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Discovering the causes of cancer and the means of prevention

Scientific Highlights March - June 2019

, by DCEG Staff

All Cancers

Leisure-Time Physical Activity

Data from the NIH-ARRP Diet and Health Study were used to evaluation the health effect of leisure-time physical activity (LTPA) participation and changes in LTPA between adolescence and middle age. Maintaining higher LTPA levels and increasing LTPA in later adulthood were associated with comparable low risk of mortality, suggesting that midlife is not too late to start physical activity. Inactive adults may be encouraged to be more active, whereas young adults who are already active may strive to maintain their activity level as they get older. (Saint-Maurice PF, Coughlan D, Kelly SP, et al. Association of leisure-time physical activity across the adult life course with all-cause and cause-specific mortality. JAMA Netw Open 2019 Mar 1). For more information, see Never Too Late to Start: Benefits of Exercise Continue Throughout Adulthood in Research News & Highlights.

Weight Training

Ample data support that leisure time aerobic moderate to vigorous physical activity (MVPA) is associated with lower risk of at least seven types of cancer. However, the link between muscle-strengthening activities and cancer etiology is not well-understood. Data from the NIH-AARP Diet and Health Study showed a significantly lower risk of colon cancer among individuals who weight lifted, for both low and high weight lifting. There was also a trend towards a lower risk of kidney cancer than participants who did not weight lift. (Mazzilli KM, Matthews CE, Salerno EA, Moore SC. Weight training and risk of 10 common types of cancer. Med Sci Sports Exerc 2019; Epub Mar 25)


Coffee and Tea Drinking

The association of coffee and tea drinking with risk of urinary tract cancer was evaluated using data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. A total of 835 incident cases of bladder cancer and 366 cases of renal cell carcinoma were ascertained. For bladder cancer, there was no association for coffee consumption and a borderline statistically significant inverse association for tea consumption. For renal cell carcinoma, there was no association for coffee or tea consumption. (Hashemian M, Sinha R, Murphy G, et al. Coffee and tea drinking and risk of cancer of the urinary tract in male smokers. Ann Epidemiol 2019 June; Epub 2019 Apr 3)


Blood DNA Methylation

A meta-analysis of four large prospective studies was conducted to investigate the role of blood DNA methylation on breast cancer risk. In contrast to previous smaller studies, the methylation measured at individual CpGs was not associated with breast cancer risk. In addition, higher average methylation level was not associated with risk of breast cancer. There was no evidence of modification of this association by age at diagnosis, estrogen-receptor status, time since blood collection, or CpG location (Bodelon C, Ambatipudi S, Dugué PA, et al. Blood DNA methylation and breast cancer risk: A meta-analysis of four prospective cohort studies. Breast Cancer Res 2019 May 17)

Inflammatory Breast Cancer

In a case-control study of inflammatory breast cancer (IBC) in Northern Africa, the reliability of IBC diagnosis was evaluated by photographic review by outside expert clinicians and by degree of adherence to the two most recent definitions of IBC: the international expert panel consensus statement and American Joint Committee on Cancer (AJCC) 8th edition. There were many differences between IBC and non-IBC cases: 54.5% versus 68.8% were estrogen receptor-positive, 39.9% versus 14.8% human epidermal growth factor receptor 2-positive, 91% versus 4% exhibited erythema, 63% versus 97% had a mass, and 57% versus 10% had mammographic evidence of skin thickening. Seventy-six percent of IBC cases adhered to the expert panel consensus statement and 36% to the AJCC definition; 86% were confirmed as IBC by either photographic review or adherence to the consensus statement. (Schairer C, Hablas A, Eldein IAS, et al. Clinico-pathologic and mammographic characteristics of inflammatory and non-inflammatory breast cancer at six centers in North Africa. Breast Cancer Res Treat 2019 Jul; Epub Apr 22)

Mammographic Density and Polygenic Risk Score

Mammographic breast density, adjusted for age and body mass index, and a polygenic risk score (PRS), comprised of common genetic variation, are both strong risk factors for breast cancer and increase discrimination of risk models. Understanding their joint contribution will be important to more accurately predict risk. Data from 3628 breast cancer cases and 5126 controls of European ancestry from eight case-control studies showed that the combined associations of a PRS—including 77-single nucleotide polymorphisms—and adjusted density measures are generally well described by multiplicative models, and both provide independent information on breast cancer risk. (Vachon CM, Scott CG, Tamimi RM, et al. Joint association of mammographic density adjusted for age and body mass index and polygenic risk score with breast cancer risk. Breast Cancer Res 2019 May 22)

Microbiota and Mammographic Density

Investigators assessed if urinary estrogens or gut microbiota alterations were associated with mammographic density among 54 cancer-free postmenopausal women in the Breast and Colon Health Study. Mammographic density was not associated with the gut microbiota, but it was inversely associated with urinary estrogen levels. (Jones GS, Spencer Feigelson H, et al. Mammographic breast density and its association with urinary estrogens and the fecal microbiota in postmenopausal women. PLoS One 2019;14(5):e0216114)

Mosaic truncating PPM1D mutations

Mosaic protein truncating variants (PTVs) in the phosphatase, Mg2+/Mn2+dependent 1D (PPM1D) gene in blood-derived DNA have been associated with increased risk of breast cancer. Investigators analyzed PPM1D PTVs in blood from 3817 breast cancer cases and 3058 controls by deep sequencing of a previously defined region in exon 6 of PPM1D. PPM1D PTVs were present at higher rates than previously reported and the frequency of PPM1D PTVs increased with age. There was limited evidence for an association between mosaic PPM1D PTVs and breast cancer risk, suggesting mosaic PPM1D PTVs in the blood likely do not influence risk of breast cancer.(Machiela MJ, Myers TA, Lyons CJ, et al. Detectible mosaic truncating PPM1D mutations, age and breast cancer risk. J Hum Genet 2019; Epub Mar 8)


Pregnancy-related Factors

Data from population registries from four Nordic countries were used to evaluate the risk of endometrial cancer, overall and by subtype, in relation to pregnancy-related factors, pregnancy complications, and birth characteristics. Based on 10,924 endometrial cancer cases and up to 10 matched controls per case, pre-existing and pregnancy-related hypertensive conditions were associated with increased endometrial cancer risk, with consistent associations across dualistic type. Increasing number of pregnancies and shorter time since last birth were associated with reduced endometrial cancer risk, with consistent associations across most subtypes. The findings support the role for both hormonal exposures and cell clearance as well as immunologic/inflammatory etiologies for endometrial cancer. (Trabert B, Troisi R, Grotmol T, et al. Associations of pregnancy-related factors and birth characteristics with risk of endometrial cancer: A Nordic population-based case-control study. Int J Cancer 2019; Epub Jun 7)


Etiological Studies in High-Risk Area

REVIEW – Wang SM, Abnet CC, Qiao YL. What have we learned from Linxian esophageal cancer etiological studies? Thorac Cancer 2019; Epub Mar 29.


Anthropometric Risk Factors

The relationship between adiposity and biliary tract cancer, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC), was evaluated in data from 27 prospective cohorts with 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases. For each 5 kg/m2 increase in body mass index, risked increased for GBC, IHBDC, and EHBDC, but not AVC. Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. (Jackson SS, Van Dyke AL, Zhu B, et al. Anthropometric risk factors for cancers of the biliary tract in the Biliary Tract Cancers Pooling Project. Cancer Res 2019; Epub May 21)

Tobacco and Alcohol

Investigators pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk (1,391 gallbladder, 758 intrahepatic bile duct (IHBDC), 1,208 extrahepatic bile duct (EHBDC), and 623 ampulla of Vater (AVC) cancer cases). Ever, former, and current smoking were associated with increased EHBDC and AVC cancers risk, with dose-response effects for smoking pack-years, duration, and intensity. Current smoking and smoking intensity were also associated with in IHBDC. No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with IHBDC, with increased risk for individuals consuming ≥5 versus 0 drinks/day. (McGee EE, Jackson SS, Petrick JL, et al. Smoking, alcohol, and biliary tract cancer risk: A pooling project of 26 prospective studies. J Natl Cancer Inst 2019; Epub May 24)

Gastrointestinal Tract

Autoimmune Diseases

REVIEW: Song M, Latorre G, Ivanovic-Zuvic D, et al. Autoimmune diseases and gastric cancer risk: A systematic review and meta-analysis. Cancer Res Treat 2019;51:841-850.


Coffee and Tea Drinking

The association of coffee and tea drinking with risk of urinary tract cancer was evaluated using data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. A total of 835 incident cases of bladder cancer and 366 cases of renal cell carcinoma were ascertained. For bladder cancer, there was no association for coffee consumption and a borderline statistically significant inverse association for tea consumption. For renal cell carcinoma, there was no association for coffee or tea consumption. (Hashemian M, Sinha R, Murphy G, et al. Coffee and tea drinking and risk of cancer of the urinary tract in male smokers. Ann Epidemiol 2019 June; Epub 2019 Apr 3)


Coffee Drinking

Coffee has been consistently associated with lower risk of liver cancer and chronic liver disease, suggesting that coffee affects mechanisms underlying disease development. Investigators measured serum metabolites using untargeted metabolomics in 1:1 matched nested case-control studies of liver cancer (n = 221 cases) and fatal liver disease (n = 242 cases) in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Overall, 21 metabolites were associated with coffee drinking and each subsequent endpoint; nine metabolites and trigonelline, a known coffee biomarker, were identified. Tyrosine and two bile acids, glycochenodeoxycholic acid and glycocholic acid, were inversely associated with coffee but positively associated with both outcomes. The remaining six metabolites and trigonelline were positively associated with coffee drinking but inversely associated with both outcomes (Loftfield E, Rothwell JA, Sinha R, et al. Prospective investigation of serum metabolites, coffee drinking, liver cancer incidence, and liver disease mortality. J Natl Cancer Inst 2019; Epub Jun 5)

Hepatitis Viral Infection Attributable Risk

Data from the Surveillance, Epidemiology, and End Results-Medicare linkage (SEER-Medicare) during 2001 through 2013 showed that overall hepatocellular carcinoma (HCC) rates among Americans of Medicare age increased by 3.4 percent per year, with the percentage of HCC cases attributable to hepatitis C virus (HCV) infection increasing from 26 percent to 32 percent. Rates of HCV‐attributable HCC increased strongly overall (5.6 percent per year) and for the majority of demographic subgroups, contributing substantially to the increase in total HCC rates over time. Although rates of hepatitis B virus-attributable HCC increased significantly over time (3.2 percent per year), absolute rates remained low. Rates of HCC unrelated to viral hepatitis also increased over time (2.4 percent per year), indicating that HCC driven by causes other than viral hepatitis also has contributed substantially to increasing overall trends. (Shiels MS, Engels EA, Yanik EL, et al. Incidence of hepatocellular carcinoma among older Americans attributable to hepatitis C and hepatitis B: 2001 through 2013. Cancer 2019; Epub Apr 12)


A study within the U.K. Clinical Practice Research Datalink, with controls matched to cases of non-alcoholic fatty liver disease (NAFLD) (n = 10,082 cases/40,344 controls) and liver cancer (n = 767 cases/3068 controls), showed that oophorectomy may increase the risk of NAFLD, but not liver cancer. Oophorectomy was associated with a 29% elevated NAFLD risk, which was more pronounced among women without diabetes and among women who had oophorectomy prior to age 50. Compared to women without oophorectomy or menopausal hormone therapy (MHT) use, oophorectomy and MHT were each associated with over 50% elevated risk of NAFLD. (Florio AA, Graubard BI, Yang B, et al. Oophorectomy and risk of non-alcoholic fatty liver disease and primary liver cancer in the Clinical Practice Research Datalink. Eur J Epidemiol 2019; Epub Jun 4)


Vitamin E

Epidemiologic data are inconsistent regarding the vitamin E-lung cancer association, so investigators examined serologic changes in vitamin E status in relation to subsequent risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Lung cancer risk was lower among men with higher baseline serum alpha-tocopherol and higher serum alpha-tocopherol at three years. Risk was also reduced among un-supplemented men with a lower serum alpha-tocopherol at baseline who had greater increases in concentrations at three years. Higher vitamin E status, as measured by serum alpha-tocopherol concentration, as well as repletion of a low vitamin E state, was related to decreased lung cancer risk during a 28-year period. (Huang J, Weinstein SJ, Yu K, et al. A prospective study of serum vitamin e and 28-year risk of lung cancer. J Natl Cancer Inst 2019; Epub May 11)


Genetic Signatures in Endemic Areas

The authors present a genome-wide analyses of genetic structure, gene flow, and natural selection in Ghana and Northern Uganda, both populations residing in the sub-Saharan endemic Burkitt Lymphoma (eBL) belt, a region with intense transmission of falciparum malaria and high eBL incidence. The genetic composition of these populations was characterized in the context of 22 additional African populations and present evidence for gene flow events that occurred in the last 3000 years, possibly related to regional migrations in Western Africa and major migrations involving Nilotic, Cushitic, and Bantu groups. A strong signal of malaria-driven selection in the ATP2B4 gene coding for a calcium transporter expressed in erythrocytes was identified among Northern Ugandans. Characterization of biological relationships between the ATP2B4 gene and malaria may inform the investigation of complex genomic disease associations in eBL belt populations. (Gouveia MH, Bergen AW, Borda V, et al. Genetic signatures of gene flow and malaria-driven natural selection in sub-Saharan populations of the "endemic Burkitt Lymphoma belt". PLoS Genet 2019;15(3):e1008027).

Insecticide Use

Previous studies have suggested associations of non-Hodgkin lymphoma (NHL) with some organophosphate and carbamate insecticides; however, many studies have been limited in their ability to evaluate associations with lymphoma subtypes. An analysis in the North American Pooled Project, which includes data from case-control studies in the United States and Canada (1690 cases/5131 controls), showed an association between ever use of malathion with increased risk of NHL overall compared with never users. There was a significant exposure-response for increasing years of use of malathion and risk of NHL. In addition, malathion use was statistically significantly associated with follicular and diffuse large B-cell lymphoma, while there were no apparent associations with small lymphocytic lymphoma or other subtypes. (Koutros S, Harris SA, Spinelli JJ, et al. Non-Hodgkin lymphoma risk and organophosphate and carbamate insecticide use in the north American pooled project. Environ Int 2019; Epub Mar 28)


Human Papillomavirus Genotype Assay

Investigators have developed a new human papillomavirus (HPV) genotyping assay for detection of 51 HPV genotypes by next-generation sequencing (NGS). The TypeSeq assay consists of three PCR steps that equalize viral load and each type's amplicon copies prior to genotyping by NGS, thereby maximizing multiple-type sensitivity with minimal sequencing reads. The analytical sensitivity of the TypeSeq assay is 10 copies per reaction for 49 of the 51 types, including 13 high-risk (HR) types. The assay was used to test 863 clinical cervical specimens previously evaluated with the Roche Linear Array HPV genotyping test (LA). The unique approach to HPV amplification achieved a multiple-type sensitivity comparable to that of LA, with 83.9% and 84.2% of specimens positive for multiple HPV types by TypeSeq or LA, respectively. A total of 48.2% of specimens showed perfect agreement for all 37 types common to both assays. The simplicity of the open-source TypeSeq assay allows for high-throughput yet scalable processing, with a single technician able to process up to 768 specimens within three days. By leveraging NGS sample multiplexing capabilities, the per-sample labor requirements are greatly reduced compared to those of traditional genotyping methods. TypeSeq is an affordable and scalable assay, highly suitable for a broad range of applications. (Wagner S, Roberson D, Boland J, et al. Development of the typeseq assay for detection of 51 human papillomavirus genotypes by next-generation sequencing. J Clin Microbiol 2019; doi: 10.1128/JCM.01794-18). For more information, see Validation of New High Throughput, Low Cost HPV Test for Cervical Cancer Prevention in DCEG News Updates.

Recall of Physical Activity

This paper describes four computerized use-of-time instruments (ACT24, PAR, MARCA and cpar24) designed to capture data on time spent sleeping, sitting, and engaging in physical activity, and presents population time-use data from a collective sample of 8,286 adults from population studies conducted in Australia, New Zealand, Germany, and the United States. Estimates of physical activity level (average daily rate of energy expenditure in metabolic equivalent hours per day (METs) ranged from 1.53 to 1.78 in the four studies, strikingly similar to population estimates derived from doubly labelled water. There was broad agreement in the amount of time spent in sleep (7.2-8.6 h), moderate-vigorous physical activity (MVPA) (1.6-3.1 h), personal care (1.6-2.4 h), and transportation (1.1-1.8 h). There were consistent sex differences, with women spending 28-81% more time on chores, 8-40% more time in light physical activity (LPA), and 3-39% less time in MVPA compared to men. Although there were many similarities between instruments, differences in operationalizing definitions of sedentary behavior and LPA resulted in substantive differences in the amounts of time reported in sedentary and physically active behaviors. Future research should focus on deriving a core set of basic activities and associated energy expenditure estimates, an agreed classificatory hierarchy for the major behavioral and activity domains, and systems to capture relevant social and environmental contexts. (Matthews CE, Berrigan D, Fischer B, et al. Use of previous-day recalls of physical activity and sedentary behavior in epidemiologic studies: Results from four instruments. BMC Public Health 2019;19(Suppl 2):478)

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