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Scientific Highlights

Recent DCEG Publications

Topics

Bladder Cancer

Genetic Susceptibility

A new genome-wide association study and meta-analysis of approximately 7,000 bladder cancer cases and 12,000 controls of European descent identified two new loci that achieved genome-wide statistical significance (rs10936599 on 3q26.2 and rs907611 on 11p15.5) as well as two additional loci that approached genome-wide statistical significance (rs6104690 on 20p12.2 and rs4510656 on 6p22.3). (Figueroa JD, Ye Y, Siddiq A, et al. Genome-wide association study identifies multiple loci associated with bladder cancer risk. Hum Mol Genet 2014;23:1387–1398)

Urine Concentration and Genetic Susceptibility

The authors found an association between a representative genetic variant (rs10775480) of SLC14A1, a gene linked to bladder cancer in genome-wide association studies, and urine concentration, as measured by urinary specific gravity, among 275 population-based controls enrolled in the New England Bladder Cancer Study, suggesting a possible mechanism for the increased bladder cancer susceptibility associated with rs10775480. (Koutros S, Baris D, Fischer A, et al. Differential urinary specific gravity as a molecular phenotype of the bladder cancer genetic association in the urea transporter gene, SLC14A1. Int J Cancer 2013;133:3008–3013)

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Breast Cancer

Gene-environment Interactions

This large international collaborative study provided the first strong evidence that breast cancer risks associated with several single nucleotide polymorphisms were modified by established risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, and physical activity). (Nickels S, Truong T, Hein R, et al. Evidence of gene-environment interactions between common breast cancer susceptibility loci and established environmental risk factors. PLoS Genet 2013;9(3):e1003284.)

Genetic Modifiers of BRCA2

Through the Consortium of Investigators of Modifiers of BRCA1/2, the investigators identified stronger associations with breast cancer risk among BRCA2 mutation carriers for genetic variants in FGFR2, MAP3K1, CDKN2A/B, and PTHLH than previously reported and identified a novel susceptibility allele at 6p24 (rs9348512) that was inversely associated with risk. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. (Gaudet MM, Kuchenbaecker KB, Vijai J, et al. Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk. PLoS Genet 2013;9(3):e1003173)

GWAS in BRCA1 Mutation Carriers

A multi-stage genome-wide association study (GWAS) of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast cancer and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers, identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854) and two novel ovarian cancer risk modifier loci at 17q21.31 (rs17631303) and 4q32.3 (rs4691139). (Couch FJ, Wang X, McGuffog L, et al. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genet 2013;9:e1003212)

Inflammatory Breast Cancer Etiology

Different associations with body mass index, age at first birth, and education level between inflammatory breast cancer cases and other types of breast cancer suggest a distinct etiology for inflammatory breast cancer. (Schairer C, Li Y, Frawley P, et al. Risk factors for inflammatory breast cancer and other invasive breast cancers. J Natl Cancer Inst 2013;105:1373–1384)

New Genetic Variants Identified Through Gene-environment Interactions

By using methods accounting for gene-environment interaction, the investigators identified novel genetic loci associated with breast cancer risk, including rs10483028 and rs2242714 on chromosome 21 and rs12197388 in ARID1B on chromosome 6. (Schoeps A, Rudolph A, Seibold P, et al. Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions. Genet Epidemiol 2014;38:84–93)

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Cervical Cancer

HPV 16 Variants in Taiwan

A study of the associations between variants of human papillomavirus (HPV) 16 and risk of cervical neoplasia among women in Taiwan showed that the Asian variant was the most prevalent variant (81.8%) of HPV 16 in Taiwan and also was associated with a 10-fold increased prevalence of histologically confirmed cervical intraepithelial neoplasia grade 3 or worse, compared to the HPV 16 European variant. (Chang YJ, Chen HC, Pan MH, et al. Intratypic variants of human papillomavirus type 16 and risk of cervical neoplasia in Taiwan. J Med Virol 2013;85:1567–1576)

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Colorectal Cancer

Innate Immunity Gene Polymorphisms

In a case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, a single nucleotide polymorphism at rs2838732 (ITGB2) was associated with colorectal neoplasia, with a stronger association for colorectal cancer than for adenoma, and among never and former smokers but not among current smokers. (Chang CM, Chia VM, Gunter MJ, et al. Innate immunity gene polymorphisms and the risk of colorectal neoplasia. Carcinogenesis 2013;34:2512–2520)

Opium Use

Long-term smoking and ingestion of opium, even in low doses, was associated with increased risk of death from both malignant and nonmalignant digestive diseases among the participants of the Golestan Cohort Study, a prospective cohort study in northeastern Iran. (Malekzadeh MM, Khademi H, Pourshams A, et al. Opium use and risk of mortality from digestive diseases: A prospective cohort study. Am J Gastroenterol 2013;108:1757–1765)

Esophageal Cancer

GWAS of Esophageal Adenocarcinoma and Barrett Esophagus

A genome-wide association study (GWAS) compared 2,390 cases of esophageal adenocarcinoma and 3,175 cases of Barrett esophagus with 10,120 controls in 2 phases and identified novel associations of loci at 19p13 (rs10419226) in CRTC1, 9q22 (rs11789015), and 3p14 (rs2687201). The study also extended the previously reported association of a loci near the putative tumor suppressor gene FOXF1 at 16q24 with Barrett esophagus to now include esophageal adenocarcinoma. (Levine DM, Ek WE, Zhang R, et al. A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus. Nat Genet 2013;45:1487–1493)

Prediagnostic Plasma Vitamin C in a Chinese Population

A case-cohort study in China showed that higher circulating vitamin C levels were associated with a reduced risk of incident gastric adenocarcinoma, but no association was found with esophageal squamous cell carcinoma. (Lam TK, Freedman ND, Fan JH, et al. Prediagnostic plasma vitamin C and risk of gastric adenocarcinoma and esophageal squamous cell carcinoma in a Chinese population. Am J Clin Nutr 2013;98:1289–1297)

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Gastric Cancer

Genetic Variants in Fas Signaling Pathway Genes

An examination of 554 single nucleotide polymorphisms in 53 Fas signaling-related genes using a pathway-based approach identified significant associations for gastric cancer overall and gastric cardia adenocarcinoma, but not gastric noncardia adenocarcinoma, among ethnic Chinese. Among examined genes in the Fas signaling pathway, MAP2K4, FAF1, MAPK8, CASP10, CASP8, CFLAR, MAP2K1, CAP8AP2, PAK2, and IKBKB were associated with risk of gastric cancer, and FAF1 and MAPK8 were significantly associated with risk of both gastric cardia adenocarcinoma and gastric noncardia adenocarcinoma. (Hyland PL, Lin SW, Hu N, et al. Genetic variants in fas signaling pathway genes and risk of gastric cancer. Int J Cancer 2014;134:822–831)

Prediagnostic Plasma Vitamin C in a Chinese Population

(See under Esophageal Cancer)

Smoking and Alcohol in Relation to EBV-positive Gastric Cancer

In an international collaborative study of 2,648 gastric cancer patients, a stronger association for smoking, but not for alcohol consumption, was observed among patients with Epstein-Barr virus (EBV)-positive tumors than among patients with EBV-negative tumors. (Camargo MC, Koriyama C, Matsuo K, et al. Case-case comparison of smoking and alcohol risk associations with Epstein-Barr virus-positive gastric cancer. Int J Cancer 2014;134:948–953)

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Liver Cancer

Vitamin D, Incident Liver Cancer, and Chronic Liver Disease Mortality

In a cohort study of a low vitamin D population in China, higher baseline serum 25(OH) vitamin D concentrations were associated with significantly lower risk of chronic liver disease deaths, and among those with higher serum calcium, incident liver cancer. (Wang JB, Abnet CC, Chen W, et al. Association between serum 25(OH) vitamin D, incident liver cancer and chronic liver disease mortality in the Linxian Nutrition Intervention Trials: A nested case-control study. Br J Cancer 2013;109:1997–2004)

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Lung Cancer

Unique EGFR and KRAS Mutation Pattern Associated with Household Coal Burning

In a study of lung cancer among never smokers from a region in China where coal is typically burned indoors, high mutation frequencies in EGFR exon 18 and KRAS and low mutation frequency in EGFR exon 21 were observed that were strikingly divergent from mutation patterns found in other smoking and never smoking populations from Asia. (Hosgood HD 3rd, Pao W, Rothman N, et al. Driver mutations among never smoking female lung cancer tissues in China identify unique EGFR and KRAS mutation pattern associated with household coal burning. Respir Med 2013;107:1755–1762)

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Lymphoma

Cigarette Smoking and Hodgkin Lymphoma

Data from 12 case-control studies in the InterLymph Consortium demonstrated an increased risk of Hodgkin lymphoma among ever smokers overall (odds ratio [OR] = 1.1), which reflected associations with mixed cellularity subtype (OR = 1.6) and Epstein-Barr virus–positive tumors (OR = 1.8) among current smokers. (Kamper-Jørgensen M, Rostgaard K, Glaser SL, et al. Cigarette smoking and risk of Hodgkin lymphoma and its subtypes: A pooled analysis from the International Lymphoma Epidemiology Consortium (InterLymph). Ann Oncol 2013;24:2245–2255)

JAK/STAT Signaling Pathway Genes

In a population-based case-control study among Connecticut women, investigators identified three single nucleotide polymorphisms in STAT3 (rs12949918 and rs6503695) and STAT4 (rs932169) associated with non-Hodgkin lymphoma risk, suggesting that genetic variation in JAK/STAT pathway genes may play a role in lymphomagenesis. (Chen Y, Lan Q, Zheng T, et al. Polymorphisms in JAK/STAT signaling pathway genes and risk of non-Hodgkin lymphoma. Leuk Res 2013;37:1120–1124)

Occupational Exposure to Trichloroethylene

A pooled analysis of four international case-control studies of non-Hodgkin lymphoma (NHL) observed that prolonged high-intensity occupational exposure to trichloroethylene conveys an increased risk of NHL, particularly for follicular lymphoma and chronic lymphocytic leukemia, but not diffuse large B cell lymphoma. (Cocco P, Vermeulen R, Flore V, et al. Occupational exposure to trichloroethylene and risk of non-Hodgkin lymphoma and its major subtypes: A pooled InterLymph analysis. Occup Environ Med 2013;70:795–802)

One-carbon Metabolizing Pathway Genes and Gene-nutrient Interaction

A population-based case-control study of non-Hodgkin lymphoma (NHL) among Connecticut women observed significantly reduced risks for the CBS Ex9+33C > T (TT vs. CC), the MBD2 −2176C > T (CC vs. TT), and the FTHFD Ex21+31A > G (AG vs. AA) genotypes, with the reduced risk mainly apparent among those who had higher dietary intakes of vitamin B6, methionine, and folate, suggesting that variation in several one-carbon metabolizing pathway genes may influence the risk of NHL through gene-nutrient interactions involving dietary nutrient intakes. (Li Q, Lan Q, Zhang Y, et al. Role of one-carbon metabolizing pathway genes and gene-nutrient interaction in the risk of non-Hodgkin lymphoma. Cancer Causes Control 2013;24:1875–1884)

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Methods

Combining P-values in Genomic Studies

After genetic regions have been identified in genome-wide association studies, investigators often follow up with more targeted investigations of specific regions. These investigations typically are based on single nucleotide polymorphisms (SNPs) with dense coverage of a region. Methods are thus needed to test the hypothesis of any association in given genetic regions, combining p-values obtained from testing individual SNPs. The authors have devised a permutation-based version of a sequential procedure for testing the global null hypothesis of no association in a region that accounts for correlations of tests based on SNPs in the same genetic region. (Chen HS, Pfeiffer RM, Zhang S. A powerful method for combining P-values in genomic studies. Genet Epidemiol 2013;37:814–819)

Metabolomics in Epidemiology

The authors assessed the variability of a large subset of metabolites among 60 women at baseline and year one of the Shanghai Physical Activity Study, and observed patterns were confirmed in the Prostate, Lung, Colorectal and Ovarian Cancer Screening study. The authors offer guidelines for determining the sample sizes needed to conduct metabolomic studies in epidemiology. (Sampson JN, Boca SM, Shu XO, et al. Metabolomics in epidemiology: Sources of variability in metabolite measurements and implications. Cancer Epidemiol Biomarkers Prev 2013;22:631–640)

Strategies for Developing Prediction Models from GWAS

The authors studied various aspects of building risk prediction models based on single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) to improve discriminatory accuracy, as measured by the area under the receiver operating characteristic curve, using realistic estimates of the distributions of genetic effect sizes, allele frequencies, and linkage disequilibrium patterns based on GWAS data for Crohn’s disease and prostate cancer. The most critical aspect of prediction model building was initial SNP selection, with a single-phase procedure and univariate (marginal) estimation performing best. For complex diseases and samples of 10,000 or fewer cases and controls, one should limit the number of SNPs to tens or hundreds. (Wu J, Pfeiffer RM, Gail MH. Strategies for developing prediction models from genome-wide association studies. Genet Epidemiol 2013;37:768–777)

Testing Multiple Biological Mediators Simultaneously

As a replacement for the Bonferroni correction, the authors propose a permutation approach that tests multiple putative mediators and controls the familywise error rate, which significantly improves the power to detect mediators even when all biomarkers are independent. (Boca SM, Sinha R, Cross AJ, et al. Testing multiple biological mediators simultaneously. Bioinformatics 2014;30:214–220)

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Multiple Myeloma

Alcohol Consumption

An analysis of six case-control studies participating in the International Multiple Myeloma Consortium (1,567 cases, 7,296 controls) observed a significantly decreased risk associated with ever drinking alcohol (men: odds ratio [OR] = 0.7; women: OR = 0.8), with a stronger inverse association when comparing current to never drinkers (men: OR = 0.6; women: OR = 0.6), but null among former drinkers. (Andreotti G, Birmann B, De Roos AJ, et al. A pooled analysis of alcohol consumption and risk of multiple myeloma in the International Multiple Myeloma Consortium. Cancer Epidemiol Biomarkers Prev 2013;22:1620–1627)

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Obesity

Sleep Duration, Weight Change, and Obesity

In a prospective cohort of 83,377 U.S. men and women aged 51–72 years, the authors observed that participants who reported less than 5 hours of sleep per night had an approximately 40% higher risk of developing obesity than those who reported 7–8 hours of sleep. (Xiao Q, Arem H, Moore SC, et al. A large prospective investigation of sleep duration, weight change, and obesity in the NIH-AARP Diet and Health Study cohort. Am J Epidemiol 2013;178:1600–1610)

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Oropharyngeal Cancer

Incidence and Clearance of Oral HPV Infection in Men

Among men residing in Brazil, Mexico, and the United States who were HIV-negative and participants in the Human Papillomavirus (HPV) Infection in Men cohort study, newly acquired oral oncogenic HPV infections were rare and most were cleared within one year. Acquisition of oral oncogenic HPV was significantly associated with smoking and not being married or cohabiting, but was similar across countries, age groups, and reported sexual behaviors. (Kreimer AR, Pierce Campbell CM, Lin HY, et al. Incidence and clearance of oral human papillomavirus infection in men: The HIM cohort study. Lancet 2013;382:877–887)

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Ovarian Cancer

GWAS in BRCA1 Mutation Carriers

(See under Breast Cancer)

Ovulation-inducing Drugs

In a retrospective cohort of 9,825 women evaluated for infertility at five clinical sites in the United States between 1965 and 1988 with follow-up through 2010, there was no association of ovarian cancer risk with ever use of clomiphene citrate (CC) or gonadotropins, and no evidence was found that any of several more detailed subgroups of usage were related to an increased risk with one exception: women who used CC and remained nulligravid did demonstrate much higher risks than those who successfully conceived compared with nonusers. (Trabert B, Lamb EJ, Scoccia B, et al. Ovulation-inducing drugs and ovarian cancer risk: Results from an extended follow-up of a large United States infertility cohort. Fertil Steril 2013;100:1660–1666)

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Pancreatic Cancer

Absolute Risk Model for Pancreatic Cancer

Using data from the PanScan Consortium, the authors developed an absolute risk model to identify individuals in the general population at elevated risk of pancreatic cancer that considered current smoking, heavy alcohol, obesity, diabetes > 3 years, family history of pancreatic cancer, non-O ABO genotype, rs3790844(chr1q32.1), rs401681(5p15.33), and rs9543325(13q22.1). (Klein AP, Lindström S, Mendelsohn JB, et al. An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population. PLoS One 2013;8:e72311)

GWAS of Survival Among Patients with Pancreatic Adenocarcinoma

A two-stage genome-wide association study (GWAS) demonstrated an association of an SBF2 locus (rs10500715 on chromosome 11p15.4) with survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. (Wu C, Kraft P, Stolzenberg-Solomon R, et al. Genome-wide association study of survival in patients with pancreatic adenocarcinoma. Gut 2014;63:152–160)

Lifetime Adiposity and Risk of Pancreatic Cancer

Using data from the NIH-AARP Diet and Health Study cohort, investigators observed that overweight and obesity at any age are associated with increased pancreatic cancer. (Stolzenberg-Solomon RZ, Schairer C, Moore S, et al. Lifetime adiposity and risk of pancreatic cancer in the NIH-AARP Diet and Health Study cohort. Am J Clin Nutr 2013;98:1057–1065)

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Prostate Cancer

Genetic Susceptibility Loci, Pesticide Exposure, and Prostate Cancer Risk

An investigation of single nucleotide polymorphisms (SNPs)–environment interactions between 30 confirmed prostate cancer susceptibility loci and 45 pesticides and prostate cancer risk in the Agricultural Health Study observed significantly elevated risk among men who carried two T alleles at rs2710647 in the EH domain binding protein 1 (EHBP1) SNP and had high exposure to malathion and among men who carried two A alleles at rs7679673 in TET2 and had high aldrin use. (Koutros S, Berndt SI, Hughes Barry K, et al. Genetic susceptibility loci, pesticide exposure and prostate cancer risk. PLoS One 2013;8(4):e58195)

GWAS of Prostate Cancer Among West African Men

A genome-wide association study (GWAS) of prostate cancer among West African men observed an association at 10p14 within an intron of a long non-coding RNA (lncRNA RP11-543F8.2) 360 kb centromeric of GATA3. (Cook MB, Wang Z, Yeboah ED, et al. A genome-wide association study of prostate cancer in West African men. Hum Genet 2013;Nov 2 [E-pub ahead of print])

Serum Sarcosine and Risk of Prostate Cancer

In an investigation within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, elevated levels of serum sarcosine were associated with an increased prostate cancer risk, suggesting that sarcosine may be an early biomarker for this disease. (Koutros S, Meyer TE, Fox SD, et al. Prospective evaluation of serum sarcosine and risk of prostate cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Carcinogenesis 2013;34:2281–2285)

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Small Intestine

Risk Factors for Adenocarcinomas and Malignant Carcinoid Tumors

Based on data from the NIH-AARP Diet and Health Study, age was associated with adenocarcinomas of the small intestine, whereas age, male sex, body mass index, and menopausal hormone therapy use were positively associated with malignant carcinoids. (Cross AJ, Hollenbeck AR, Park Y. A large prospective study of risk factors for adenocarcinomas and malignant carcinoid tumors of the small intestine. Cancer Causes Control 2013;24:1737–1746)

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Thyroid Cancer

Iodine-131 Dose-dependent Gene Expression in Post-Chernobyl Thyroid Cancers

An evaluation of gene expression in 63 paired RNA specimens from frozen normal and tumor thyroid tissues with individual iodine-131 (I-131) doses received from Chernobyl fallout during childhood observed significant associations with expression of eight genes (ABCC3, C1orf9, C6orf62, FGFR1OP2, HEY2, NDOR1, STAT3, and UCP3) in normal tissue and six genes (ANKRD46, CD47, HNRNPH1, NDOR1, SCEL, and SERPINA1) in tumor tissue. PANTHER/DAVID pathway analyses demonstrated significant over-representation of genes coding for nucleic acid binding in normal and tumor tissues and for p53, EGF, and FGF signaling pathways in tumor tissue. (Abend M, Pfeiffer RM, Ruf C, et al. Iodine-131 dose-dependent gene expression: Alterations in both normal and tumour thyroid tissues of post-Chernobyl thyroid cancers. Br J Cancer 2013;109:2286–2294)

SNPs in Genes Related to Immune Function and Risk of Papillary Thyroid Cancer

A study of genetic markers in immune-related pathways observed increased risk of papillary thyroid cancer associated with single nucleotide polymorphisms (SNPs) (rs6115, rs6112) in the SERPINA5 gene. (Brenner AV, Neta G, Sturgis EM, et al. Common single nucleotide polymorphisms in genes related to immune function and risk of papillary thyroid cancer. PLoS One 2013;8:e57243)

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Back to the Spring 2014 issue of Linkage