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Scientific Highlights November 2016 - February 2017

, by DCEG Staff

Cancer Topics

All-Cause Mortality


Data on 290,215 adults in the National Institutes of Health-AARP Diet and Health Study showed that individuals who smoke fewer than 1, or 1 to 10 cigarettes per day over their lifetime have higher mortality risks than never smokers and would benefit from cessation. These results provide further evidence that there is no safe level of exposure to tobacco smoke. (Inoue-Choi M, Liao LM, Reyes-Guzman C, et al. Association of long-term, low-intensity smoking with all-cause and cause-specific mortality in the National Institutes of Health-AARP Diet and Health Study. JAMA Intern Med 2017)

Trends in Premature Mortality

An analysis of mortality in the U.S. between 1999 and 2014 among people aged 25-64 years showed that important public health successes, including HIV treatment and smoking cessation, have contributed to declining premature mortality in Hispanic individuals, black individuals, and Asians and Pacific Islanders. However, this progress has largely been negated among young and middle-aged (25-49 years) white individuals, and American Indians and Alaska Natives, primarily due to drug poisonings, suicide, and chronic liver disease and cirrhosis. (Shiels MS, Chernyavskiy P, Anderson WF, et al. Trends in premature mortality in the USA by sex, race, and ethnicity from 1999 to 2014: An analysis of death certificate data. Lancet 2017; Epub Jan 26) Read more about these trends in the NCI press release.

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Smoking and Occupation

Using data from The Cancer Genome Atlas (TCGA) project on 406 patients with muscle-invasive bladder cancer, investigators found that current smoking and employment in a high-risk occupation—one with probable diesel exhaust exposure, or in production occupations—are related to increased risk of recurrence. (Wilcox AN, Silverman DT, Friesen MC, et al. Smoking status, usual adult occupation, and risk of recurrent urothelial bladder carcinoma: Data from The Cancer Genome Atlas (TCGA) Project. Cancer Causes Control 2016)

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Diabetes and Dyslipidemia

Using the SEER-Medicare database, investigators found that diabetes was associated with increased risk of distant inflammatory breast cancer (IBC), distant and regional locally advanced non-IBC, and distant and unstaged other breast cancers. Dyslipidemia was associated with reduced risk of IBC and other breast cancers except localized disease. Results were similar by tumor estrogen receptor status. Abnormal glucose levels and hypertension had little association with risk of any tumor type. (Schairer C, Gadalla SM, Pfeiffer RM, et al. Diabetes, abnormal glucose, dyslipidemia, hypertension and risk of inflammatory and other breast cancer. Cancer Epidemiol Biomarkers Prev 2017; Epub Jan 13)

Estrogen Metabolism

Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1298 cases of postmenopausal breast cancer and 1524 matched controls to evaluate how metabolism of the parent estrogens may influence risk. Total estrogen levels (summing all 15 estrogens/estrogen metabolites) were associated strongly and positively with breast cancer risk. A relative increase in levels of 2-hydroxylation pathway metabolites, or in the ratio of 2-hydroxylation:16-hydroxylation pathway metabolites, was associated inversely with breast cancer risk. These associations varied by total estrogen levels, with the largest risk reductions occurring in women in the highest tertile. The findings suggest opportunities for breast cancer prevention by modifying individual estrogen metabolism profiles through either lifestyle alterations or chemopreventive strategies. (Sampson JN, Falk RT, Schairer C, et al. Association of estrogen metabolism with breast cancer risk in different cohorts of postmenopausal women. Cancer Res 2016; Epub Dec 23)

Genetic Variation and Terminal Duct Lobular Unit Involution

Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Single nucleotide polymorphisms associated with breast cancer risk in earlier research were not found to strongly influence TDLU involution in a pooled analysis of 872 women from two studies. (Bodelon C, Oh H, Chatterjee N, et al. Association between breast cancer genetic susceptibility variants and terminal duct lobular unit involution of the breast. Int J Cancer 2017)

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Serum Choline Levels

The authors evaluated the relationship between baseline serum concentrations of TMAO, a choline-derived metabolite produced by gut microbiota, and its biomarker precursors (choline, carnitine and betaine) and incident colorectal cancer risk in a nested case-control study of male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Higher serum choline concentration (but not TMAO, carnitine, or betaine) was associated with increased risk of colorectal cancer. Men with higher serum choline at ATBC baseline had approximately 3-fold greater risk of developing colorectal cancer over the ensuing 14 ±10 years. The prognostic value of serum choline for prediction of incident colorectal cancer development was similarly robust for proximal, distal and rectal colon cancers (Guertin KA, Li XS, Graubard BI, et al. Serum trimethylamine N-oxide, carnitine, choline and betaine in relation to colorectal cancer risk in the Alpha Tocopherol and Beta Carotene Study. Cancer Epidemiol Biomarkers Prev 2017; Epub Jan 11)

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Inflammation Markers

In a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial, investigators measured serum levels of 64 inflammation-related biomarkers in 284 incident endometrial cancer cases and 284 matched controls. Several inflammation markers were prospectively associated with endometrial cancer, including adipokines, pro- and anti-inflammatory cytokines, angiogenic factors and acute phase proteins. Inverse associations with anti-inflammatory markers (IL13, IL21), other inflammation markers/mediators (CCL3, IL1B, IL23), and a robust positive association between VEGFA and endometrial cancer risk were independent of BMI and estradiol, suggesting that these factors may influence risk through other mechanisms. (Trabert B, Eldridge RC, Pfeiffer RM, et al. Prediagnostic circulating inflammation markers and endometrial cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial. Int J Cancer 2017)

Nonsteroidal Anti-inflammatory Drugs

Recent data suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with reductions in endometrial cancer risk, yet very few have examined whether their use is related to prognosis among endometrial cancer patients. Data on 4,374 participants of the NRG Oncology/Gynecology Oncology Group 210 Study with endometrial carcinoma showed that use of NSAIDs was associated with increased endometrial carcinoma-specific mortality, especially in patients with type I tumors. (Brasky TM, Felix AS, Cohn DE, et al. Nonsteroidal anti-inflammatory drugs and endometrial carcinoma mortality and recurrence. J Natl Cancer Inst 2017; Epub Dec 16, 2016)

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Metabolic Syndrome

Metabolic syndrome (MetS) is associated with cancer risk and increases the risk of Barrett esophagus, the precursor lesion of esophageal adenocarcinoma (EA), primarily in the absence of gastroesophageal reflux disease (GERD). Data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database showed that MetS was associated with an increased risk of EA in males without GERD and females regardless of GERD status. There was no association when compared with Barrett esophagus controls. MetS may impact EA risk by primarily increasing the risk of the precursor lesion, Barrett esophagus. (Drahos J, Ricker W, Pfeiffer RM, Cook M. Metabolic syndrome and risk of esophageal adenocarcinoma in elderly patients in the United States: An analysis of SEER-Medicare data. Cancer 2017; Epub Nov 8, 2016)

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Telomere Length

Summary data from 103 genome-wide association studies showed that increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers, notably glioma, serous low-malignant-potential ovarian cancer, lung adenocarcinoma, neuroblastoma, melanoma, and cancers of the bladder, testes, kidney, and endometrium. Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for reduced risk for coronary heart disease, abdominal aortic aneurysm, celiac disease, and interstitial lung disease. (Telomeres Mendelian Randomization Collaboration, Haycock PC, Burgess S, Nounu A, et al. Association between telomere length and risk of cancer and non-neoplastic diseases: A Mendelian randomization study. JAMA Oncol 2017; Epub Feb 23)


Clonal Evolution

Chronic lymphocytic leukemia (CLL) is a frequent B-cell malignancy, characterized by recurrent somatic chromosome alterations and a low level of point mutations. Investigators presented single-nucleotide polymorphism microarray analyses of a single CLL patient over 29 years of observation and treatment, and transcriptome and whole-genome sequencing at selected time points. They identified chromosome alterations 13q14-, 6q- and 12q+ in early cell clones, elimination of clonal populations following therapy, and subsequent appearance of a clone containing trisomy 12 and chromosome 10 copy-neutral loss of heterogeneity that marks a major population dominant at death. Serial single-cell RNA sequencing reveals an expression pattern with high FOS, JUN and KLF4 at disease acceleration, which resolves following therapy, but reoccurs following relapse and preceding death. Transcriptome evolution indicates complex changes in expression occur over time. In conclusion, in this case of CLL the disease evolved gradually during indolent phases, and underwent rapid changes following therapy. (Zhao Z, Goldin L, Liu S, et al. Evolution of multiple cell clones over a 29-year period of a CLL patient. Nat Commun 2016; Epub Dec 16). For more information, read “Patient at NIH Clinical Center Provides Invaluable Resource for the Study of Cancer’s Evolution” in Research News Highlights.

Dysregulation of Immunity Genes

A meta-analysis of six genome-wide association studies of chronic lymphocytic leukemia identified nine risk loci at 1p36.11 (rs34676223), 1q42.13 (rs41271473), 4q24 (rs71597109), 4q35.1 (rs57214277), 6p21.31 (rs3800461), 11q23.2 (rs61904987), 18q21.1 (rs1036935), 19p13.3 (rs7254272), and 22q13.33 (rs140522). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response. (Law PJ, Berndt SI, Speedy HE, et al. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia. Nat Commun 2017; Epub Feb 6)

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Germline Variants and EGFR Mutations

To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, investigators conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance: rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1-DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. (Seow WJ, Matsuo K, Hsiung CA, et al. Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations. Hum Mol Genet 2016; Epub Dec 26)

Nut Consumption

Higher frequency of nut consumption was inversely associated with overall lung cancer risk, regardless of smoking status, in the Environment And Genetics in Lung cancer Etiology (EAGLE) study, a population-based case-control study, and the NIH-AARP Diet and Health Study, a prospective cohort. Results from the prospective cohort showed similar associations across histological subtypes, and more pronounced benefits from nut consumption for those who smoked 1-20 cigarettes/day. (Lee JT, Lai GY, Liao LM, et al. Nut consumption and lung cancer risk: Results from two large observational studies. Cancer Epidemiol Biomarkers Prev 2017; Epub Jan 11)

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Dietary Patterns

Healthy dietary patterns that conform to national dietary guidelines are related to lower chronic disease incidence and longer life span. However, the precise mechanisms involved are unclear. This study examined the correlation of four diet quality indexes (the Healthy Eating Index 2010, the Alternate Mediterranean Diet Score, the WHO Healthy Diet Indicator, and the Baltic Sea Diet) with serum metabolites among participants in the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study cohort. Diet quality, measured by healthy diet indexes, was associated with serum metabolites, with the specific metabolite profile of each diet index related to the diet components used to score adherence. (Playdon MC, Moore SC, Derkach A, et al. Identifying biomarkers of dietary patterns by using metabolomics. Am J Clin Nutr 2016; Epub Dec 28)

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There is increasing interest in studying the relationship between the microbiome and human health and disease. To aid in the design of future prospective cohort studies of the fecal microbiome, investigators determined technical reproducibility, stability at ambient temperature, and accuracy of five fecal collection methods (no additive, 95% ethanol, RNAlater Stabilization Solution, fecal occult blood test cards, and fecal immunochemical test tubes). All the fecal sample collection methods appear relatively reproducible, stable, and accurate. (Vogtmann E, Chen J, Amir A, et al. Comparison of collection methods for fecal samples in microbiome studies. Am J Epidemiol 2017; Epub Dec 16, 2016)

Polygenic Risk Modeling

Recent heritability analyses have indicated that genome-wide association studies (GWAS) have the potential to improve risk prediction for complex diseases based on polygenic risk score (PRS), a simple modelling technique that can be implemented using summary-level data from discovery samples. The investigators propose modifications to improve the performance of PRS. They introduce threshold-dependent winner's-curse adjustments for marginal association coefficients that are used to weight the single-nucleotide polymorphisms (SNPs) in PRS. Further, as a way to incorporate external functional/annotation knowledge that could identify subsets of SNPs highly enriched for associations, they propose variable thresholds for SNPs selection. Applying the methods, a simple winner's curse correction uniformly led to enhancement of performance of the models, whereas incorporation of functional SNPs was beneficial only for selected diseases. Compared to the standard PRS algorithm, the proposed methods in combination led to notable gain in efficiency (25-50% increase in the prediction R2) for five of 14 diseases. The simulation studies illustrate why differential treatment of certain categories of functional SNPs, even when shown to be highly enriched for GWAS-heritability, does not lead to proportionate improvement in genetic risk-prediction because of non-uniform linkage disequilibrium structure. (Shi J, Park JH, Duan J, et al. Winner's curse correction and variable thresholding improve performance of polygenic risk modeling based on genome-wide association study summary-level data. PLoS Genet 2016)

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Biomarkers by Smoking Status

Circulating concentrations of C-peptide and total adiponectin, two biomarkers related to obesity and insulin secretion and sensitivity, were evaluated in relation to risk of pancreatic ductal adenocarcinoma (PDA) in a pooled nested case-control analysis of data from three prospective cohorts. Circulating C-peptide concentration was not associated with PDA among never or former smokers, but was inversely associated with PDA among current smokers. High molecular weight adiponectin was inversely associated among never smokers, not associated in former smokers, and positively associated in smokers. Total adiponectin was not associated with PDA in nonsmokers or current smokers. Smoking-induced pancreatic damage may explain the associations among smokers while mechanisms related to insulin resistance may explain associations in non-smokers. (Nogueira LM, Newton CC, Pollak MN, et al. Serum C-peptide, total and high molecular weight adiponectin, and pancreatic cancer: Do associations differ by smoking? Cancer Epidemiol Biomarkers Prev 2017; Epub Jan 17)

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Genetic Loci for Prostate-Specific Antigen Levels

Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa, such as genetics, can impact PSA. A genome-wide association study of PSA detected 40 genome-wide significant single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing overdiagnosis and overtreatment. (Hoffmann TJ, Passarelli MN, Graff RE, et al. Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer. Nat Commun 2017)

Genetic Susceptibility and Pesticides

Using data from the Agricultural Health Study, investigators evaluated whether single-nucleotide polymorphisms (SNPs) involved in hormone homeostasis alter the effect of pesticide exposure on prostate cancer risk. There was an interaction, which remained significant after correction for multiple testing, between the herbicide dicamba and rs8192166 in the testosterone metabolizing gene SRD5A1. There was an inverse association between exposure to dicamba and prostate cancer risk among those carrying the homozygous wild-type genotype at a locus in this important hormone metabolism and regulatory gene. In addition, interactions between two organophosphate insecticides and SNPs related to estradiol metabolism were observed to result in an increased risk of prostate cancer. (Christensen CH, Barry KH, Andreotti G, et al. Sex steroid hormone single-nucleotide polymorphisms, pesticide use, and the risk of prostate cancer: A nested case-control study within the Agricultural Health Study. Front Oncol 2016)

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Incidence Forecast

Testicular germ cell tumors (TGCTs) are the most commonly occurring malignancy among males between ages 15 and 44 years in the U.S. Although non-Hispanic whites (NHWs) have the highest incidence, rates among Hispanics have increased the most in recent years. Between 1999 and 2012, TGCT incidence rates, both overall and by histology, were highest among NHWs, followed by Hispanics, Asian/Pacific Islanders, and non-Hispanic blacks. Using age-period-cohort models, rates among Hispanics were forecast to increase annually by 3.96% between 2013 and 2026, resulting in the highest rate of increase of any racial/ethnic group. Rates among NHWs will slightly increase, whereas rates among other groups will slightly decrease. (Ghazarian AA, Kelly SP, Altekruse SF, et al. Future of testicular germ cell tumor incidence in the United States: Forecast through 2026. Cancer 2017; Epub Feb 27)

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Upper Gastrointestinal Tract

Body Weight Trajectories

Data from two prospective cohort studies (NIH-AARP Diet and Health Study and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO)) were used to evaluate the effects of adiposity over the life course in relation to esophageal adenocarcinoma (EA) and gastric cardia adenocarcinoma (GCA). Being overweight in early adulthood and weight gain later in life were each associated with increased risks of EA and GCA. This underscores the potential of weight control programs for reducing EA and GCA risk. (Petrick JL, Kelly SP, Liao LM, et al. Body weight trajectories and risk of oesophageal and gastric cardia adenocarcinomas: A pooled analysis of NIH-AARP and PLCO Studies. Br J Cancer 2017; Epub Feb 14)

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