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Discovering the causes of cancer and the means of prevention

Scientific Highlights July - October, 2015

, by DCEG Staff

Cancer Topics

All Cancers

Oral Contraceptives

COMMENTARY: Wentzensen N, Berrington de González A. The Pill's gestation: From birth control to cancer prevention. Lancet Oncol 2015;Epub Aug 4.

Vitamin D

COMMENTARY: Albanes D. Vitamin D and cancer: Diversity, complexity, and still a ways to go. Cancer Prev Res (Phila) 2015;8:657-661.


Gene-Environment Interaction

Investigators observed a significant additive interaction between a known bladder cancer susceptibility genetic variant (rs798766:TMEM129-TACC3-FGFR3) and occupational exposure to straight metalworking fluids in a study of high-risk occupations for 2,258 case patients and 2,410 control patients from two bladder cancer studies. The interaction was more apparent in patients with tumors positive for FGFR3 expression. (Figueroa JD, Koutros S, Colt JS, et al. Modification of occupational exposures on bladder cancer risk by common genetic polymorphisms. J Natl Cancer Inst 2015; Epub Sep 14)


Red and Processed Meat

High consumption of red meat and processed meat was associated with an increased risk of postmenopausal breast cancer in an analysis of 9,305 breast cancer cases from the NIH-AARP Diet and Health Study. Added nitrite and heme iron may partly contribute to these observed associations. (Inoue-Choi M, Sinha R, Gierach GL, Ward MH. Red and processed meat, nitrite, and heme iron intakes and postmenopausal breast cancer risk in the NIH-AARP Diet and Health Study. Int J Cancer 2015; Epub Oct 27)


HPV Typing and Cervical Cancer Screening  

In U.S. cervical cancer screening, immediate colposcopy is recommended for women with human papillomavirus (HPV)-positive ASC-US (equivocal) cytology. This study demonstrated a type-dependent 10-fold range in 3-year risks of CIN 3+ for women whose screening result was HPV-positive ASC-US. The findings suggest those with high risk (16.0%) should have immediate colposcopy while low risk (2.0%) might be better managed with repeat testing at 1 year. ASC-US linked to HPV types 16, 18, 31, or 33/58 was considered high risk, warranting immediate colposcopy. Optimal management of women with HPV 52 or 45 remains uncertain. Risk for women with HPV 51, 39, 68/35, or 59/56/66 might be low enough to recommend one-year retesting. (Schiffman M, Vaughan LM, Raine-Bennett TR, et al. A study of HPV typing for the management of HPV-positive ASC-US cervical cytologic results. Gynecol Oncol 2015;138:573-578)

p16/Ki-67 Dual Stain Cytology

Human papillomavirus (HPV)-based cervical cancer screening requires triage markers to decide who should be referred to colposcopy. Based on data from a cohort of women who participated in the HPV/cytology cotesting program at Kaiser Permanente California, the p16/Ki-67 dual stain cytology showed good risk stratification for all HPV-positive women and for HPV-positive women with normal cytology. Additional follow-up is needed to determine how long dual stain negative women remain at low risk of precancer. (Wentzensen N, Fetterman B, Castle PE, et al. p16/Ki-67 dual stain cytology for detection of cervical precancer in HPV-positive women. J Natl Cancer Inst 2015; Epub Sep 15)


Etiologic Factors in Relation to Prognosis

A study of endometrial cancer patients in the NRG Oncology/Gynecologic Oncology Group 210 trial demonstrated that etiologic risk factors, particularly age at diagnosis and body mass index, were associated with tumor-subtype-specific prognosis. (Felix AS, Scott McMeekin D, Mutch D, et al. Associations between etiologic factors and mortality after endometrial cancer diagnosis: The NRG Oncology/Gynecologic Oncology Group 210 trial. Gynecol Oncol 2015;139:70-76)


Age-Specific Risk Factor Profiles

Investigators pooled data from eight population-based, case-control studies within the international Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) to evaluate age-specific risk factor profiles for esophageal (EA) and esophagogastric junction (EGJA) adenocarcinoma. Body mass index (BMI), smoking status and pack-years, recurrent gastroesophageal reflux, and frequency of gastroesophageal reflux were positively associated with EA and EGJA in each age group. Early-onset EA (<50 years) had stronger associations with recurrent gastroesophageal reflux and BMI, relative to older age groups. In contrast, inverse associations of non-steroidal anti-inflammatory drugs use were strongest in the oldest age group (≥70 years). Age-specific associations with EGJA showed similar, but slightly weaker patterns. (Drahos J, Xiao Q, Risch HA. Age-specific risk factor profiles of adenocarcinomas of the esophagus: A pooled analysis from the international BEACON consortium. Int J Cancer 2015; Epub Jul 14)

Gastrointestinal Tract

Oral Biphosphonate Use

Investigators observed no association between oral bisphosphonate use and esophageal cancer risk in a study of the Kaiser Permanente Northern California population. However, a significant association was detected with gastric cardia adenocarcinoma risk. (Vogtmann E, Corley DA, Almers LM, et al. Oral bisphosphonate exposure and the risk of upper gastrointestinal cancers. PLoS One 2015;10:e0140180)


Gene-Gene Interactions

Meta-analysis combining different genotyping platforms can increase power to assess gene-gene interactions but requires a test for interaction on untyped single nucleotide polymorphisms (SNPs). The author describes a novel Wald-type method for testing gene-gene interaction on marginally imputed values of untyped SNPs that corrects for the uncertainty in imputation through the variance estimator using the jackknife, one of resampling techniques. Simulation studies and real data analysis demonstrate that the authors’ approaches outperform the application of traditional dosage method to detection of gene-gene interaction in terms of power while providing control of the type I error. (Song M. Jackknife-based gene-gene interaction tests for untyped SNPs. BMC Genet 2015;16:85)

Heritability and Genetic Correlation Attributable to SNPs

Using data from previous genome-wide association studies for cancer at 13 anatomical sites, investigators estimated the heritability of individual cancers and genetic correlation between pairs as well as the contribution of the heritability of smoking behaviors to the heritability of cancer. Esophageal, prostate, and testicular cancers had the highest heritable components while genetic correlation between pairs of cancer was modest. Smoking heritability contributed more to the heritability of lung than bladder cancer. (Sampson JN, Wheeler WA, Yeager M, et al. Analysis of heritability and shared heritability based on genome-wide association studies for thirteen cancer types. J Natl Cancer Inst 2015; Epub Oct 12)

Somatic Mutation in Cancer Susceptibility Regions

Researchers observed only limited evidence that cancer susceptibility regions that harbor common alleles with small estimated effect sizes are preferential targets for altered somatic mutation frequencies. The findings suggest a complex interplay between germline susceptibility and somatic mutation, underscoring the cumulative effect of common variants on redundant pathways as opposed to driver genes. (Machiela MJ, Ho BM, Fisher VA, et al. Limited evidence that cancer susceptibility regions are preferential targets for somatic mutation. Genome Biol 2015;16:193 doi:10.1186/s13059-015-0755-5)

Web-based Application to Assess Linkage Disequilibrium

LDlink is a web-based collection of bioinformatic modules that query single nucleotide polymorphisms (SNPs) in population groups of interest to generate haplotype tables and interactive plots to assess linkage disequilibrium (LD). Phase 3 haplotype data from the 1000 Genomes Project are referenced for calculating pairwise metrics of LD, searching for proxies in high LD, and enumerating all observed haplotypes. LDlink is tailored for investigators interested in mapping common and uncommon disease susceptibility loci by focusing on output linking correlated alleles and highlighting putative functional variants. LDlink is free and publically available at (Machiela MJ, Chanock SJ. LDlink: A web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics 2015; Epub Jul 2)

Human Papillomavirus

Effect of HPV Vaccine on Miscarriage

Data from the NCI Costa Rica Human Papillomavirus (HPV) Vaccine Trial showed no evidence that bivalent HPV vaccination affects the risk of miscarriage for pregnancies conceived less than 90 days from vaccination. An increased risk observed for miscarriages at weeks 13-20 of gestation for pregnancies conceived any time after vaccination may be an artifact of a thorough set of sensitivity analyses, but should be explored further in existing and future studies. (Panagiotou OA, Befano BL, Gonzalez P, et al. Effect of bivalent human papillomavirus vaccination on pregnancy outcomes: Long term observational follow-up in the Costa Rica HPV Vaccine Trial. BMJ 2015;351:h4358). Read more on the research news highlights page: Long-term study finds no increased risk of miscarriage after HPV vaccination.

HPV Typing and Cervical Cancer Screening  

In U.S. cervical cancer screening, immediate colposcopy is recommended for women with human papillomavirus (HPV)-positive ASC-US (equivocal) cytology. This study demonstrated a type-dependent 10-fold range in 3-year risks of CIN 3+ for women whose screening result was HPV-positive ASC-US. The findings suggest those with high risk (16.0%) should have immediate colposcopy while low risk (2.0%) might be better managed with repeat testing at 1 year. ASC-US linked to HPV types 16, 18, 31, or 33/58 was considered high risk, warranting immediate colposcopy. Optimal management of women with HPV 52 or 45 remains uncertain. Risk for women with HPV 51, 39, 68/35, or 59/56/66 might be low enough to recommend one-year retesting. (Schiffman M, Vaughan LM, Raine-Bennett TR, et al. A study of HPV typing for the management of HPV-positive ASC-US cervical cytologic results. Gynecol Oncol 2015;138:573-578)

Therapeutic HPV Vaccination

COMMENTARY: Schiffman M, Wentzensen N. Towards therapeutic vaccination against cervical precancer? Lancet 2015; Epub Sep 16.



A 28-year follow-up of 73,789 Chinese benzene-exposed workers and 34,504 unexposed workers demonstrated increased risks among the exposed workers for a broad range of myeloid and lymphoid neoplasms, lung cancer, and respiratory diseases, and suggested possible associations with other malignant and non-malignant disorders. (Linet MS, Yin SN, Gilbert ES, et al. A retrospective cohort study of cause-specific mortality and incidence of hematopoietic malignancies in Chinese benzene-exposed workers. Int J Cancer 2015;137:2184-2197)

Formaldehyde Exposure and Immune/Inflammation Markers

Formaldehyde has been classified as a human myeloid leukemogen. However, the mechanistic basis for this association is still debated. Measurements of serum levels of 38 immune/inflammation markers in a cross-sectional study of 43 formaldehyde-exposed and 51 unexposed factory workers in Guangdong, China, demonstrated significantly lower circulating levels of two markers among exposed factory workers compared with unexposed controls, which suggests immunosuppression among formaldehyde-exposed workers. (Seow WJ, Zhang L, Vermeulen R, et al. Circulating immune/inflammation markers in Chinese workers occupationally exposed to formaldehyde.Carcinogenesis 2015;36:852-857)

Malignant Transformation in Inherited Bone Marrow Failure Syndromes

COMMENTARY: Alter BP, Rosenberg PS. Comment on: "The impact of category, cytopathology and cytogenetics on development and progression of clonal and malignant myeloid transformation in inherited bone marrow failure syndromes". Haematologica 2015;100(9):e378.


Non-Steroidal Anti-Inflammatory Drugs

The Liver Cancer Pooling Project, based on ten U.S.-based prospective cohort studies, showed an inverse association between aspirin use and liver cancer, which was stronger for users who reported daily use, longer duration use, and lower dosage. Aspirin use was also associated with a reduced risk of intrahepatic cholangiocarcinoma among men, but not women. The data suggest the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for hepatocellular carcinoma and possibly intrahepatic cholangiocarcinoma. (Petrick JL, Sahasrabuddhe VV, Chan AT, et al. NSAID use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project. Cancer Prev Res (Phila) 2015;Epub Sep 21)


Fertility Drugs

A cohort study of approximately 10,000 women evaluated for infertility showed a significant association of clomiphene citrate treatment with risk of melanoma and a nonsignificant association with thyroid cancer risk. Gonadotropins were not related to risk of any of the assessed cancers. (Brinton LA, Moghissi KS, Scoccia B, et al. Effects of fertility drugs on cancers other than breast and gynecologic malignancies. Fertil Steril 2015;104:980-988)


Effect Measures

COMMENTARY: Panagiotou OA, Trikalinos TA. Commentary: On effect measures, heterogeneity, and the laws of nature. Epidemiology 2015;26:710-713. 

Test for Genetic Associations Integrating Environmental Risk Factors

Investigators developed a test for genetic association, encompassing a broad range of risk models, including linear, logistic, and probit, for specifying joint effects of genetic and environmental exposures. Test statistics were obtained by maximizing over a class of score tests, each of which involves modified standard tests of genetic association through a weight function. This weight function reflects the potential heterogeneity of the genetic effects by levels of environmental exposures under a particular model. (Han SS, Rosenberg PS, Ghosh A, et al. An exposure-weighted score test for genetic associations integrating environmental risk factors. Biometrics 2015;71:596-605)


Epidemiologic Risk Factors and Germline Variants

REVIEW: Stolzenberg-Solomon RZ, Amundadottir LT. Epidemiology and inherited predisposition for sporadic pancreatic adenocarcinoma. Hematol Oncol Clin North Am 2015;29:619-640.


Adiposity is associated with pancreatic cancer; however, the underlying mechanism(s) is uncertain. Leptin is an adipokine involved in metabolic regulation, and obese individuals have higher concentrations. In a pooled, nested case-control study of participants in three cohorts, prediagnostic serum leptin was not associated with pancreatic cancer overall, but there was a significant interaction by follow-up time, such that elevated risk was apparent only during follow-up of more than 10 years after blood draw. (Stolzenberg-Solomon RZ, Newton CC, Silverman DT, et al. Circulating leptin and risk of pancreatic cancer: A pooled analysis from 3 cohorts. Am J Epidemiol 2015;182:187-197)


Organophosphates and Hormonally-Related Cancers

Personal use of organophosphate insecticides (OP) by female spouses of pesticide applicators in the Agricultural Health Study was associated with an elevated risk of breast cancer. Malathion, the most commonly reported OP, was associated with increased risk of thyroid cancer and decreased risk of non-Hodgkin lymphoma. Diazinon use was associated with ovarian cancer. These results suggest potential for hormonally-mediated effects. (Lerro CC, Koutros S, Andreotti G, et al. Organophosphate insecticide use and cancer incidence among spouses of pesticide applicators in the Agricultural Health Study. Occup Environ Med 2015;72:736-744)

Relative Telomere Length

Researchers analyzed associations between occupational pesticide use reported at three time points and relative telomere length (RTL) in the Agricultural Health Study (AHS), a prospective cohort study of pesticide applicators in Iowa and North Carolina. Cumulative and more recent use of certain pesticides was linked to alterations in RTL, which may be a potential intermediate in cancer. The strongest association was for 2, 4-D and shorter telomere length, which was borderline significant after accounting for multiple comparisons. (Andreotti G, Hoppin JA, Hou L, et al. Pesticide use and relative leukocyte telomere length in the Agricultural Health Study. PLoS One 2015;10(7):e0133382)

Physical Activity

Harmonize International Accelerometry Data

REVIEW: Wijndaele K, Westgate K, Stephens SK, et al. Utilization and harmonization of adult accelerometry data: Review and expert consensus. Med Sci Sports Exerc 2015;47:2129-2139.


Influence of Screening on Estimates of Epidemiologic Associations

COMMENTARY: García-Closas M, Berrington de González A. Screening and the elusive etiology of prostate cancer. Am J Epidemiol 2015;182:390-393.


Nuclear Weapons Testing

COMMENTARY: Simon SL, Bouville A. Health effects of nuclear weapons testing. Lancet 2015;386:407-409.


Cooperation of Oncogene and Susceptibility Variants

Findings from a recent genome-wide association study of Ewing sarcoma, followed by targeted germline deep sequencing, gene expression studies, and other functional assays, established cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis. (Grünewald TG, Bernard V, Gilardi-Hebenstreit P, et al. Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite. Nat Genet 2015;47:1073-1078)


Rising Rates among Hispanics

Examination of racial/ethnic-specific incidence rates for testicular germ cell tumors between 1998 and 2011 from 39 U.S. cancer registries shows that the highest rates are among non-Hispanic whites, followed by Hispanics, American Indians/Alaska Natives, Asians/Pacific Islanders, and non-Hispanic blacks. The greatest increase in incidence was experienced by Hispanics. (Ghazarian AA, Trabert B, Graubard BI, et al. Incidence of testicular germ cell tumors among US men by census region. Cancer 2015; Epub Aug 17)


Circulating Growth Factors and Organ Transplantation

Transplant recipients have elevated cancer risk, perhaps partly due to direct carcinogenic effects of immunosuppressive medications. Experimental evidence indicates that calcineurin inhibitors given to transplant recipients increase cellular expression of transforming growth factor β1 (TGF-β1) and vascular endothelial growth factor (VEGF), which could promote cancer. A case-control study of nonmelanoma skin cancer and cancers of the lung, kidney, and colorectum, nested in a cohort of liver recipients, was conducted to evaluate these pathways. TGF-β1 and VEGF levels were increased in association with lung cancer among transplant recipients, which may be explained by increased platelet counts and platelet degranulation in lung cancer cases. (Engels EA, Jennings L, Kemp TJ, et al. Circulating TGF-β1 and VEGF and risk of cancer among liver transplant recipients. Cancer Med 2015;4:1252-1257)

Sirolimus Treatment after Kidney Transplant

Sirolimus, an immunosuppressant option for kidney transplant recipients, may reduce cancer risk by interrupting the mammalian target of rapamycin pathway. A meta-analysis of twenty clinical trials and two observational studies showed that sirolimus use was associated with lower overall cancer incidence, driven by a reduction in incidence of nonmelanoma skin cancer. Sirolimus use was also associated with lower kidney cancer incidence and higher prostate cancer incidence. (Yanik EL, Siddiqui K, Engels EA. Sirolimus effects on cancer incidence after kidney transplantation: A meta-analysis. Cancer Med 2015;4:1448-1459)

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