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939239PMC
August 2016

Identification of new susceptibility loci for gastric non-cardia adenocarcinoma: pooled results from two Chinese genome-wide association studies.

Gut 2017 04 23;66(4):581-587. Epub 2015 Dec 23.

Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, P.R. China.

Objective: Although several genome-wide association studies (GWAS) of non-cardia gastric cancer have been published, more novel association signals could be exploited by combining individual studies together, which will further elucidate the genetic susceptibility of non-cardia gastric cancer.

Design: We conducted a meta-analysis of two published Chinese GWAS studies (2031 non-cardia gastric cancer cases and 4970 cancer-free controls) and followed by genotyping of additional 3564 cases and 4637 controls in two stages.

Results: The overall meta-analysis revealed two new association signals. The first was a novel locus at 5q14.3 and marked by rs7712641 (per-allele OR=0.84, 95% CI 0.80 to 0.88; p=1.21×10). This single-nucleotide polymorphism (SNP) marker maps to the intron of the long non-coding RNA, lnc-POLR3G-4 (), which we observed has lower expression in non-cardia gastric tumour compared with matched normal tissue (P=7.20×10). We also identified a new signal at the 1q22 locus, rs80142782 (per-allele OR=0.62; 95% CI 0.56 to 0.69; p=1.71×10), which was independent of the previously reported SNP at the same locus, rs4072037 (per-allele OR=0.74; 95% CI 0.69 to 0.79; p=6.28×10). Analysis of the new SNP conditioned on the known SNP showed that the new SNP remained genome-wide significant (P=3.47×10). Interestingly, rs80142782 has a minor allele frequency of 0.05 in East Asians but is monomorphic in both European and African populations.

Conclusion: These findings add new evidence for inherited genetic susceptibility to non-cardia gastric cancer and provide further clues to its aetiology in the Han Chinese population.
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http://dx.doi.org/10.1136/gutjnl-2015-310612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963301PMC
April 2017

Deep sequencing of HPV16 genomes: A new high-throughput tool for exploring the carcinogenicity and natural history of HPV16 infection.

Papillomavirus Res 2015 Dec;1:3-11

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

For unknown reasons, there is huge variability in risk conferred by different HPV types and, remarkably, strong differences even between closely related variant lineages within each type. HPV16 is a uniquely powerful carcinogenic type, causing approximately half of cervical cancer and most other HPV-related cancers. To permit the large-scale study of HPV genome variability and precancer/cancer, starting with HPV16 and cervical cancer, we developed a high-throughput next-generation sequencing (NGS) whole-genome method. We designed a custom HPV16 AmpliSeq™ panel that generated 47 overlapping amplicons covering 99% of the genome sequenced on the Ion Torrent Proton platform. After validating with Sanger, the current "gold standard" of sequencing, in 89 specimens with concordance of 99.9%, we used our NGS method and custom annotation pipeline to sequence 796 HPV16-positive exfoliated cervical cell specimens. The median completion rate per sample was 98.0%. Our method enabled us to discover novel SNPs, large contiguous deletions suggestive of viral integration (OR of 27.3, 95% CI 3.3-222, =0.002), and the sensitive detection of variant lineage coinfections. This method represents an innovative high-throughput, ultra-deep coverage technique for HPV genomic sequencing, which, in turn, enables the investigation of the role of genetic variation in HPV epidemiology and carcinogenesis.
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http://dx.doi.org/10.1016/j.pvr.2015.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669577PMC
December 2015

Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions.

Hum Mol Genet 2015 Oct 10;24(19):5603-18. Epub 2015 Jul 10.

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.
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http://dx.doi.org/10.1093/hmg/ddv269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572069PMC
October 2015

Genome-wide association study of gastric adenocarcinoma in Asia: a comparison of associations between cardia and non-cardia tumours.

Gut 2016 10 30;65(10):1611-8. Epub 2015 Jun 30.

Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Objective: Genome-wide association studies (GWAS) of gastric cancer have reported differences in single-nucleotide polymorphism (SNP) associations for tumour subtypes, particularly when divided by location into the gastric cardia versus the non-cardia.

Design: Here we present results for a GWAS using 2350 East Asian gastric cancer cases divided as 1189 gastric cardia and 1027 gastric non-cardia cases and 2708 controls. We also included up to 3042 cardia cases, 4359 non-cardia cases and 7548 controls for replication from two Chinese studies and one Korean study. From the GWAS, we selected 12 top SNPs for each gastric cancer subtype, 4 top SNPs for total gastric cancer and 1 SNP in MUC1 for replication testing.

Results: We observed genome-wide significant associations for rs10074991 in PRKAA1 at 5p13.1 for cardia (p=7.36×10(-12)) and non-cardia cancers (p=2.42×10(-23)) with per allele OR (95% CI) for the combined endpoint of 0.80 (0.77 to 0.83). At 6p21.1, rs2294693 near UNC5CL was significantly associated with gastric non-cardia cancer risk (p=2.50×10(-8)), with OR (95% CI) of 1.18 (1.12 to 1.26), but there was only a nominal association for cardia cancer (p=1.47×10(-2)). We also confirmed a previously reported association for rs4072037 in MUC1 with p=6.59×10(-8) for total gastric cancer and similar estimates for cardia and non-cardia cancers. Three SNPs in PSCA previously reported to be associated with gastric non-cardia cancer showed no apparent association for cardia cancer.

Conclusions: Our results suggest that associations for SNPs with gastric cancer show some different results by tumour location in the stomach.
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http://dx.doi.org/10.1136/gutjnl-2015-309340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568652PMC
October 2016

Genetic susceptibility to diffuse large B-cell lymphoma in a pooled study of three Eastern Asian populations.

Eur J Haematol 2015 Nov 13;95(5):442-8. Epub 2015 Mar 13.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Objectives: Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) and is the most common NHL subtype diagnosed worldwide. The first large-scale genome-wide association study (GWAS) of DLBCL with over 4000 cases conducted among individuals of European ancestry recently identified five independent SNPs that achieved genome-wide significance, and two SNPs that showed a suggestive association with DLBCL risk.

Methods: To evaluate whether Eastern Asians and individuals of European ancestry share similar genetic risk factors for this disease, we attempted to replicate these GWAS findings in a pooled series of 1124 DLBCL cases and 3596 controls from Hong Kong, South Korea, and Thailand.

Results: Three of the five genome-wide significant SNPs from the DLBCL GWAS were significantly associated with DLBCL in our study population, including the top finding from the GWAS, EXOC2 rs116446171, which achieved genome-wide significance in our data (per allele OR = 2.04, 95% CI = 1.63-2.56; ptrend = 3.9 × 10(-10)). Additionally, we observed a significant association with PVT1 rs13255292 (per allele OR = 1.34, 95% CI = 1.19-1.52; ptrend = 2.1 × 10(-6)), which was the second strongest finding in the GWAS, and with HLA-B rs2523607 (per allele OR = 3.05, 95% CI = 1.32-7.05; ptrend = 0.009).

Conclusions: Our study, which provides the first evaluation in Eastern Asians of SNPs definitively associated with DLBCL risk in individuals of European ancestry, indicates that at least some of the genetic factors associated with risk of DLBCL are similar between these populations.
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http://dx.doi.org/10.1111/ejh.12513DOI Listing
November 2015

Interactions between household air pollution and GWAS-identified lung cancer susceptibility markers in the Female Lung Cancer Consortium in Asia (FLCCA).

Hum Genet 2015 Mar 8;134(3):333-41. Epub 2015 Jan 8.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Ave. Belfer 1309, 10461, Bronx, NY, USA,

We previously carried out a multi-stage genome-wide association study (GWAS) on lung cancer among never smokers in the Female Lung Cancer Consortium in Asia (FLCCA) (6,609 cases, 7,457 controls) that identified novel susceptibility loci at 10q25.2, 6q22.2, and 6p21.32, and confirmed two previously identified loci at 5p15.33 and 3q28. Household air pollution (HAP) attributed to solid fuel burning for heating and cooking, is the leading cause of the overall disease burden in Southeast Asia, and is known to contain lung carcinogens. To evaluate the gene-HAP interactions associated with lung cancer in loci independent of smoking, we analyzed data from studies participating in FLCCA with fuel use information available (n = 3; 1,731 cases; 1,349 controls). Coal use was associated with a 30% increased risk of lung cancer (OR 1.3, 95% CI 1.0-1.6). Among the five a priori SNPs identified by our GWAS, two showed a significant interaction with coal use (HLA Class II rs2395185, p = 0.02; TP63 rs4488809 (rs4600802), p = 0.04). The risk of lung cancer associated with coal exposure varied with the respective alleles for these two SNPs. Our observations provide evidence that genetic variation in HLA Class II and TP63 may modify the association between HAP and lung cancer risk. The roles played in the cell cycle and inflammation pathways by the proteins encoded by these two genes provide biological plausibility for these interactions; however, additional replication studies are needed in other non-smoking populations.
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http://dx.doi.org/10.1007/s00439-014-1528-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537621PMC
March 2015

The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease.

Cancer Res 2014 Oct;74(20):5808-18

Ramón y Cajal Hospital, Madrid, Spain.

A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 × 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P(trend) = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-1531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203382PMC
October 2014

A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.

Nat Genet 2014 Oct 14;46(10):1103-9. Epub 2014 Sep 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institute of Health, Bethesda, Maryland, USA.

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.
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http://dx.doi.org/10.1038/ng.3094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383163PMC
October 2014

Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations.

Nat Genet 2014 Sep 17;46(9):1001-1006. Epub 2014 Aug 17.

Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) in individuals of Chinese ancestry (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.82-0.88; P = 7.72 × 10(-20)) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85-0.91; P = 3.10 × 10(-13)). rs7447927 is a synonymous SNP in TMEM173, and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR = 1.33, 95% CI = 1.22-1.46; P = 1.99 × 10(-10)). Our joint analysis identifies new ESCC susceptibility loci overall as well as a new locus unique to the population in the Taihang Mountain region at high risk of ESCC.
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http://dx.doi.org/10.1038/ng.3064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212832PMC
September 2014

Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer.

Nat Genet 2014 Sep 3;46(9):994-1000. Epub 2014 Aug 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.
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http://dx.doi.org/10.1038/ng.3052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191666PMC
September 2014

Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.

Hum Mol Genet 2014 Dec 15;23(24):6616-33. Epub 2014 Jul 15.

Department of Preventive Medicine, Biostatistics Division, Keck School of Medicine and.

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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http://dx.doi.org/10.1093/hmg/ddu363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240198PMC
December 2014

Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma.

Hum Genet 2014 Oct 4;133(10):1289-97. Epub 2014 Jul 4.

Department of Medicine, Duke University Medical Center, Durham, NC, 27705, USA.

Chordoma is a rare bone cancer that is believed to originate from notochordal remnants. We previously identified germline T duplication as a major susceptibility mechanism in several chordoma families. Recently, a common genetic variant in T (rs2305089) was significantly associated with the risk of sporadic chordoma. We sequenced all T exons in 24 familial cases and 54 unaffected family members from eight chordoma families (three with T duplications), 103 sporadic cases, and 160 unrelated controls. We also measured T copy number variation in all sporadic cases. We confirmed the association between the previously reported variant rs2305089 and risk of familial [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 0.93, 7.25, P = 0.067] and sporadic chordoma (OR = 2.85, 95% CI = 1.89, 4.29, P < 0.0001). We also identified a second common variant, rs1056048, that was strongly associated with chordoma in families (OR = 4.14, 95% CI = 1.43, 11.92, P = 0.0086). Among sporadic cases, another common variant (rs3816300) was significantly associated with risk when jointly analyzed with rs2305089. The association with rs3816300 was significantly stronger in cases with early age onset. In addition, we identified three rare variants that were only observed among sporadic chordoma cases, all of which have potential functional relevance based on in silico predictions. Finally, we did not observe T duplication in any sporadic chordoma case. Our findings further highlight the importance of the T gene in the pathogenesis of both familial and sporadic chordoma and suggest a complex susceptibility related to T.
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http://dx.doi.org/10.1007/s00439-014-1463-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938388PMC
October 2014

Genome-wide interaction study of smoking and bladder cancer risk.

Carcinogenesis 2014 Aug 24;35(8):1737-44. Epub 2014 Mar 24.

Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.

Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 × 10(-) (5) were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20-1.50, P value = 5.18 × 10(-) (7)]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67-0.84, P value = 6.35 × 10(-) (7)). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers-including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene-environment interactions for tobacco and bladder cancer.
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http://dx.doi.org/10.1093/carcin/bgu064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123644PMC
August 2014

Genome-wide association study identifies multiple loci associated with bladder cancer risk.

Hum Mol Genet 2014 Mar 24;23(5):1387-98. Epub 2013 Oct 24.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10(-9)) and rs907611 on 11p15.5 (P = 4.11 × 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 × 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
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http://dx.doi.org/10.1093/hmg/ddt519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919005PMC
March 2014

Telomere length and the risk of cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations.

PLoS One 2013 19;8(8):e71121. Epub 2013 Aug 19.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, United States of America.

Introduction: Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations.

Materials And Methods: We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT.

Results: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02-7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction.

Discussion: Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071121PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747185PMC
April 2014

Germline variation in NCF4, an innate immunity gene, is associated with an increased risk of colorectal cancer.

Int J Cancer 2014 Mar 14;134(6):1399-407. Epub 2013 Nov 14.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892.

Chronic inflammation has been implicated in the etiology of colorectal adenoma and cancer; however, few key inflammatory genes mediating this relationship have been identified. In this study, we investigated the association of germline variation in innate immunity genes in relation to the risk of colorectal neoplasia. Our study was based on the analysis of samples collected from the prostate, lung, colorectal and ovarian (PLCO) Cancer Screening Trial. We investigated the association between 196 tag single nucleotide polymorphisms (SNPs) in 20 key innate immunity genes with risk of advanced colorectal adenoma and cancer in 719 adenoma cases, 481 cancer cases and 719 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). After Bonferroni correction, the AG/GG genotype of rs5995355, which is upstream of NCF4, was associated with an increased risk of colorectal cancer (OR = 2.43, 95% CI = 1.73-3.39; p < 0.0001). NCF4 is part of the NAPDH complex, a key factor in biochemical pathways and the innate immune response. While not definitive, our analyses suggest that the variant allele does not affect expression of NCF4, but rather modulates activity of the NADPH complex. Additional studies on the functional consequences of rs5995355 in NCF4 may help to clarify the mechanistic link between inflammation and colorectal cancer.
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http://dx.doi.org/10.1002/ijc.28457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947351PMC
March 2014

Association of genetic variants in CDK6 and XRCC1 with the risk of dysplastic nevi in melanoma-prone families.

J Invest Dermatol 2014 Feb 26;134(2):481-487. Epub 2013 Jul 26.

Division of Cancer Epidemiology and Genetics, NCI/NIH, Bethesda, Maryland, USA. Electronic address:

Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each single-nucleotide polymorphism (SNP) separately, adjusted for age, sex, CMM, and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific P-values. Two genes, CDK6 (cyclin-dependent kinase 6) and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation-positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and -negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent data sets (random-effect meta-analysis: P<0.0001). Our findings suggest that some genetic variants may contribute to DN risk independently of their association with CMM in melanoma-prone families.
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http://dx.doi.org/10.1038/jid.2013.316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873368PMC
February 2014

Pesticide exposure and inherited variants in vitamin d pathway genes in relation to prostate cancer.

Cancer Epidemiol Biomarkers Prev 2013 Sep 5;22(9):1557-66. Epub 2013 Jul 5.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD 20852, USA.

Background: Vitamin D and its metabolites are believed to impede carcinogenesis by stimulating cell differentiation, inhibiting cell proliferation, and inducing apoptosis. Certain pesticides have been shown to deregulate vitamin D's anticarcinogenic properties. We hypothesize that certain pesticides may be linked to prostate cancer via an interaction with vitamin D genetic variants.

Methods: We evaluated interactions between 41 pesticides and 152 single-nucleotide polymorphisms (SNP) in nine vitamin D pathway genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of Caucasian pesticide applicators within the Agricultural Health Study. We assessed Pinteraction values using likelihood ratio tests from unconditional logistic regression and a false discovery rate (FDR) to account for multiple comparisons.

Results: Five significant interactions (P < 0.01) displayed a monotonic increase in prostate cancer risk with individual pesticide use in one genotype and no association in the other. These interactions involved parathion and terbufos use and three vitamin D genes (VDR, RXRB, and GC). The exposure-response pattern among participants with increasing parathion use with the homozygous CC genotype for GC rs7041 compared with unexposed participants was noteworthy [low vs. no exposure: OR, 2.58, 95% confidence interval (CI), 1.07-6.25; high vs. no exposure: OR, 3.09, 95% CI, 1.10-8.68; Pinteraction = 3.8 × 10(-3)].

Conclusions: In this study, genetic variations in vitamin D pathway genes, particularly GC rs7041, an SNP previously linked to lower circulating vitamin D levels, modified pesticide associations with prostate cancer risk.

Impact: Because our study is the first to examine this relationship, additional studies are needed to rule out chance findings.
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http://dx.doi.org/10.1158/1055-9965.EPI-12-1454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773544PMC
September 2013