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Scientific Highlights July-October 2014

Recently Published DCEG Papers

Posted on November 10, 2014

Cancer Topics

All-Cause Mortality

Obesity

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). Read more about obesity and mortality risk.

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Bladder Cancer

Genetic Markers for Aggressive Disease

Through fine-mapping of a genetic marker for bladder cancer within the 19q12 region located upstream of the CCNE1 gene, along with functional studies, the investigators identified a functional promoter variant, rs7257330, as the first genome-wide association study (GWAS) signal for aggressive bladder cancer. (Fu YP, Kohaar I, Moore LE, et al. The 19q12 bladder cancer GWAS signal: Association with cyclin E function and aggressive disease. Cancer Res 2014;74:5808-5818). Read more about the genetic marker identified for aggressive bladder cancer.

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Breast Cancer

Alcohol

The effects of alcohol consumption, an established risk factor for breast cancer, were found to vary by tumor characteristics with positive associations limited to ER+/PR+ tumors, and within this subgroup, risks were observed for ductal and mixed ductal/lobular cancers. Analyses incorporating multiple tumor characteristics indicated that PR status, and not necessarily ER status, may characterize alcohol-associated etiological heterogeneity for breast cancer subtypes. (Falk RT, Maas P, Schairer C, et al. Alcohol and risk of breast cancer in postmenopausal women: An analysis of etiological heterogeneity by multiple tumor characteristicsAm J Epidemiol 2014;180:705-717)

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; E-pub July 23)

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; E-pub July 9)

Terminal Duct Lobular Unit Involution

Using normal tissues donated by volunteers, the investigators show that age, menopausal status, and parity are critical determinants of breast terminal duct lobular unit (TDLU) involution, which has been linked to lower breast cancer risk. Morphometric analysis of TDLU involution warrants further evaluation to understand the pathogenesis of breast cancer and assessing its role as a progression marker for women with benign biopsies or as an intermediate endpoint in prevention studies. (Figueroa JD, Pfeiffer RM, Patel DA, et al. Terminal duct lobular unit involution of the normal breast: Implications for breast cancer etiology. J Natl Cancer Inst 2014;106: E-pub October 1)

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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; E-pub July 18). Read more about HPV testing and future risk of precancer and cancer.

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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Chordoma

T Gene Sequence Variants and Germline Duplications

After previously identifying germline T duplication as a major susceptibility mechanism in several chordoma families, the authors measured T copy number variants and sequenced all T exons in familial cases, unaffected family members, sporadic cases, and unrelated controls, and identified a second common variant, rs1056048, that was strongly associated with chordoma in families and another common variant, rs3816300, that was associated with sporadic cases, particularly those with early age at onset. (Kelley MJ, Shi J, Ballew B, et al. Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma. Hum Genet 2014;133:1289-1297)

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Colorectal Cancer

Tobacco

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)

Intrauterine Devices

In a pooled analysis of data on approximately 9,000 cases and 15,000 controls in the Epidemiology of Endometrial Cancer Consortium, the investigators found that ever use of intrauterine devices was inversely related to risk, older age at first use, older age at last use, longer duration of use, and recent use. Future studies are needed to assess the respective roles of detection biases and biologic effects related to foreign body responses in the endometrium, heavier bleeding (and increased clearance of carcinogenic cells) and localized hormonal changes. (Felix AS, Gaudet MM, Vecchia CL, et al. Intrauterine devices and endometrial cancer risk: A pooled analysis of the Epidemiology of Endometrial Cancer Consortium. Int J Cancer 2014; E-pub September 20)

Methylation

The investigators performed DNA methylation profiling on population-based endometrial cancers to identify early detection biomarkers and replicated top candidates in two independent studies. They identified eight genes (ADCYAP1, ASCL2, HS3ST2, HTR1B, MME, NPY and SOX1) associated with odds ratios ranging from 3.44 for ASCL2 to 18.61 for HTR1B. An area under the curve of 0.93 was achieved for discriminating carcinoma from benign endometrium. Methylation markers 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)

Menopausal Hormone Therapy

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)

Genome-wide Association Studies

A joint (pooled) analysis of three genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) in individuals of Chinese ancestry  identified new susceptibility loci at rs7447927 at 5q31.2 and rs1642764 at 17p13.1, as well as a locus in the HLA class II region at 6p21.32 among the Taihang Mountain region at high risk of ESCC. (Wu C, Wang Z, Song X, et al. Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations. Nat Genet 2014;46:1001-1006)

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Inherited Bone Marrow Failure Syndromes

Telomeric Shelterin Complex and Dyskeratosis Congenita

This is the first report of Hoyeraal-Hreidarsson syndrome, a clinically severe variant of the inherited bone marrow failure and cancer predisposition syndrome dyskeratosis congenita, caused by germline mutations in TPP1, illustrating the importance of this shelterin component in human telomere biology. (Kocak H, Ballew BJ, Bisht K, et al. Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TE1 patch of the telomere protein TPP1. Genes Dev 2014;28:2090-2102)

Pearson Syndrome

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; E-pub August 5)

Micronutrients

In a prospective study of male smokers, higher baseline serum concentrations of β-carotene and retinol were associated with incident liver cancer and chronic liver disease. However, long-term supplemental α-tocopherol or β-carotene had no effect on liver cancer or chronic liver disease mortality over 24 years of follow-up. (Lai GY, Weinstein SJ, Albanes D, et al. Association of serum α-tocopherol, β-carotene, and retinol with liver cancer incidence and chronic liver disease mortality. Br J Cancer 2014; E-pub October 14); (Lai GY, Weinstein SJ, Taylor PR, et al. Effects of α-tocopherol and β-carotene supplementation on liver cancer incidence and chronic liver disease mortality in the ATBC study. Br J Cancer 2014; E-pub October 14)

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; E-pub August 8)

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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). Read more about time to first cigarette and lung cancer risk.

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Lymphoma

Etiologic Heterogeneity

In a large international collaborative analysis of risk factors for non-Hodgkin lymphoma (NHL), based on over 17,000 cases and 23,000 controls, investigators were able to quantify risk associated with medical history, lifestyle factors, family history of blood or lymph-borne cancers, and occupation for 11 different NHL subtypes, including less common subtypes. They identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. (Morton LM, Slager SL, Cerhan JR, et al. Etiologic heterogeneity among non-Hodgkin lymphoma subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014;2014:130-144). Read more about etiologic heterogeneity among NHL subtypes.

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Methods

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 2014; E-pub July 15)

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Myeloma

Obesity

In a pooled analysis of multiple myeloma (MM) mortality using 1.5 million participants (including 1,388 MM deaths) from 20 prospective cohorts in the National Cancer Institute Cohort Consortium, associations with elevated MM mortality were observed for higher early-adult body mass index (BMI) and for higher cohort-entry BMI and waist circumference. (Teras LR, Kitahara CM, Birmann BM, et al. Body size and multiple myeloma mortality: A pooled analysis of 20 prospective studies. Br J Haematol 2014;166:667-676)

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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; E-pub August 23)

Risk-Reducing Salpingo-Oophorectomy

Data from the surgical treatment arm of a nonrandomized prospective clinical trial of women at high risk of ovarian cancer found that 2.6% of the women undergoing risk-reducing salpingo-oophorectomy had clinically occult ovarian/tubal neoplasms, including 4.6% of BRCA1 mutation carriers, 3.5% of BRCA2 mutation carriers, and 0.5% of noncarriers. These data can inform management decisions among women at high risk of ovarian/tubal cancer. (Sherman ME, Piedmonte M, Mai PL, et al. Pathologic findings at risk-reducing salpingo-oophorectomy: Primary results from Gynecologic Oncology Group Trial GOG-0199. J Clin Oncol 2014;32:3275-3283). Read more about outcomes of risk-reducing surgery to prevent ovarian cancer.

Talc Use

COMMENTARY: Wentzensen N, Wacholder S. Talc use and ovarian cancer: Epidemiology between a rock and a hard place. J Natl Cancer Inst 2014;106: E-pub September 10

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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)

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)

Genetic Susceptibility

A meta-analysis of 10 million single nucleotide polymorphisms (SNPs) in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry identified 23 new susceptibility loci; 15 variants were identified among men of European ancestry, 7 among multiple ancestry groups and one in association with early-onset prostate cancer. (Al Olama AA, Kote-Jarai Z, Berndt SI, et al. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet 2014;46:1103-1109). Read more about genetic risk variants and prostate cancer.

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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Second Cancers

Cancer Risk among Retinoblastoma Survivors

A long-term follow-up study of approximately 900 hereditary retinoblastoma survivors demonstrated, consistent with other reports, elevated risk for subsequent bone tumors, soft tissue sarcomas, and melanomas. For the first time, elevations in risks for subsequent bone tumors and leiomyoarcomas were shown to be higher among survivors who had been treated with alkylating agents (predominantly triethylenemelamine) plus radiotherapy versus those who received radiotherapy without chemotherapy, whereas use of alkylating agents plus radiotherapy was not associated with elevated risk for melanoma. (Wong JR, Morton LM, Tucker M, et al. Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy. J Clin Oncol 2014; E-pub Sept 2)

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Thyroid Cancer

Nuclear Power

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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Tobacco

Immune and Inflammation Markers

In a study of levels of 78 inflammation, immune, and metabolic markers measured using multiplex immune assays in 1,819 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) participants, smoking was associated with a broad range of alterations in systemic immune and inflammation marker levels among older, long-term smokers. Smoking cessation may result in marker levels reverting to those of never-smokers over time. (Shiels MS, Katki HA, Freedman ND, et al. Cigarette smoking and variations in systemic immune and inflammation markers. J Natl Cancer Inst 2014; E-pub October 1)

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