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Discovering the causes of cancer and the means of prevention

Scientific Highlights

Recently Published DCEG Papers

November 2013 - Linkage Newsletter


All Cancers

Cancer After Solid Organ Transplantation

Subgroups of transplantation recipients, generally defined by age and type of transplant, have a high absolute risk of some cancers and may benefit from targeted prevention or screening. (Hall EC, Pfeiffer RM, Segev DL, Engels EA. Cumulative incidence of cancer after solid organ transplantation. Cancer 2013;119:2300–2308)

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Anal Cancer

Risk Factors for Anal Human Papillomavirus Infection and Anal Precancer

The investigators found distinct risk factors for anal human papillomavirus infection and anal precancer—including low CD4 counts; previous Chlamydia trachomatis infection; and history, duration, recency, and dose of smoking—that were similar to established risk factors for cervical cancer progression. (Schwartz LM, Castle PE, Follansbee S, et al. Risk factors for anal HPV infection and anal precancer in HIV-infected men who have sex with men. J Infect Dis 2013; Sep 4 [E-pub ahead of print])

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Bladder Cancer

Sex Hormones and Bladder Cancer Among Women

Reduced bladder cancer risk among parous women, women who reported late age at menarche, and women who reported ever using estrogen and progestin therapy suggest a putative role for sex hormones in the etiology of bladder cancer among women. (Daugherty SE, Lacey JV Jr, Pfeiffer RM, et al. Reproductive factors and menopausal hormone therapy and bladder cancer risk in the NIH-AARP Diet and Health Study. Int J Cancer 2013;133:462–472)

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Breast Cancer

Circulating Estrogens and Androgens

Prediagnostic serum levels of estradiol, estrone, androstenedione, dehydroepiandrosterone sulphate, testosterone, and calculated free testosterone were associated with breast cancer risk among premenopausal women. (Endogenous Hormones and Breast Cancer Collaborative Group: Key TJ, Appleby PN, Reeves GK, et al. Sex hormones and risk of breast cancer in premenopausal women: A collaborative reanalysis of individual participant data from seven prospective studies. Lancet Oncol 2013;14:1009–1019)

Endometrial Thickness and Risk of Breast and Endometrial Carcinomas

Endometrial thickness, which may be a biological marker of excess estrogen stimulation, was associated with increased risk of breast and endometrial carcinomas. (Felix AS, Weissfeld JL, Pfeiffer RM, et al. Endometrial thickness and risk of breast and endometrial carcinomas in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Int J Cancer 2013; Jul 31 [E-pub ahead of print])

Gestational Factors and Breast Cancer

Multiple gestation pregnancies and prepregnancy obesity were associated with decreased breast cancer risk, whereas greater infant birth weight, first trimester bleeding, and placental abnormality/insufficiency were associated with increased risk. (Troisi R, Doody DR, Mueller BA. A linked-registry study of gestational factors and subsequent breast cancer risk in the mother. Cancer Epidemiol Biomarkers Prev 2013;22:835–847)

Risk Factors for Subtypes of Postmenopausal Breast Cancer

Differing associations for hormonal factors and mucinous and tubular cancers suggest etiologies distinct from those of common breast cancers. (Nyante SJ, Dallal CM, Gierach GL, et al. Risk factors for specific histopathological types of postmenopausal breast cancer in the NIH-AARP Diet and Health Study. Am J Epidemiol 2013;178:359–371)

Risk Prediction Models for Breast, Endometrial, and Ovarian Cancer

The authors developed absolute risk prediction models for breast, endometrial, and ovarian cancer by combining data from two large prospective cohorts and validating the models using independent data from a third cohort study. The models predict risk from easily obtainable risk factors and may assist in clinical decision-making. (Pfeiffer RM, Park Y, Kreimer AR, et al. Risk prediction for breast, endometrial, and ovarian cancer in white women aged 50 y or older: Derivation and validation from population-based cohort studies. PLoS Med 2013;10:e1001492)

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Cervical Cancer

Clinical Utility of Human Papillomavirus Genotyping

Although genotyping for human papillomavirus (HPV) 16, 18, and 45 provided additional risk stratification in carcinogenic HPV-positive women with minor cytologic abnormalities, the risk among genotype-negative women was still high enough to warrant immediate colposcopy referral, suggesting that adding genotyping in HPV-positive women with minor cytologic abnormalities will likely not alter clinical management. (Gage JC, Schiffman M, Solomon D, et al. Risk of precancer determined by HPV genotype combinations in women with minor cytologic abnormalities. Cancer Epidemiol Biomarkers Prev 2013;22:1095–1101)

Impact of Human Papillomavirus Vaccination on Health Services

Women who received the human papillomavirus vaccine had a lower prevalence of cervical cytological abnormalities, colposcopy referral, and treatment than women who received the hepatitis A vaccine, but the data suggest that the impact on health services will be modest in the first years after vaccine introduction among young adult women, even in regions with high coverage. (Rodríguez AC, Solomon D, Herrero R, et al. Impact of human papillomavirus vaccination on cervical cytology screening, colposcopy, and treatment. Am J Epidemiol 2013;178:752–760)

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Endometrial Cancer

Adiponectin, Leptin, and Endometrial Cancer Risk

Prediagnostic serum levels of adiponectin were inversely associated with risk of endometrial cancer, whereas elevated leptin levels showed a positive association among postmenopausal women not currently on menopausal hormone therapy. (Luhn P, Dallal CM, Weiss JM, et al. Circulating adipokine levels and endometrial cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cancer Epidemiol Biomarkers Prev 2013;22:1304–1312)

Endometrial Thickness and Risk of Breast and Endometrial Carcinomas

(See under Breast Cancer)

Risk Factors Vary by Histologic Type

Data from the Gynecology Oncology Group show that risk factors for aggressive endometrial cancers, including grade 3 endometrioid and non-endometrioid tumors, appear to differ from lower grade endometrioid carcinomas. (Brinton LA, Felix AS, McMeekin DS, et al. Etiologic heterogeneity in endometrial cancer: Evidence from a Gynecologic Oncology Group trial. Gynecol Oncol 2013;129:277–284)

Risk Prediction Models for Breast, Endometrial, and Ovarian Cancer

(See under Breast Cancer)

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Esophageal Cancer

DNA Repair Pathway Genes

Using data from a genome-wide association study in a Han Chinese population in which esophageal squamous cell carcinoma (ESCC) and gastric cancer (GC) are the predominant cancers, DNA repair pathway genes were associated with ESCC (CHEK2, SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE, and BRCA1) and GC (CLK2, MRE11A, RAD54L, and POLE). (Li WQ, Hu N, Hyland PL, et al. Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population. Carcinogenesis 2013;34:1536–1542)

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Gastric Cancer

Opium and Gastric Adenocarcinoma

In a case-control study in Golestan Province, Iran, use of opium, but not tobacco, was associated with an increased risk of gastric adenocarcinoma for both cardia and noncardia subsites. (Shakeri R, Malekzadeh R, Etemadi A, et al. Opium: An emerging risk factor for gastric adenocarcinoma. Int J Cancer 2013;133:455–461)

Risk Among Hodgkin Lymphoma Survivors

In an international study of Hodgkin lymphoma survivors, stomach cancer risk increased with increasing radiation dose to the stomach and with increasing number of chemotherapy cycles containing alkylating agents. (Morton LM, Dores GM, Curtis RE, et al. Stomach cancer risk after treatment for Hodgkin lymphoma. J Clin Oncol 2013;31:3369–3377)

Tooth Loss and Oral Hygiene

A case-control study in Golestan Province, Iran, showed associations between tooth loss and decayed, missing, and filled teeth with risk of overall gastric cancer and at each anatomic subsite, as well as significantly higher risk for gastric cardia adenocarcinoma among subjects who brushed their teeth less than daily. (Shakeri R, Malekzadeh R, Etemadi A, et al. Association of tooth loss and oral hygiene with risk of gastric adenocarcinoma. Cancer Prev Res (Phila) 2013;6:477–482)

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Genetic Variants Associated with Height and Obesity

Investigators identified four new loci (IGFBP4, H6PD, RSRC1, and PPP2R2A) influencing height and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, and ZZZ3) for clinical classes of obesity. (Berndt SI, Gustafsson S, Mägi R, et al. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nat Genet 2013;45:501–512)

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Genetic Variants Associated with Chronic Lymphocytic Leukemia

A genome-wide association study of chronic lymphocytic leukemia identified risk associated with 10 independent single nucleotide polymorphisms in 9 new loci at 10q23.31 (ACTA2 or FAS [ACTA2/FAS]), 18q21.33 (BCL2), 11p15.5 (C11orf21), 4q25 (LEF1), 2q33.1 (CASP10 or CASP8 [CASP10/CASP8]), 9p21.3 (CDKN2B-AS1), 18q21.32 (PMAIP1), 15q15.1 (BMF), and 2p22.2 (QPCT), as well as an independent signal at an established locus 2q13, (ACOXL) and two additional promising loci below genome-wide significance at 8q22.3 (ODF1) and 5p15.33 (TERT). (Berndt SI, Skibola CF, Joseph V, et al. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia. Nat Genet 2013;45:868–876)

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Liver Cancer

Coffee Reduced Risk of Liver Cancer and Chronic Liver Disease

Data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study showed coffee intake inversely associated with liver cancer incidence and chronic liver disease mortality. (Lai GY, Weinstein SJ, Albanes D, et al. The association of coffee intake with liver cancer incidence and chronic liver disease mortality in male smokers. Br J Cancer 2013;109:1344–1351)

Risk Factors for Liver Cancer in the United States

Using the Surveillance, Epidemiology, and End Results-Medicare database, the authors found the dominant risk factors for liver cancer in the United States overall were diabetes/obesity, with a population attributable fraction of 37%, followed by alcohol-related disorders (24%), hepatitis C virus (22%), hepatitis B virus (6%), and rare genetic disorders (3%), with some variation by sex and race/ethnicity. (Welzel TM, Graubard BI, Quraishi S, et al. Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. Am J Gastroenterol 2013;108:1314–1321)

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Lung Cancer

Reproductive and Hormonal Factors

Lung cancer risk was reduced among women with a later age at first birth, later age at menopause, longer reproductive periods, oral contraceptive use, and use of hormonal replacement therapy. (Pesatori AC, Carugno M, Consonni D, et al. Reproductive and hormonal factors and the risk of lung cancer: The EAGLE study. Int J Cancer 2013;132:2630–2639)

Risk-based Targeting of Computerized Tomography Screening for Lung Cancer

Screening with low-dose computerized tomography prevented the greatest number of deaths from lung cancer among participants who were at highest risk and prevented very few deaths among those at lowest risk, providing empirical support for risk-based targeting of smokers for such screening. (Kovalchik SA, Tammemagi M, Berg CD, et al. Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med 2013;369:245–254)

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Impact of Human Immunodeficiency Virus on Non-Hodgkin Lymphoma Trends

After separating human immunodeficiency virus (HIV)-infected non-Hodgkin lymphoma cases from general population rates, U.S. SEER (Surveillance, Epidemiology, and End Results) data suggest that general population rates increased for decades through the early 2000s then stabilized, independent of HIV. (Shiels MS, Engels EA, Linet MS, et al. The epidemic of non-Hodgkin lymphoma in the United States: Disentangling the effect of HIV, 1992–2009. Cancer Epidemiol Biomarkers Prev 2013;22:1069–1078)

Risk of Lymphoma Subtypes Among Transplant Recipients

In a record linkage study of data from the U.S. Scientific Registry of Transplant Recipients and state and regional cancer registries, risk of lymphoma varied widely across subtypes, with strong elevations for hepatosplenic T-cell lymphoma, Burkitt’s lymphoma, NK/T-cell lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma; moderate elevations for Hodgkin lymphoma and lymphoplasmacytic, peripheral T-cell, and marginal zone lymphomas; and no elevation for indolent lymphoma subtypes. (Clarke CA, Morton LM, Lynch C, et al. Risk of lymphoma subtypes after solid organ transplantation in the United States. Br J Cancer 2013;109:280–288)

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Identifying Associations with Rare and Uncommon Genetic Variants

The authors evaluate generalized score statistics, a class of statistics that can test for an association between a group of genetic variants and a phenotype, taking into consideration their use in identifying associations with rare and uncommon variants. Their newly developed software package, CRaVe, is publicly available at (Ferguson J, Wheeler W, Fu Y, et al. Statistical tests for detecting associations with groups of genetic variants: Generalization, evaluation, and implementation. Eur J Hum Genet 2013;21:680–686)

Rank-based Nonparametric Tests for Quantitative Traits

The authors evaluate various nonparametric tests for the analysis of quantitative traits and propose a new class of nonparametric tests that have robust performance for traits with various distributions and under different genetic models. (Li Q, Li Z, Zheng G, et al. Rank-based robust tests for quantitative-trait genetic association studies. Genet Epidemiol 2013;37:358–365)

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Occupational Cancer

Mortality Among Formaldehyde Workers

Extending the follow-up of a large cohort of workers exposed to formaldehyde by 10 years, the updated analysis continues to suggest a link with nasopharyngeal cancer. (Beane Freeman LE, Blair A, Lubin JH, et al. Mortality from solid tumors among workers in formaldehyde industries: An update of the NCI cohort. Am J Ind Med 2013;56:1015–1026)

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Oropharyngeal Cancer

Human Papillomavirus Antibodies and Oropharyngeal Cancer

Antibodies against human papillomavirus (HPV) 16 E6 protein were observed more than 10 years before diagnosis of oropharyngeal cancers, suggesting potential as a biomarker to identify individuals who are at increased risk of HPV-related cancer of the oropharynx. (Kreimer AR, Johansson M, Waterboer T, et al. Evaluation of human papillomavirus antibodies and risk of subsequent head and neck cancer. J Clin Oncol 2013;31:2708–2715)

Impact of Human Papillomavirus Vaccine on Oral HPV

Oral human papillomavirus (HPV) prevalence 4 years after vaccination with the HPV 16/18 vaccine was much lower among women in the vaccine arm than in those in the control arm, suggesting that the vaccine affords strong protection against oral HPV 16/18 infection, with potentially important implications for prevention of increasingly common HPV-associated oropharyngeal cancer. (Herrero R, Quint W, Hildesheim A, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One 2013;8:e68329)

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Genetic Variants Associated with Osteosarcoma

A genome-wide association study of osteosarcoma identified two novel loci: a locus in the GRM4 gene at 6p21.3, which encodes glutamate receptor metabotropic 4, and a locus in the gene desert at 2p25.2. (Savage SA, Mirabello L, Wang Z, et al. Genome-wide association study identifies two susceptibility loci for osteosarcoma. Nat Genet 2013;45:799–803)

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Ovarian Cancer

Menopausal Hormone Therapy Use

After a marked reduction in menopausal hormone therapy use in the United States around 2002, ovarian cancer incidence rates demonstrated an accelerated decline, with the largest changes for endometrioid carcinomas, suggesting that hormonal exposures play a role in the development and behavior of subtypes of ovarian cancer. (Yang HP, Anderson WF, Rosenberg PS, et al. Ovarian cancer incidence trends in relation to changing patterns of menopausal hormone therapy use in the United States. J Clin Oncol 2013;31:2146–2151)

Risk Prediction Models for Breast, Endometrial, and Ovarian Cancer

(See under Breast Cancer)

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Prostate Cancer

Genetic Variants Within TERT

Fine-mapping of the telomerase reverse transcriptase (TERT) gene identified four signals in the promoter or intronic regions that were independently associated with prostate cancer risk, one of which was also associated with TERT expression, providing a potential mechanism for predisposition to disease. (Kote-Jarai Z, Saunders EJ, Leongamornlert DA, et al. Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression. Hum Mol Genet 2013;22:2520–2528)

Red Hair Phenotype and Prostate Cancer Risk

The red hair phenotype, which results from polymorphisms in the melanocortin-1-receptor (MC1R) gene, was associated with lower risk of prostate cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort, possibly due to genetic effects or regulatory mechanisms related to MC1R, another nearby gene, or other pigmentation genes, or indirectly, through associations with other exposures such as sunlight or vitamin D status. (Weinstein SJ, Virtamo J, Albanes D. Pigmentation-related phenotypes and risk of prostate cancer. Br J Cancer 2013;109:747–750)

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Renal Cancer

Reproductive Factors and Renal Cancer

Analyses within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial and the NIH-AARP Diet and Health Study showed that women who had undergone a hysterectomy were at a significantly elevated risk of kidney cancer. Within the NIH-AARP study only, an inverse association was observed with increasing age at menarche and increasing years of oral contraceptive use. (Karami S, Daugherty SE, Schonfeld SJ, et al. Reproductive factors and kidney cancer risk in 2 US cohort studies, 1993–2010. Am J Epidemiol 2013;177:1368–1377)

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Testicular Cancer

Developmental Urogenital Abnormalities

Using Swedish population-based registries, developmental urogenital abnormalities—specifically, hypospadias, inguinal hernia, and the well-established risk factor of cryptorchidism—were associated with an increased risk of testicular germ cell tumor. This finding supports the hypothesis that prenatal exposure(s) related to proper genital development are related to this tumor. (Trabert B, Zugna D, Richiardi L, et al. Congenital malformations and testicular germ cell tumors. Int J Cancer 2013;133:1900–1904)

Genetic Variants Associated with Testicular Germ Cell Tumor

A meta-analysis of three genome-wide association studies and replication in six independent sample sets found the risk of testicular germ cell tumor associated with four new loci on 4q22.2, 7p22.3, 16q22.3, and 17q22, which contain genes plausibly involved in germ cell development, chromosomal segregation, and DNA repair. (Chung CC, Kanetsky PA, Wang Z, et al. Meta-analysis identifies four new loci associated with testicular germ cell tumor. Nat Genet 2013;45:680–685)

UCK2 and Testicular Germ Cell Tumor

A meta-analysis of two genome-wide association studies of testicular germ cell tumor and a replication analysis found genome-wide significant associations for several markers in the UCK2 gene, with additional support from an independent familial study. (Schumacher FR, Wang Z, Skotheim RI, et al. Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23. Hum Mol Genet 2013;22:2748–2753)

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Thyroid Cancer

Chromosomal Rearrangements in Post-Chernobyl Thyroid Cancer

This study of post-Chernobyl thyroid tumors confirms the high frequency of chromosomal rearrangements, particularly RET/PTC, and lower frequency of BRAF and RAS point mutations, compared with those typically observed in sporadic tumors and reports for the first time the occurrence of PAX8/PPARγ rearrangements in post-Chernobyl papillary thyroid carcinomas (PTCs). (Leeman-Neill RJ, Brenner AV, Little MP, et al. RET/PTC and PAX8/PPARγ chromosomal rearrangements in post-Chernobyl thyroid cancer and their association with iodine-131 radiation dose and other characteristics. Cancer 2013;119:1792–1799)

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Back to the November 2013 issue of DCEG Linkage