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Discovering the causes of cancer and the means of prevention

Scientific Highlights July - October 2018

, by DCEG Staff

All-Cause Mortality

Fish and Omega-3 Fatty Acids

Data from the NIH-AARP Diet and Health Study showed that higher fish and long-chain omega-3 polyunsaturated fatty acids (LCn-3 PUFAs) were significantly associated with lower total mortality. Comparing the highest with lowest quintiles of fish intake, men had 9% lower total mortality, 10% lower cardiovascular disease (CVD) mortality, 6% lower cancer mortality, 20% lower respiratory disease mortality, and 37% lower chronic liver disease mortality, while women had 8% lower total mortality, 10% lower CVD mortality, and 38% lower Alzheimer's disease mortality. Fried fish consumption was not related to mortality among men whereas among women it was positively associated with mortality from all causes, CVD, and respiratory disease. (Zhang Y, Zhuang P, He W, et al. Association of fish and long-chain omega-3 fatty acids intakes with total and cause-specific mortality: Prospective analysis of 421,309 individuals. J Intern Med 2018; Epub Jul 17).

Infant and Youth Mortality Trends

Investigators examined death certificate data from the U.S. National Center of Health Statistics, Statistics Canada, and the U.K. Office of National Statistics, focusing on deaths that occurred between 1999 and 2015 among children and young-adults aged 25 or younger in the United States, Canada, and England/Wales. In 2015, declines in mortality rates resulted in approximately 12,000 fewer deaths compared to what was expected based on 1999-2002 rates. Increases in infant mortality rates due to accidental suffocation and strangulation in bed resulted in 560 additional deaths; increases in suicide and drug poisoning rates in youth, resulted in an additional 1,700 and 2,100 deaths, respectively. The authors noted striking racial disparities in the U.S. Even though the infant mortality rate declined by 20% between 1999 and 2015, infant mortality rates in 2015 remained exceptionally high for blacks (11 deaths/1,000 infants) and American Indians and Alaska Natives (9.7 deaths/1,000 infants). (Khan SQ, Berrington de Gonzalez A, Best AF, et al. Infant and youth mortality trends by race/ethnicity and cause of death in the United States. JAMA Pediatr 2018; Epub Oct 1).  For more information, read Pediatric Mortality Decreases in U.S., but Rates Still Higher than Canada and U.K. in Research News & Highlights.

Mosaic Chromosome Y Loss

The authors characterized mosaic loss of the Y chromosome (mLOY) in relation to age, smoking, and other exposures in a large cohort of 223,338 men from the U.K. Biobank. A total of 3,789 (1.7%) men showed evidence for mLOY, with less occurring among men of African ancestry than men of European ancestry. mLOY increases occurred exponentially with age and were strongly associated with current smoking and mortality from diabetes and cardiovascular disease. mLOY was also associated with all-cause mortality among men with a high proportion of cells affected (hazard ration (HR)=1.35). Further functional studies are warranted to understand how and in what way mLOY could influence adult male health. (Loftfield E, Zhou W, Graubard BI, et al. Predictors of mosaic chromosome Y loss and associations with mortality in the U.K. Biobank. Sci Rep 2018; 8:12316).

Neighborhood Socioeconomic Deprivation

Low neighborhood socioeconomic status has been linked to adverse health outcomes. However, it is unclear whether changes to the neighborhood may influence health. Data from the NIH-AARP Diet and Health Study showed that improvement in neighborhood socioeconomic status was associated with lower mortality rate, while deterioration was associated with higher mortality rate. More specifically, a 30-percentile point reduction in neighborhood deprivation among more deprived neighborhoods was associated with 11% and 19% reduction in total mortality rate among men and women respectively. On the other hand, a 30-point increase in neighborhood deprivation in less deprived neighborhoods was associated with a 11% increase in mortality rate in men. (Xiao Q, Berrigan D, Powell-Wiley TM, et al. Changes in neighborhood socioeconomic deprivation and mortality in U.S. adults. Am J Epidemiol 2018; Epub Aug 22).

Premature Mortality Projections

Using age-period-cohort models and death certificate data from the National Center for Health Statistics, investigators projected future premature death rates and the number of excess deaths for the U.S. population aged 25 to 64 by race or ethnicity and sex. Projected increases in premature deaths among non-Hispanic white women and American Indians or Alaska Natives are estimated to result in an additional 240,000 deaths between 2017 and 2030, compared to the number expected if death rates remained stable over that period—an increase of 10 percent. The majority of those deaths—over 100,000—are expected to be accidental, a category that includes drug overdoses. In contrast, continued declines are projected for non-Hispanic white men, and black, Hispanic, and Asian or Pacific Islander men and women, resulting in nearly 1,000,000 fewer premature deaths during the same period—a reduction of 14 percent, driven mostly by the estimated 300,000 fewer deaths from cancer. (Best AF, Haozous EA, de Gonzalez AB, et al. Premature mortality projections in the USA through 2030: A modelling study. Lancet Public Health 2018;3:e374-e384). See Premature Mortality Projections in Research News & Highlights for more information.

Reductions in Cigarettes per Day

Many smokers do not quit but instead reduce the number of cigarettes that they smoke per day (CPD) over their lifetime. The associations of such changes in CPD with health risks are unclear. Data from the NIH-AARP Diet and Health Study showed that, relative to never smokers, smokers who maintained a consistent CPD had 2.93 times higher all-cause mortality risk, with still higher risks observed in participants who increased their CPD (HR: 3.37). Risks were lower among participants who decreased their CPD (HR: 2.38) or quit smoking (HR: 1.32). Similar patterns were observed for smoking-related causes of death, with particularly strong associations for lung cancer and respiratory disease. (Inoue-Choi M, Hartge P, Park Y, et al. Reductions in cigarettes per day and mortality among older adults in the United States. Am J Epidemiol 2018; Epub Oct 9).

Smoking Daily vs Non-Daily 

Using data from the U.S. National Health Interview Surveys (NHIS), investigators reported that that lifelong non-daily cigarette smokers who had never smoked daily were 1.7 times more likely to die from any cause during the follow-up period than never smokers. Additionally, relative to never smokers, lifelong non-daily smokers lived five years less and daily smokers lived ten years less. (Inoue-Choi M, McNeel TS, Hartge P, et al. Non-Daily Cigarette Smokers: Mortality Risks in the U.S. Am J Prev Med 2018 Oct 24; Epub ahead of print).

See No Safe Level of Smoking: Mortality Risks Described for Occasional Smokers and Smokers Who Cut Back in Research News & Highlights for more information.

Vitamin C

To evaluate the relationship between vitamin C intake and mortality, investigators randomly selected 948 subjects (473 males and 475 females) aged 53-84 years from a Chinese cohort and measured meta-phosphoric acid-preserved vitamin C concentrations in plasma samples collected in 1999-2000. There were a total of 551 deaths through 2016, including 141 from cancer, 170 from stroke and 174 from heart diseases. In this long-term prospective Chinese cohort study, higher plasma vitamin C concentration was associated with lower total mortality, heart disease mortality and cancer mortality. (Wang SM, Fan JH, Taylor PR, et al. Association of plasma vitamin C concentration to total and cause-specific mortality: A 16-year prospective study in China. J Epidemiol Community Health 2018; Epub Aug 12).

Vitamin D and Survival

Investigators examined the accepted biomarker of vitamin D status, serum 25-hydroxyvitamin D [25(OH)D], and cancer survival in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Serum 25(OH)D was significantly lower among cases who subsequently died from their malignancy compared with those who did not. Higher 25(OH)D was associated with lower overall cancer mortality (hazard ratio (HR) = 0.76 for highest vs. lowest quintile). Higher 25(OH)D was related to lower mortality from prostate (HR = 0.74) and kidney (HR = 0.59) cancers, as well as melanoma (HR = 0.39), but increased mortality from lung cancer (HR = 1.28). Improved survival was also suggested for head and neck, gastric, pancreatic, and liver cancers, though not significantly. (Weinstein SJ, Mondul AM, Yu K, et al. Circulating 25-hydroxyvitamin D up to 3 decades prior to diagnosis in relation to overall and organ-specific cancer survival. Eur J Epidemiol 2018; Epub Aug 2).



Populations exposed to arsenic in drinking water have an increased bladder cancer risk and evidence suggests that several factors may modify arsenic metabolism, influencing disease risk. Data from a population-based case-control study of 1,213 bladder cancer cases and 1,418 controls provided some limited evidence of modifying roles of age, sex, smoking, body mass index (BMI), folate, and alcohol on arsenic-related bladder cancer risk. Among former smokers and current smokers, those with the highest cumulative arsenic intake had elevated risks of bladder cancer (odds ratio (OR)=1.4 and OR=1.6, respectively; while the OR among never smokers was 1.1, p-interaction=0.49). Among those classified as normal or overweight, based on usual adult BMI, the highest level of cumulative arsenic intake was associated with elevated risks of bladder cancer (OR=1.3 and OR=1.6, respectively), while risk was not elevated among those who were obese (OR=0.9, p-interaction=0.14). (Koutros S, Baris D, Waddell R, et al. Potential effect modifiers of the arsenic-bladder cancer risk relationship. Int J Cancer 2018; Epub Jul 7).


Serum Cytokines

Because of growing evidence that history of allergic or autoimmune disease is associated with reduced risk of glioma, investigators assessed associations of immune conditions with levels of 14 cytokines in serial prediagnostic serum samples in a nested case-control study of glioma/brain among military personnel. A total of 457 case-control sets were ascertained from the Department of Defense (DoD) Automated Central Tumor Registry, Defense Medical Surveillance System (DMSS) database, and DoD Serum Repository. The overall association between glioma and prior immune-related conditions was null, however higher levels of IL-15 and IL-16 were independently significantly associated with lower glioma risks, particularly among individuals with prior immune conditions. (Brenner AV, Inskip PD, Rusiecki J, et al. Serially measured pre-diagnostic levels of serum cytokines and risk of brain cancer in active component military personnel. Br J Cancer 2018 Oct).


Black-White Incidence Trends

Recent reports of converging black and white breast cancer incidence rates have gained much attention, however the incidence rates have been based on the sum of non-Hispanics and Hispanics, which may mask important ethnicity-specific trends. Race- and ethnicity-specific breast cancer rates from the NCI Surveillance, Epidemiology, and End Results (SEER) 13 Registries Database from 1992-2014 were used in age-period-cohort models to project rates for 2015-2030. Results confirmed merging of age-standardized incidence rates for blacks and whites circa 2012, but not for non-Hispanic black (NHB) and non-Hispanic white (NHW) women. Incidence rates were highest for NHW women, followed by NHB women, and then Hispanic white women. The sample size for Hispanic blacks was too small for analysis. (Davis Lynn BC, Rosenberg PS, Anderson WF, et al. Black-white breast cancer incidence trends: Effects of ethnicity. J Natl Cancer Inst 2018; Epub Jul 5).

Estrogen Metabolism

The Women’s Health Initiative (WHI) Clinical Trial found an unexpected reduced breast cancer risk in women using conjugated equine estrogens (CEE) alone. Investigators hypothesized CEE alone induces estrogen hydroxylation along the 2-pathway rather than the competing 16-pathway, a pattern linked to reduced postmenopausal breast cancer risk. Data from a nested case-control study of estrogen metabolites in relation to ovarian and endometrial cancer risk in the WHI Observational Study, suggest that estrogen metabolism may differ for estrogen alone compared to estrogen plus progestin users, with estrogen alone inducing estrogen metabolism away from the 16‐pathway and toward the 2‐pathway, a pattern shown to reduce breast cancer risk in postmenopausal women. Whether this pattern of estrogen metabolism persists after cessation of hormone therapy is not known. (Falk RT, Manson JE, Barnabei VM, et al. Estrogen metabolism in menopausal hormone users in the Women's Health Initiative Observational Study: Does it differ between estrogen plus progestin and estrogen alone? Int J Cancer 2018; Epub Sep 5).

Pregnancy Complications

A large registry‐linked pooled study based on data from four Nordic countries showed that women with a history of hypertension, both prior to and newly occurring in pregnancy, and preeclampsia were associated with an ∼10% reduction in subsequent maternal breast cancer risk. The associations did not appear to be explained by factors that predispose to the development of either of these conditions and breast cancer, and generally did not vary by several other pregnancy factors associated with breast cancer risk. The mechanisms mediating these modest risk reductions are unknown and warrant further laboratory, clinical and epidemiological investigation. (Troisi R, Gulbech Ording A, Grotmol T, et al. Pregnancy complications and subsequent breast cancer risk in the mother: A Nordic population-based case-control study. Int J Cancer 2018; Epub August 10).

Tumor Molecular Subtypes

Etiologic differences in risk factors for various subtypes of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) were examined in two recent studies:

Risks among women primarily of European descent were investigated using pooled data from nine cohort studies. Ever parous compared to never was associated with lower risk of luminal A-like (hazard ratio (HR)=0.78)) and luminal B-like (HR=0.74), as well as a higher risk of triple negative disease (HR=1.23). Direct associations with luminal-like, but not HER2-enriched or triple negative, tumors were found for age at first birth, years between menarche and first birth, and age at menopause. Age-specific associations with baseline body mass index differed for risk of luminal A-like and triple-negative breast cancer. (Gaudet MM, Gierach GL, Carter BD, et al. Pooled analysis of nine cohorts reveals breast cancer risk factors by tumor molecular subtype. Cancer Res 2018; Epub Sep 5).

A study of women with invasive breast cancer in Sarawak, Malaysia, demonstrated heterogeneity in the relationships between parity/breastfeeding, age at first full-term pregnancy (FFP), family history, body mass index (BMI), and tumor subtype. Among luminal A-like patients only, older age at menarche and being underweight or overweight were associated with adverse prognosis, while parity/breastfeeding and older age at FFP were associated with good prognosis. (Abubakar M, Sung H, Bcr D, et al. Breast cancer risk factors, survival and recurrence, and tumor molecular subtype: Analysis of 3012 women from an indigenous Asian population. Breast Cancer Res 2018).


Circulating Markers of Inflammation

A nested case-control study of 296 esophageal adenocarcinoma cases and 296 controls from seven prospective cohort studies was conducted to evaluate 69 circulating inflammation markers in relation to cancer risk, as well as the direct and indirect role of obesity and smoking. Soluble tumor necrosis factor receptor 2 (sTNFR2) was significantly associated with esophageal adenocarcinoma. Additional markers close to the adjusted significance threshold included C reactive protein, serum amyloid A, lipocalin-2, resistin, interleukin (IL) 3, IL17A, soluble IL-6 receptor and soluble vascular endothelial growth factor receptor 3. Adjustment for body mass index, waist circumference or smoking status slightly attenuated biomarker-cancer associations. Mediation analysis indicated that sTNFR2 may account for 33% of the effect of waist circumference on esophageal adenocarcinoma risk. For smoking status, only plasminogen activator inhibitor 1 was a nominally statistically significant mediator of cancer risk. This prospective study provides evidence of a link between systemic inflammation and esophageal adenocarcinoma risk. In addition, this study provides the first evidence that indirect effects of excess adiposity and cigarette smoking, via systemic inflammation, increase the risk of esophageal adenocarcinoma. (Cook MB, Barnett MJ, Bock CH, et al. Prediagnostic circulating markers of inflammation and risk of oesophageal adenocarcinoma: A study within the National Cancer Institute Cohort Consortium. Gut 2018; Epub Aug 18).

Ewing Sarcoma

Genetic Susceptibility

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. A genome-wide association study (GWAS) of 733 EWS cases and 1346 unaffected individuals of European ancestry replicated previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identified new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk single nucleotide polymorphisms constitute a significant fraction of risk. (Machiela MJ, Grünewald TGP, Surdez D, et al. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility. Nat Commun 2018;9:3184). See Ewing Sarcoma in Research News & Highlights for more information.



A nested case-control study of renal cell carcinoma (RCC) within the Kaiser Permanente Northern California (KPNC) health care network showed that obesity (BMI ≥ 30 kg/m2) was associated with clear cell RCC (odds ratio (OR)=1.5)) and chromophobe RCC (OR=2.5), but not with papillary RCC (OR=1.0). In a meta-analysis including three additional studies, a similar pattern of summary relative risks (SRR) for obesity was observed across subtypes (clear cell: SRR=1.8; chromophobe: SRR=2.2; papillary, SRR=1.2). These findings support the hypothesis that histologic subtypes of RCC possess distinct etiologic pathways, with obesity important for the development of clear cell and, possibly, chromophobe RCC, but not papillary RCC. (Callahan CL, Hofmann JN, Corley DA, et al. Obesity and renal cell carcinoma risk by histologic subtype: A nested case-control study and meta-analysis. Cancer Epidemiol 2018; Epub July 18).

Vitamin D Binding Protein

Investigators conducted a nested case-control study in the American Cancer Society Cancer Prevention Study-II (CPS-II) Nutrition Cohort to prospectively examine circulating vitamin D binding protein (DBP) concentration and renal cell carcinoma risk. There was a statistically significant inverse trend across quartiles of DBP such that participants with higher DBP had a markedly decreased risk of renal cell carcinoma (vs. Q1: Q2 odds ratio (OR)=0.93; Q3 OR=0.42; Q4 OR=0.33, p for trend=0.03). The strong inverse association between circulating DBP and risk of renal cell carcinoma supports the findings from one previous report. (Mondul AM, Weinstein SJ, Parisi D, et al. Vitamin D binding protein and risk of renal cell carcinoma in the Cancer Prevention Study-II Cohort. Cancer Epidemiol Biomarkers Prev 2018; Epub Jul 20).


Risk from Low-Dose Radiation Exposure

Substantial evidence links exposure to moderate or high doses of ionizing radiation, particularly in childhood, with increased risk of leukemia. The role of low-dose (< 100 mSv) radiation is less certain, although this is the dose range most relevant to the general population. Data from nine historical cohorts from Canada, France, Japan, Sweden, the UK, and the USA were used to evaluate leukemia risk among 262,573 people who had been exposed to less than 100 mSv enrolled between 1915 and 2004. Mean follow-up was 19·63 years (SD 17·75) and mean cumulative ABM dose was 19·6 mSv (SD 22·7). The risks of acute myeloid leukemia and acute lymphoblastic leukemia were significantly increased after cumulative doses of ionizing radiation of less than 100 mSv, with an excess risk also apparent for cumulative radiation doses of less than 50 mSv for some endpoints. These findings support an increased risk of leukemia associated with low-dose exposure to radiation and imply that the current system of radiological protection is prudent and not overly protective. (Little MP, Wakeford R, Borrego D, et al. Leukaemia and myeloid malignancy among people exposed to low doses (<100 mSv) of ionising radiation during childhood: A pooled analysis of nine historical cohort studies. Lancet Haematol 2018;5:e346-e358). See Low-dose Radiation in Research News & Highlights for more information.


Autoimmune Conditions

Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, investigators evaluated associations between autoimmune conditions and hepatobiliary cancers by anatomic site in a large, U.S. population‐based case–control study of Medicare‐aged adults. In combined as well as in separate analyses for inpatient versus outpatient-only diagnoses, there was a 1.1‐ to 31.3‐fold increased risk of hepatobiliary cancer after diagnosis of a range of different autoimmune diseases. Several autoimmune conditions with gastrointestinal tract involvement (Crohn's diseases, primary biliary cholangitis, primary sclerosing cholangitis and ulcerative colitis) were associated with increased risk at multiple hepatobiliary cancer sites, with the strongest risk estimate (odds ratio (OR)=31.33) observed for primary biliary cholangitis and hepatocellular carcinoma. Associations for hepatobiliary‐related autoimmune conditions were especially strong, with ORs ranging from 4.53 to 7.18 in the combined inpatient and outpatient analysis. In addition, generalized systemic conditions, such as ankylosing spondylitis and systemic lupus erythematosus, were associated with increased risk at some hepatobiliary cancer sites. These data support a shared immuno-inflammatory etiology to these cancers. (McGee EE, Castro FA, Engels EA, et al. Associations between autoimmune conditions and hepatobiliary cancer risk among elderly U.S. adults. Int J Cancer 2018; Epub Aug 28).

Body Mass Index and Diabetes

The association between obesity and diabetes and intrahepatic cholangiocarcinoma (ICC) risk was evaluated in data from the Liver Cancer Pooling Project (LCPP), a consortium of 13 U.S.-based, prospective cohort studies, as well as through a systematic review/meta-analysis of the literature. In the LCPP, obesity and diabetes were associated with a 62% and an 81% increased ICC risk, respectively. In the meta-analysis, obesity and diabetes were associated with a 49% and 53% increased ICC risk, respectively. (Petrick JL, Thistle JE, Zeleniuch-Jacquotte A, et al. Body mass index, diabetes and intrahepatic cholangiocarcinoma risk: The Liver Cancer Pooling Project and meta-analysis. Am J Gastroenterol 2018; Epub Sep 5).

Tooth Loss

Tooth loss has been reported to be associated with the risk of liver cancer in studies in economically advantaged countries. Data from the Nutrition Intervention Trials, two randomized placebo-controlled trials of vitamin/mineral supplementation in Linxian, China, were used to evaluate whether this relationship is also evident in economically disadvantaged populations. Overall, persons in the highest quartile of age-specific tooth loss had an increased risk of liver cancer (hazard ratio (HR)=1.27)), which was not statistically significant. Results varied by sex and body mass index (BMI), however. Women in the highest quartile of age-specific tooth loss had a significantly increased risk (HR=1.64), while men did not (HR=1.08), and persons with a BMI > 23.0 kg/m2 (HR=1.71) had a significantly increased risk, while persons with a BMI <23.0 kg/m2 (HR=1.14) did not. (Thistle JE, Yang B, Petrick JL, et al. Association of tooth loss with liver cancer incidence and chronic liver disease mortality in a rural Chinese population. PLoS One 2018;13(9):e0203926).


Air Pollution

The association between exposure to outdoor particulate matter with aerodynamic diameter ≤10 μm (PM10) and lung cancer risk was analyzed quantitatively using The Environment And Genetics in Lung cancer Etiology (EAGLE) case-control study conducted in highly polluted areas in Italy. Lung cancer risk increased with increasing PM10 category (P-value for trend: 0.04). The association appeared stronger for squamous cell carcinoma. This study illustrates the need to strengthen policies to reduce airborne pollution. (Consonni D, Carugno M, De Matteis S, et al. Outdoor particulate matter (PM10) exposure and lung cancer risk in the EAGLE study. PLoS One. 13(9):e0203539)

Genetic Susceptibility Pathways

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. Investigators explored the pathogenic pathways, through which susceptibility single nucleotide polymorphisms within chromosome 15q25.1 affect lung cancer risk, using data from three cohorts with GWAS data from 42,901 individuals and lung expression quantitative trait loci (eQTL) data from 409 individuals. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. (Ji X, Bossé Y, Landi MT, et al. Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk. Nat Commun 2018;9:3221).


Genetic Susceptibility

A two-stage genome-wide association study of Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) identified two high-risk loci at 6p25.3 (rs116446171, near EXOC2 and IRF4; odds ratio (OR)=21.14)) and 14q32.13 (rs117410836, near TCL1; OR=4.90). In silico data suggest that rs116446171 may have functional importance, and in functional studies, investigators demonstrated increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. These loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy. (McMaster ML, Berndt SI, Zhang J, et al. Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia. Nat Commun 2018 Oct 10).


Oral Sample Collection Methods

A number of cohort studies have collected Scope® mouthwash samples by mail, which are being used for microbiota measurements. Investigators studied the stability of Scope mouthwash samples at ambient temperature and determined the comparability of Scope mouthwash with saliva collection using the OMNIgene•ORAL by comparing aliquots of oral samples collected with the OMNIgene•ORAL and Scope mouthwash that were frozen immediately with aliquots that remained at ambient temperature for four days and then frozen. The overall stability of the Scope mouthwash samples was relatively high for alpha and beta diversity. Similarly, the intraclass correlations for the relative abundance of the top 25 genera were generally high. Overall, the Scope mouthwash samples appear to be stable at ambient temperature, which suggests that oral rinse samples received by the mail can be used for microbial analyses. However, Scope mouthwash samples were distinct compared to OMNIgene•ORAL samples. Studies should try to compare oral microbial metrics within one sample collection type. (Vogtmann E, Chen J, Kibriya MG, et al. Comparison of oral collection methods for studies of microbiota. Cancer Epidemiol Biomarkers Prev 2018; Epub Sep 27).

Multiple Myeloma

Alcohol Consumption

The risk of multiple myeloma (MM) in relation to alcohol consumption was investigated among 499,292 participants enrolled in the prospective NIH-AARP Diet and Health Study. A total of 1,312 MM cases were identified during follow-up through 2011. Overall, increasing frequency of alcohol consumption was inversely associated with MM (p for trend=0.01), with a significant association among those who consumed two drinks per day); similar but not significant associations were observed for greater frequency of alcohol consumption. Among women, risk of MM was reduced among those who consumed less than one drink per day (HR=0.73), and associations with greater frequency of alcohol consumption were inverse although not statistically significant. The findings of this large prospective investigation suggest that moderate alcohol consumption may be associated with reduced risk of MM. (Santo L, Liao LM, Andreotti G, et al. Alcohol consumption and risk of multiple myeloma in the NIH-AARP Diet and Health Study. Int J Cancer 2018; Epub Jul 4).


Epstein-Barr Virus

Epstein-Barr virus (EBV) is an obligatory factor in the development of nasopharyngeal carcinoma (NPC), and anti-EBV IgA antibodies are elevated many years prior to the development of NPC. Nearly all adults are infected with EBV, but only a few develop cancer, suggesting that additional co-factors, including genetic susceptibility, must be required for the disease to manifest. Investigators compared anti-EBV IgA antibody seropositivity between family members in the Taiwan Family Study predicted to be carriers of NPC-linked genetic variants and those with a lower likelihood of carrying such variants. Obligate carriers of NPC susceptibility variants were nine-fold more likely to be anti-EBV IgA positive compared to family members predicted not to carry disease-causing variants. Genetic susceptibility associated with control over this common herpes virus is likely a co-factor in determining which EBV-infected adults develop NPC. (Coghill AE, Hsu WL, Yang Q, et al. Elevated antibodies against Epstein-Barr virus among individuals predicted to carry nasopharyngeal carcinoma susceptibility variants. J Gen Virol 2018; Epub July 5).

Occupational Exposure

Gene Expression Predictors

Previously, investigators used microarrays and mRNA-Sequencing (mRNA-Seq) to demonstrate that occupational exposure to a range of benzene levels perturbed gene expression in peripheral blood mononuclear cells. In the current study, the investigators used the nCounter platform and SuperLearner to validate the altered expression of multiple mRNAs by benzene and identified gene pairs predictive of exposure to benzene at levels below the U.S. occupational standard of 1ppm. The predictive gene pairs are PRG2/CLEC5A, NFKBI/CLEC5A, and ACSL1/CLEC5A. They play roles in innate immunity and inflammatory responses. (Schiffman C, McHale CM, Hubbard AE, et al. Identification of gene expression predictors of occupational benzene exposure. PLoS One 2018 Oct 9).


Childhood Body Size

Using data from the Copenhagen School Health Records Register, investigators evaluated if childhood body mass index, height, and growth patterns were associated with ovarian cancer overall and by histologic subtypes. Compared with non-overweight girls, at most ages, overweight girls had increased risks of ovarian cancer overall, mucinous, endometrioid and clear cell ovarian cancers, but not serous and other ovarian cancers. Childhood height had positive and significant associations with ovarian cancer overall and the endometrioid subtype but not with the other sub-types. Adjusting for birth weight minimally altered the associations with childhood body size. In growth analyses, overweight girls or those who were taller than average at ages 7 and 13 had increased risks of ovarian cancer overall compared with average-sized girls at both ages. (Aarestrup J, Trabert B, Ulrich LG, et al. Childhood overweight, tallness and growth increase risks of ovarian cancer. Cancer Epidemiol Biomarkers Prev 2018; Epub Sep 27).

Fatty Acid Metabolites

Evidence suggests that inflammation increases risk for ovarian cancer. Studies of inflammatory markers, lipid molecules such as arachidonic acid, linoleic acid, and alpha linoleic acid metabolites, and development of ovarian cancer are essential to understand the potential mechanisms. A nested case-control study within the PLCO Cancer Screening Trial found that five out of 31 fatty acid metabolites (8-HETE, 12,13-DHOME, 13-HODE, 9-HODE, and 9,12,13-THOME) were associated with increased ovarian cancer risk. 8-HETE is produced by the metabolism of arachidonic acid and four metabolites (12,13-DHOME, 13-HODE, 9-HODE), and 9,12,13-THOME, are derived from linoleic acid oxidation. Further supporting the individual metabolite associations, a meta-analysis found that linoleic acid pathways increased ovarian cancer risk. The identification of these risk-related fatty acid metabolites provides mechanistic insights into the etiology of ovarian cancer and indicates the direction for future research. (Hada M, Edin ML, Hartge P, et al. Pre-diagnostic serum levels of fatty acid metabolites and risk of ovarian cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial. Cancer Epidemiol Biomarkers Prev 2018; Epub Sep 27).

Physical Activity

Energy Expenditure

A study of 1,020 adults who completed previous-day recalls that provided a profile of time spent in sedentary and physical activity was used to evaluate physical activity energy expenditure for each type of day (exercise, prolonged TV, work). Exercise days had more physical activity energy expenditure, but because of reductions in other activities (i.e., household, work, and shopping activities), only about half of the energy expended during exercise was added to total daily physical activity energy expenditure. Prolonged TV viewing days had less physical activity energy expenditure and less moderate-vigorous activity. (Matthews CE, Keadle SK, Saint-Maurice PF, et al. Use of time and energy on exercise, prolonged tv viewing, and work days. Am J Prev Med 2018 Sep; Epub Jul 19).

Estrogen Metabolism

Lowering endogenous estrogen levels is one mechanism whereby physical activity may lower postmenopausal breast cancer risk. Several prospective studies have suggested that increased 2-hydroxylation of estrogens may also reduce postmenopausal breast cancer risk, but whether exercise alters estrogen metabolism through this mechanism is unclear. Investigators measured total circulating concentrations of parent estrogens (estrone, estradiol) and 13 estrogen metabolites, among 153 postmenopausal women randomized to 12-months of moderate-vigorous exercise and 153 controls. Although women randomized to exercise averaged 178 minutes/week of exercise over 12 months, with cardiorespiratory fitness 13% greater than controls at 12 months and total estradiol reduced by 10%, there were no significant effects of exercise on circulating concentrations of estrogen metabolites in the 2-, 4-, or 16-pathways, or on the 2-pathway/parent estrogens ratio. However, they observed a significant association between increased fitness and reduced concentration of 2-pathway metabolites. The protective effect of exercise on postmenopausal breast cancer is unlikely to be mediated by changes in estrogen metabolism. (Matthews CE, Sampson JN, Brenner DR, et al. Effects of exercise and cardiorespiratory fitness on estrogen metabolism in postmenopausal women. Cancer Epidemiol Biomarkers Prev 2018; Epub Aug 14).

White Blood Cell Counts

Data collected from the National Health and Nutrition Examination Survey (NHANES) were used to assess blood cell counts in relation to objectively measured physical activity and sedentary time. Higher levels of moderate-vigorous physical activity and lower sedentary time were associated with lower white blood cell counts. These results suggest that modifiable health behaviors, such as physical activity and sedentary time, may be associated with inflammatory status through white blood cell counts, which may be important for future disease risk. (Willis EA, Shearer JJ, Matthews CE, et al. Association of physical activity and sedentary time with blood cell counts: National Health and Nutrition Survey 2003-2006. PLoS One 2018 Sep 25).


Risk Factors by Race

Race-specific prostate cancer risk associations were examined among men in the NIH-AARP Diet and Health Study. Risks were found to be similar among black and white men across disease subtypes only for history of diabetes (hazard ratio (HR)=0.77 and HR=0.72, respectively). In contrast, there was a positive risk association with height for white men and inverse for black men. This difference remained for at least two years of follow-up among men diagnosed with non-advanced disease, but not for men with advanced disease or after adjustment for prostate cancer screening. The only other evidence of interaction with race was observed for dietary vitamin D intake and non-advanced disease, but only after adjustment for screening. Cumulative adjustment for each factor increased the HR for black race by 32.9% for overall cancer and 12.4% for advanced disease. These data suggest few of the dietary, nutrient, and health-related factors associated with prostate cancer risk among predominantly non-Hispanic white men were associated with risk among black men, and adjustment for these factors widen the black-white difference in risk. Larger studies of black men, particularly with prospective data, are needed to help identify risk factors relevant to this population. (Layne TM, Graubard BI, Ma X, et al. Prostate cancer risk factors in black and white men in the NIH-AARP Diet and Health Study. Prostate Cancer Prostatic Dis 2018; Epub Aug 14).



Data from the U.S. Radiologic Technologists Study was used to investigate whether exposure to low-dose (< 100 mGy) ionizing radiation increases risk for cataracts. During follow-up, over 12,000 eligible technologists reported a history of diagnosis of cataract and 5509 reported undergoing cataract surgery. Cataract risk was significantly associated with cumulative occupational radiation exposure, even when analysis was restricted to < 100 mGy exposure to the eye lens. (Little MP, Kitahara CM, Cahoon EK, et al. Occupational radiation exposure and risk of cataract incidence in a cohort of U.S. radiologic technologists. Eur J Epidemiol 2018; Epub Aug 27). See Low-dose Ionizing Radiation and Cataract Risk in Research News & Highlights for more information.

Risk from Low-Dose Radiation Exposure

Substantial evidence links exposure to moderate or high doses of ionizing radiation, particularly in childhood, with increased risk of leukemia. The role of low-dose (<100 mSv) radiation is less certain, although this is the dose range most relevant to the general population. Data from nine historical cohorts from Canada, France, Japan, Sweden, the UK, and the USA were used to evaluate leukemia risk among 262,573 people who had been exposed to less than 100 mSv enrolled between 1915 and 2004. Mean follow-up was 19·63 years (SD 17·75) and mean cumulative ABM dose was 19·6 mSv (SD 22·7). The risks of acute myeloid leukemia and acute lymphoblastic leukemia were significantly increased after cumulative doses of ionizing radiation of less than 100 mSv, with an excess risk also apparent for cumulative radiation doses of less than 50 mSv for some endpoints. These findings support an increased risk of leukemia associated with low-dose exposure to radiation and imply that the current system of radiological protection is prudent and not overly protective. (Little MP, Wakeford R, Borrego D, et al. Leukaemia and myeloid malignancy among people exposed to low doses (<100 mSv) of ionising radiation during childhood: A pooled analysis of nine historical cohort studies. Lancet Haematol 2018;5:e346-e358). See Low-dose Radiation in Research News & Highlights for more information.


Circulating Inflammation Markers

Chronic Helicobacter pylori (H. pylori) infection causes gastric mucosal inflammation, an important antecedent of gastric cancer. Investigators compared pre-treatment serum levels of immune- and inflammation-related markers between 99 individuals with intestinal metaplasia or dysplasia, and 75 control individuals with non-atrophic gastritis within an H. pylori eradication trial in Mexico. Five markers were associated with the presence of advanced premalignant gastric lesions: CCL3/MIP1a, CCL20/MIP3a, IL1β, IL4, and IL5. Two (IL4 and IL5) of the five markers had false discovery rate adjusted p-trend <0.2. The results suggest certain Th2 and other cytokines may have a role in promoting carcinogenesis in the setting of H. pylori infection. (Song M, Rabkin CS, Torres J, et al. Circulating inflammation-related markers and advanced gastric premalignant lesions. J Gastroenterol Hepatol 2018; Epub Oct 24).

Epstein-Barr Virus

Epstein-Barr virus (EBV)-positive gastric adenocarcinoma exhibits locally intense inflammation but systemic manifestations are uncertain. This study examined whether circulating mediators of inflammation and immune response differ by tumor EBV status among a Latvian series of 302 gastric cancer cases. After measuring plasma levels of 92 immune-related proteins in the 28 patients with EBV-positive tumors and 34 patients with EBV-negative tumors, eight markers were significantly higher with tumor EBV positivity: chemokine C-C motif ligand (CCL) 20 (Odds Ratio (OR)=3.6), chemokine C-X-C motif ligand 9 (OR=3.6), programmed death-ligand 1 (PD-L1; OR=3.4), interleukin (IL)-10 (OR=2.4), CCL19 (OR=2.3), CCL11 (OR=2.2), IL-17A (OR=2.0) and CCL8 (OR=1.9). Systemic responses to EBV-positive gastric cancer are characterized by alterations in chemokines and PD-L1. Profiling of these molecules may enable non-invasive diagnosis of EBV status when tumor tissue is unavailable. Our findings provide theoretical justification for clinical evaluations of immune checkpoint therapy for EBV-positive gastric cancer. (Camargo MC, Sivins A, Isajevs S, et al. Associations of Epstein-Barr virus-positive gastric adenocarcinoma with circulating mediators of inflammation and immune response. Cancers (Basel) 2018; Epub Aug 23).


REVIEW - Song M, Rabkin CS, Camargo MC. Gastric cancer: An evolving disease. Curr Treat Options Gastroenterol 2018; Epub Oct 25).

H. pylori Serum Biomarkers

In populations with a high prevalence of the known carcinogen H. pylori and a high incidence of gastric cancer, biomarkers are needed to identify individuals at highest risk of developing cancer for targeted eradication. In this study, investigators identified, replicated, and validated two novel H. pylori biomarkers for gastric cancer risk in East Asia, Omp and HP0305. These biomarkers will help develop a high-risk classification model for targeted H. pylori eradication schemes, beyond use of the established risk marker CagA. Moreover, they can be easily measured and result in better prediction than models that include larger panels of biomarkers that are more cost- and time-intensive to assay. (Epplein M, Butt J, Zhang Y, et al. Validation of a blood biomarker for identification of individuals at high risk for gastric cancer. Cancer Epidemiol Biomarkers Prev 2018; Epub Aug 29).

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