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Scientific Highlights July-August 2014

Recently Published DCEG Papers

Posted on August 18, 2014

Cancer Topics

All Causes Mortality


Adults with extreme obesity have increased risks of dying at a younger age from cancer and many other causes including heart disease, stroke, diabetes, and kidney and liver diseases, according to a pooled analysis of data from 20 large studies. Risks rose continuously with increasing body mass index (BMI) within the class III obesity group (BMI of 40-59 kg/m2), with years of life lost ranging from 6.5 years for participants with a BMI of 40-44.9 to 13.7 years for a BMI of 55-59.9. (Kitahara CM, Flint AJ, Berrington de Gonzalez A, et al. Association between class III obesity (BMI of 40-59 kg/m2) and mortality: A pooled analysis of 20 prospective studies. PLOS Medicine 2014;11:e1001673)

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Breast Cancer

Detecting Genetic Variants with Heterogeneous Effects

The investigators propose a robust statistical procedure to identify genetic risk factors that have either a uniform effect for all disease subtypes or heterogeneous effects across different subtypes, in situations where the subtypes are not predefined but can be characterized roughly by a set of clinical and/or pathologic markers. They demonstrate the advantage of the new procedure through numeric simulation studies and an application to a breast cancer study. (Yu K, Zhang H, Wheeler W, et al. A robust association test for detecting genetic variants with heterogeneous effects. Biostatistics 2014; July 23 [E-pub ahead of print])

Fertility Treatment

Norwegian women exposed to assisted reproductive technology, which involves hormonal exposures, had an elevated risk of breast cancer (hazard ratio [HR] 1.20, 95% confidence interval [CI] 1.01-1.42), with HRs of 1.30 (CI 1.07-1.57) for women treated with in vitro fertilization and 1.35 (CI 1.07-1.71) for women with follow-up >10 years, compared with controls. Continued monitoring of women treated with assisted reproductive technology is warranted as this population advances into more typical cancer age ranges. (Reigstad MM, Larsen IK, Myklebust TA, et al. Risk of breast cancer following fertility treatment-A registry based cohort study of parous women in Norway. Int J Cancer 2014; July 9 [E-pub ahead of print])

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Cervical Cancer

Acquired Immunity Against Reinfection

An investigation of the association between enrollment human papillomavirus (HPV) serostatus and risk of type-specific HPV reinfection and incident cervical intraepithelial neoplasia 2+ over a two-year follow-up period in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS) found that seroprevalence conferred protection against subsequent HPV infection for HPV 16 and indicated possible protection for HPV 18 and 31, suggesting that this effect is common to several HPV genotypes. (Wilson L, Pawlita M, Castle PE, et al. Seroprevalence of 8 oncogenic human papillomavirus genotypes and acquired immunity against reinfection. J Infect Dis 2014;210:448–455)

Human Papillomavirus Testing

Using data from over one million women who underwent routine cervical cancer screening at Kaiser Permanente Northern California, the authors found that primary human papillomavirus (HPV) testing every three years might provide as much, if not more, reassurance against precancer and cancer, compared to primary Pap testing every three years and cotesting every five years. These findings suggest that primary HPV testing merits consideration as another alternative for cervical screening. (Gage JC, Schiffman M, Katki HA, et al. Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test. J Natl Cancer Inst 2014; July 18 [E-pub ahead of print])

Novel Urine-based HPV Detection Assay

In a pilot study among 72 women referred to colposcopy following abnormal cervical cancer screening, the authors found that the prototype Trovagene human papillomavirus (HPV) test, a novel polymerase chain reaction assay that targets the E1 region of the HPV genome and detects and amplifies short fragments of cell-free HPV DNA, had high sensitivity for urine-based detection of cervical precancer and merits evaluation in larger studies. (Sahasrabuddhe VV, Gravitt PE, Dunn ST, et al. Evaluation of clinical performance of a novel urine-based HPV detection assay among women attending a colposcopy clinic. J Clin Virol 2014;60:414–417)

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Colorectal Cancer


In a nested case-control study of 255 colorectal cancers and 254 matched controls identified in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, baseline serum was used to identify metabolites that represent smoking habits and individual variation in tobacco metabolism. The biomarkers exhibited stronger associations with colorectal cancer than self-reported smoking histories, which are subject to misclassification, providing additional evidence for a role for tobacco in this malignancy. (Cross AJ, Boca S, Freedman ND, et al. Metabolites of tobacco smoking and colorectal cancer risk. Carcinogenesis 2014;35:1516–1522)

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Endometrial Cancer

Genetic Susceptibility

The authors examined 213 single nucleotide polymorphisms (SNPs) previously associated with 14 other cancers for their associations with endometrial cancer in 3,758 endometrial cancer cases and 5,966 controls of European ancestry from two consortia: Population Architecture Using Genomics and Epidemiology and the Epidemiology of Endometrial Cancer Consortium. SNP rs7679673, ~6.3kb upstream of TET2 and previously reported to be associated with prostate cancer risk, was associated with endometrial cancer risk in the direction opposite to that for prostate cancer. (Setiawan VW, Schumacher F, Prescott J, et al. Cross-cancer pleiotropic analysis of endometrial cancer: PAGE and E2C2 consortia. Carcinogenesis 2014;35:2068–2073)

Methylation Markers

DNA methylation profiling on population-based endometrial cancers and replication of the top candidates in two independent studies identified biomarkers (CpG sites in eight genes: ADCYAP1, ASCL2, HS3ST2, HTR1B, MME, NPY and SOX1) that may be used to evaluate women with abnormal vaginal bleeding to distinguish women with endometrial carcinoma from the majority of women without malignancy. (Wentzensen N, Bakkum-Gamez JN, Killian JK, et al. Discovery and validation of methylation markers for endometrial cancer. Int J Cancer 2014;135:1860–1868)

REVIEW: Brinton LA, Felix AS. Menopausal hormone therapy and risk of endometrial cancer. J Steroid Biochem Mol Biol 2014;142:83–89.

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Esophageal Cancer

Gastroesophageal Reflux

A study conducted in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) indicates that the association between heartburn/regurgitation symptoms and esophageal adenocarcinoma is strong, increases with increased duration and/or frequency, and is consistent across major risk factors. Weaker associations for esophagogastric junction adenocarcinoma suggest that this cancer site has a dissimilar pathogenesis or represents a mixed population of patients. (Cook MB, Corley DA, Murray LJ, et al. Gastroesophageal reflux in relation to adenocarcinomas of the esophagus: A pooled analysis from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). PLoS One 2014;9(7):e103508)

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Inherited Bone Marrow Failure Syndromes

COMMENTARY: Alter BP. Pearson syndrome in a Diamond-Blackfan anemia cohort. Blood 2014;124:312–313.

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Kidney Cancer

Vitamin D-Binding Protein

A nested case-control analysis within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study observed that men with higher serum concentrations of vitamin D-binding protein (DBP) experienced lower risk of renal cell carcinoma, whereas the molar ratio of circulating 25-hydroxyvitamin D [25(OH)D] to DBP, a proxy for free circulating 25(OH)D, showed a possible positive risk association. Combined, the two findings suggest that the DBP association may reflect a biological mechanism unrelated to vitamin D status. The relationship of circulating bound and free 25(OH)D and DBP with tissue-level availability of 25(OH)D also warrants examination, and may help elucidate some of the conflicting results observed in epidemiologic studies of vitamin D and cancer. (Mondul AM, Weinstein SJ, Moy KA, et al. Vitamin D-binding protein, circulating vitamin D and risk of renal cell carcinoma. Int J Cancer 2014;134:2699–2706)

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Liver Cancer

Anti-Diabetic Medications

Investigators conducted the first study among people with type II diabetes to evaluate the association of anti-diabetic medications and liver cancer using a comparator group of non-users of any anti-diabetic drugs. Anti-diabetic medications were not associated with liver cancer, though there was a suggestion of a small protective effect for metformin. Stratification by duration of diabetes did not alter the results. (Hagberg KW, McGlynn KA, Sahasrabuddhe VV, et al. Anti-diabetic medications and risk of primary liver cancer in persons with type II diabetes. Br J Cancer 2014; Aug 5 [E-pub ahead of print])

Statin Use

Observational studies in populations at high-risk of hepatocellular carcinoma (HCC), mostly in Asia, have suggested that statins, medications widely prescribed to reduce cholesterol levels, are associated with a reduced risk of HCC. A nested case-control study conducted among members of the Health Alliance Plan HMO of the Henry Ford Health System showed that the use of statins is also associated with decreased risk of HCC among populations in low-risk HCC areas. (McGlynn KA, Divine GW, Sahasrabuddhe VV, et al. Statin use and risk of hepatocellular carcinoma in a U.S. population. Cancer Epidemiol 2014; Aug 8 [E-pub ahead of print])

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Lung Cancer

Rare Variants of BRCA2 and CHEK2

The authors conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. They identified BRCA2 Thr9976, which is the strongest genetic association in lung cancer reported so far. They also identified CHEK2 p.Ile157Thr and an association between common variation at 3q28 (TP63, rs13314271) and lung adenocarcinoma that had been previously reported only in Asians. (Wang Y, McKay JD, Rafnar T, et al. Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nat Genet 2014;46:736–741)

Time to First Morning Cigarette

Investigators have found that lung cancer risk increases with shorter time to first cigarette after waking (TTFC), a single-item measure of nicotine dependency. TTFC improved lung cancer risk stratification beyond standard smoking measures, such as intensity, duration, and pack-years, which suggests that TTFC may be useful in lung cancer screening and smoking cessation programs. (Gu F, Wacholder S, Kovalchik S, et al. Time to smoke first morning cigarette and lung cancer in a case-control study. J Natl Cancer Inst 2014;106:dju118)

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Absolute Risks

EDITORIAL: Gail MH. Using absolute risks to assess the risks and benefits of treatment. Thorax 2014;69:604–605

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Multiple Cancers

Risk Loci in TERT-CLPTM1L Region

Genome-wide association studies have mapped risk alleles for at least ten distinct cancers to the TERT-CLPTM1L region of chromosome 5p15.33. An agnostic subset-based meta-analysis (ASSET) across six distinct cancers in 34,248 cases and 45,036 controls identified as many as six independent risk loci: five in the TERT gene and one in the neighboring CLPTM1L gene. Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. 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. (Wang Z, Zhu B, Zhang M, et al. 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  2104; July 15 [E-pub ahead of print])

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Ovarian Cancer

Inflammation Markers

Pre-diagnostic serum levels of 46 inflammation-related biomarkers were measured in 149 incident ovarian cancer cases and 149 matched controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. CRP, IL-1α, IL-8, and TNF-α were associated with increased risk of subsequently developing ovarian cancer, with associations for CRP and IL-8 remaining or strengthened in analyses restricted to serous ovarian cancer. (Trabert B, Pinto L, Hartge P, et al. Pre-diagnostic serum levels of inflammation markers and risk of ovarian cancer in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial. Gynecol Oncol 2014; Aug 23 [E-pub ahead of print])

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Pancreatic Cancer

Diabetes and Survival

Diabetes is a risk factor for pancreatic cancer but its association with survival from pancreatic cancer is poorly understood. Prospectively collected data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial indicated that diabetes is associated with worse survival among patients with pancreatic cancer. (Toriola AT, Stolzenberg-Solomon R, Dalidowitz L, et al. Diabetes and pancreatic cancer survival: A prospective cohort-based study. Br J Cancer 2014;111:181–185)

Genetic Susceptibility

A multistage genome-wide association study of 7,683 pancreatic cancer cases and 14,397 controls identified four new loci that are located near the genes LINC-PINT, BCAR/CTRB1/CTRB2, PDX1, and ZNRF3, as well as an independent signal in exon 2 of TERT at a previously established region, and a locus in PVT1 that approached genome-wide significance. (Wolpin BM, Rizzato C, Kraft P, et al. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nat Genet 2014;doi10.1038)

New Genetic Susceptibility Alleles

A multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent identified multiple new susceptibility alleles that are worthy of follow-up studies, including rs6971499 at 7q32.3 (LINC-PINT), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2), rs9581943 at 13q12.2 (PDX1), rs16986825 at 22q12.1 (ZNRF3), and an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098), as well as a locus at 8q24.21 (rs1561927) that approached genome-wide significance located 455 kb telomeric of PVT1. (Wolpin BM, Rizzato C, Kraft P, et al. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nat Genet 2014;46:994–1000)

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Prostate Cancer

Childhood Body Mass Index

To further research a previously found association between prostate cancer and childhood height, investigators evaluated childhood body mass index (BMI), independently and adjusted for height, in a cohort from the Copenhagen School Health Records Register, born 1930-1969 with height and weight measurements at 7-13 years. The study found that at most childhood ages, BMI does not confer an additional risk for prostate cancer beyond that of height. (Aarestrup J, Gamborg M, Cook MB, et al. Childhood body mass index and the risk of prostate cancer in adult men. Br J Cancer 2014;111:207–212)

Insulin-like Growth Factor Signaling Pathway and Survival

The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer initiation, but its role in progression remains unknown. Using data from the seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, investigators found that single nucleotide polymorphisms in the IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in prostate cancer survival. (Cao Y, Lindström S, Schumacher F, et al. Insulin-like growth factor pathway genetic polymorphisms, circulating IGF1 and IGFBP3, and prostate cancer survival. J Natl Cancer Inst 2014;106:dju085)

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Thyroid Cancer

COMMENTARY: Mabuchi K, Schneider AB. Thyroid gland: Do nuclear power plants increase the risk of thyroid cancer? Nat Rev Endocrinol 29014;10:385–387

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