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Scientific Highlights March - June 2017

, by DCEG Staff

Cancer Topics

All Causes


REVIEW: Brinton LA. Fertility status and cancer. Semin Reprod Med 2017.

All-Cause Mortality

Meat, Heme Iron, Nitrates, and Nitrites

Using baseline dietary data and 16 years of follow-up data from the NIH-AARP Diet and Health Study, the authors observed that increased risks of all-cause mortality and death due to nine different causes were associated with both processed and unprocessed red meat, accounted for, in part, by heme iron and nitrate/nitrite from processed meat. They also observed reduced risks associated with substituting white meat, particularly unprocessed white meat. (Etemadi A, Sinha R, Ward MH, et al. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: Population-based cohort study. BMJ 2017; Epub May 9)


Genetic Variants among Malaysian Women

Germline DNA from 467 breast cancer patients in Malaysia was used to characterize the spectrum of germline mutations in BRCA1, BRCA2, and PALB2 in population-based breast cancer cases in an Asian population. Investigators found a prevalence of germline mutations of 2.8, 3.23, and 0.86 percent for BRCA1, BRCA2, and PALB2, respectively. Compared to mutation non-carriers, BRCA1 mutation carriers were more likely to have an earlier age at onset, triple-negative subtype, and lower body mass index, whereas BRCA2 mutation carriers were more likely to have a positive family history. Nineteen variants of unknown significance were also identified, with some predicted to alter splicing or transcription factor binding sites. (Yang XR, Devi BCR, Sung H, et al. Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia. Breast Cancer Res Treat 2017; Epub Jun 29)

Risk Factors for In Situ and Invasive Breast Cancer

Data from the NIH-AARP Diet and Health Study showed younger age at menopause associated with increased risk of incident ductal carcinoma in situ (DCIS) but reduced risks of lobular carcinoma in situ (LCIS) and invasive ductal carcinomas. Prior breast biopsy was more strongly associated with risk of LCIS than DCIS. Increased risks associated with menopausal hormone therapy were stronger for LCIS than DCIS or invasive lobular carcinomas. Associations were similar for race, ages at menarche or first birth, family history, alcohol consumption and smoking, suggesting that most risk factor associations are similar for in situ and invasive cancers, and may influence early stages of tumorigenesis. (Mullooly M, Khodr ZG, Dallal CM, et al. Epidemiologic risk factors for in situ and invasive breast cancer among postmenopausal women in the NIH-AARP Diet and Health Study. Am J Epidemiol 2017; Epub Jun 16)


Investigators examined prediagnostic serum concentrations of diet-related metabolites in a nested case-control study of 621 postmenopausal invasive breast cancer cases and 621 matched controls in the multicenter PLCO cohort. Of 113 diet-related metabolites, 3 were associated with overall breast cancer risk: caprate, a saturated fatty acid; γ-carboxyethyl hydrochroman (γ-CEHC), a vitamin E (γ-tocopherol) derivative; and 4-androsten-3β,17β-diol-monosulfate (1), an androgen. Nineteen metabolites were significantly associated with estrogen receptor (ER)-positive (ER(+)) breast cancer (418 cases): 12 alcohol-associated metabolites, including 7 androgens and α-hydroxyisovalerate; 3 vitamin E (tocopherol) derivatives; and fried food-associated 2-hydroxyoctanoate. No metabolites were significantly associated with ER-negative breast cancer (144 cases). (Playdon MC, Ziegler RG, Sampson JN, et al. Nutritional metabolomics and breast cancer risk in a prospective study. Am J Clin Nutr 2017; Epub June 28)


Host DNA Methylation Markers

A tissue-based biomarker discovery effort identified host DNA methylation markers associated with cervical cancer and precancer. The findings were validated in liquid-based cytology samples using two different high-resolution DNA-methylation detection methods. Of 15 candidate gene markers, 10 had an area under the curve (AUC) of ≥ 0.75 for discrimination of high-grade squamous intraepithelial lesions or worse (HSIL+) from <HSIL cytology using at least one assay. Overall, SOX1, DCC, and EPB41L3 showed the best discrimination with AUC values of ≥0.80, irrespective of methylation detection assay. In addition to verifying candidate DNA methylation markers, several novel candidate markers for detection of cervical precancer in cytology specimens were identified that warrant further validation in prospective studies. (Clarke MA, Luhn P, Gage JC, et al. Discovery and validation of candidate host DNA methylation markers for detection of cervical precancer and cancer. Int J Cancer 2017; Epub May 26)


Racial and Ethnic Disparities

Data from the NCI Surveillance, Epidemiology, and End Results database demonstrated decreased racial and ethnic disparities in esophageal squamous cell carcinoma from 1992 to 2013 in the United States, while disparities increased in adenocarcinoma as measured on the absolute scale. (Xie SH, Rabbani S, Petrick J, et al. Racial and ethnic disparities in the incidence of esophageal cancer in the United States, 1992-2013. Am J Epidemiol 2017; Epub Jun 21)



Aflatoxin, which causes hepatocellular carcinoma, may also cause gallbladder cancer. The investigators analyzed a marker of aflatoxin exposure in 209 gallbladder cancer patients and 250 controls with gallstones but no sign of cancer. The marker, the aflatoxin B1 (AFB1)-lysine molecule, was detected in plasma samples from 32 percent of cases and 15 percent of controls. Among individuals with detectable AFB1-lysine, individuals with levels in the highest 25 percent of the population were over seven times more likely to have gallbladder cancer, compared to those in the lowest 25 percent. (Koshiol J, Gao YT, Dean M, et al. Association of aflatoxin and gallbladder cancer. Gastroenterology 2017; Epub Apr 17). For more information, read Exposure to Mold Toxin Linked to Gallbladder Cancer Risk in Research News & Highlights.

Body Size Indicators

Analyses based on individual-level data from nearly 2 million participants in 19 prospective cohort studies showed higher adult body mass index (BMI), young-adult BMI, adult weight gain, height, waist circumference, waist-height ratio, and hip circumference, but not waist-hip ratio, were associated with higher risks of gallbladder cancer. Results did not differ meaningfully by sex or other demographic/lifestyle factors. Measures of overall and central excess body weight are associated with higher gallbladder cancer risks. (Campbell PT, Newton CC, Kitahara CM, et al. Body size indicators and risk of gallbladder cancer: Pooled analysis of individual-level data from 19 prospective cohort studies. Cancer Epidemiol Biomarkers Prev 2017; Epub Mar 17)


Data from a case-control study of biliary tract cancer in Shanghai, China, were used to examine the effects of shifts to a more Western diet. The allium food group, consisting of onions, garlic, and shallots, and the food group containing seaweed and kelp, were inversely associated with gallbladder cancer. In contrast, both preserved vegetables and salted meats food groups showed positive associations with gallbladder cancer. Each of these four food groups showed similar trends for extrahepatic bile duct and ampulla of Vater cancers. The analysis suggests that intake of foods with greater anti-inflammatory properties may play a role in decreasing the risk of biliary tract cancers. (Nelson SM, Gao YT, Nogueira LM, et al. Diet and biliary tract cancer risk in Shanghai, China. PLoS One 2017)

Germline Susceptibility

A genome-wide scan of gallbladder cancer cases and hospital visitor controls, both of Indian descent, followed by imputation across the genome, identified genome-wide significant associations for several markers in the chromosomal region 7q21.12 harboring both the ABCB1 and ABCB4 genes, with the most notable SNPs after replication and meta-analysis being rs1558375, rs17209837, and rs4148808. These findings, along with in-silico and biological evidence indicating the potential functional significance of ABCB1 and ABCB4, underlines the likely importance of these hepatobiliary phospholipid transporter genes in the pathology of gallbladder cancer. (Mhatre S, Wang Z, Nagrani R, et al. Common genetic variation and risk of gallbladder cancer in India: A case-control genome-wide association study. Lancet Oncol 2017; Epub Mar 5). For more information, read From India, first evidence of common genetic variation associated with gallbladder cancer risk in Research News & Highlights.


Functional Characterization of a Multi-cancer Risk Locus on Chr5p15.33

Genome-wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Investigators have uncovered a likely causal variant in the TERT-CLPTM1L Region 2 susceptibility locus and identified ZNF148 as a potential effector of a gene-regulatory element that mediates increased TERT expression in an allele-specific manner. Fine-mapping results highlight the complexity of this region and indicate that Region 2 may, in some cancers, consist of more than one underlying functional signal. The results are remarkably consistent in eight cell lines across four different cancer types and explain, at least in part, the biological underpinnings of risk for rs36115365. The data suggest that the mechanism by which ZNF148 influences TERT is similar for cancer types in which the C-allele of rs36115365 contributes to increased risk, or alternatively to disease protection. (Fang J, Jia J, Makowski M, et al. Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. Nat Commun 2017; Epub May 2). Read more about the Multi-cancer risk locus on chr5p15.33 in Research News & Highlights.

Stem Cells

COMMENTARY: Chanock S. Stem cells: Subclone wars. Nature 2017.


Genome-wide Association Study

A meta-analysis of two new genome-wide scans of 5,198 renal cell carcinoma (RCC) cases and 7,331 controls and four existing scans, totaling 10,784 cases and 20,406 controls, confirmed the six known RCC risk loci and identified seven new loci at 1p32.3 (rs4381241), 3p22.1 (rs67311347), 3q26.2 (rs10936602), 8p21.3 (rs2241261), 10q24.33-q25.1 (rs11813268), 11q22.3 (rs74911261) and 14q24.2 (rs4903064). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility. (Scelo G, Purdue MP, Brown KM, et al. Genome-wide association study identifies multiple risk loci for renal cell carcinoma. Nat Commun 2017)


Adiposity Throughout Adult Life

Obesity relatively late in adulthood has been consistently associated with increased risk of primary liver cancer. However, little is known about the role of early adult adiposity and evolution of adiposity across adulthood in hepatocarcinogenesis. Investigators evaluated weight at ages 18, 35, 50, and at study baseline in relation to subsequent development of liver cancer.  Being obese (BMI ≥ 30) at ages 18, 35, 50 and at baseline (mean age 62.3 years, range 50.3-71.5 years) was associated with an 86 percent to 119 percent elevated risk of HCC. BMI trajectories that resulted in obesity were associated with ∼80 percent higher HCC incidence. BMI at age 18, per 5 kg/m(2), was associated with a 34 percent  higher risk of ICC, but the association attenuated for BMI at older ages. The findings suggest that maintaining a healthy BMI throughout the lifetime may reduce liver cancer risk. (Yang B, Petrick JL, Kelly SP, et al. Adiposity across the adult life course and incidence of primary liver cancer: The NIH-AARP cohort. Int J Cancer 2017; Epub April 26)

Tooth Loss and Liver Cancer

The association between tooth loss and primary liver cancer incidence was examined in a prospective cohort of Finnish male smokers (n = 29,096). Among the 213 incident primary liver cancer cases that occurred over 17 years of follow-up, having 11-31 permanent teeth lost or all 32 teeth lost was each associated with higher risk of liver cancer, compared to those having 0-10 teeth lost. Adjusting for Helicobactor pylori seropositivity yielded a small attenuation of the effect estimate. (Yang B, Petrick JL, Abnet CC, et al. Tooth loss and liver cancer incidence in a Finnish cohort. Cancer Causes Control 2017)


Gene-set Analysis

Gene-set analysis (GSA) is an approach using the results of single-marker genome-wide association studies when investigating pathways with respect to the genetic basis of a disease. Investigators applied the META-GSA method to data from the lung cancer TRICL/ILCCO consortium, studying 234 pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The systemic lupus erythematosus KEGG pathway hsa05322, driven by the gene region 6p21-22, was implicated in lung cancer. This gene region is known to be associated with squamous cell lung carcinoma. The most important genes driving the significance of this pathway belong to the genomic areas HIST1-H4L, -1BN, -2BN, -H2AK, -H4K and C2/C4A/C4B. Within these areas, the markers most significantly associated with LC are rs13194781 (located within HIST12BN) and rs1270942 (located between C2 and C4A). (Rosenberger A, Sohns M, Friedrichs S, et al. Gene-set meta-analysis of lung cancer identifies pathway related to systemic lupus erythematosus. PLoS One 2017)

Genetic Susceptibility Across Histologic Subtypes

An analysis of new and existing genome-wide association study data on 29,266 lung cancer cases and 56,450 controls identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four associated with lung cancer overall and six associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L, and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. (McKay JD, Hung RJ, Han Y, et al. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nat Genet 2017; Epub June 12)


Epidemiologic Research Consortia

REVIEW: Cannioto RA, Trabert B, Poole EM, Schildkraut JM. Ovarian cancer epidemiology in the era of collaborative team science. Cancer Causes Control 2017; Epub Mar 10.


Adolescent and Midlife Diet

Data from the NIH-AARP Diet and Health Study show that carbohydrate intake during adolescence and calcium intake ten years before baseline were associated with a significant reduction in risk of pancreatic cancer, while total fat intake at both times and intake of butter and margarine in midlife were associated with significantly increased risk. There also appeared to be differences in risk when intakes at both time points were considered together. These results suggest that intake of dietary nutrients and food groups over the life course, rather than at one specific point in time, may play an important role in the etiology of pancreatic cancer. (Gordon-Dseagu VLZ, Thompson FE, Subar AF, et al. A cohort study of adolescent and midlife diet and pancreatic cancer risk in the NIH-AARP Diet and Health Study. Am J Epidemiol 2017; Epub Apr 28)

Functional Regulatory Variants

Investigators conducted an in-depth study of the impact of inherited genetic variants on the pancreatic transcriptome. By correlating genotypes with gene expression, close to 40,000 cis-e expression quantitative trait loci (QTLs) in histologically normal and tumor-derived pancreatic tissue samples were identified, corresponding to 484 and 237 eGenes, respectively. Forty-two percent of eGenes were specific for the normal-derived pancreatic tissue samples and 23 percent for pancreatic tumors. eQTLs were enriched close to transcriptional start sites and in non-coding functional elements important for pancreatic exocrine tissues, as well as highly shared with the endocrine pancreas. A large number of eQTLs were shared between normal and tumor-derived pancreatic tissue samples; these eQTLs had stronger effect sizes and were located closer to transcriptional start sites than non-shared eQTLs. Pancreatic cancer risk alleles on chr9q34.2 were strongly associated with ABO gene expression; this effect may be due to allele-specific effects of the risk variants on a non-coding gene regulatory element. (Zhang M, Lykke-Andersen S, Zhu B, et al. Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues. Gut 2017; Epub Jun 20)

Pediatric Cancers

Pediatric Solid Organ Transplantation

Using data from nearly 18,000 pediatric transplant recipients, the Transplant Cancer Match Study found that the overall cancer incidence among pediatric transplant recipients was over 19 times higher than that of the general pediatric population. The risk of non-Hodgkin lymphoma (NHL), the most common cancer among this population, was increased 212-fold, and was especially high during the first year following transplantation, as well as in individuals younger than five years of age and those receiving an intestine transplant. NHL risk was also very high in individuals who did not have antibodies to Epstein-Barr virus (EBV) at the time of transplantation, reflecting the effects of primary EBV infection following transplantation. Pediatric transplant patients also experience relatively high risks of a number of other cancers, including Hodgkin lymphoma, myeloma, leukemia, and cancers of the liver, soft tissue, ovary, vulva, testis, bladder, kidney, and thyroid. Given the strongly elevated risk for NHL, these results highlight the potential for substantial reduction in cancer risk among pediatric transplant patients if EBV infection can be prevented or controlled. (Yanik EL, Smith JM, Shiels MS, et al. Cancer risk after pediatric solid organ transplantation. Pediatrics 2017). For more information, read Increased risk of cancer after pediatric organ transplantation in Research News & Highlights.

Physical Activity

Reducing Sitting Time

REVIEW: Keadle SK, Conroy DE, Buman MP, et al. Targeting reductions in sitting time to increase physical activity and improve health. Med Sci Sports Exerc 2017; Epub Mar 8)


TMPRSS2-ERG Gene Fusions and Race

Immunohistochemistry was used to assess ERG expression as the established surrogate of ERG fusion genes among 262 prostate cancer biopsies from the Ghana Prostate Study. A total of 47 of 262 (18 percent) prostate cancers were ERG-positive, and negative ERG staining was associated with higher Gleason score. A meta-analysis combining results from Ghana with 40 additional studies showed the prevalence of TMPRSS2-ERG fusions in prostate cancer to be highest in men of European descent (49 percent) followed by Asian (27 percent) and then African (25 percent). The lower prevalence of TMPRSS2-ERG fusions in men of African descent implies that alternative genomic mechanisms might explain the disproportionately high prostate cancer burden in such populations. (Ke Zhou C, Young D, Yeboah ED, et al. TMPRSS2-ERG gene fusions in prostate cancer of West African men and a meta-analysis of racial differences. Am J Epidemiol 2017; Epub Jun 12)

Vitamin D

Data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were used to examine prospectively the relationship between vitamin D status and prostate cancer risk among black men, a group at high risk for both low vitamin D status and prostate cancer. Serum 25(OH)D and 25(OH)D:DBP were not associated with overall prostate cancer risk, although 25(OH)D appeared inversely associated with nonaggressive disease, with a similar pattern of association among older men. There was significantly lower prostate cancer risk among men with higher circulating DBP concentrations, independent of 25(OH)D status, which represents a novel finding. (Layne TM, Weinstein SJ, Graubard BI, et al. Serum 25-hydroxyvitamin D, vitamin D binding protein, and prostate cancer risk in black men. Cancer 2017; Epub Apr 3)



To determine the epidemiologic and clinical relevance of gastric microbiota, investigators used 16 S ribosomal RNA gene sequencing analysis to characterize the composition and structure of the gastric microbial community of 80 paired samples (non-malignant and matched tumor tissues) from gastric cardia adenocarcinoma (GCA) patients. PICRUSt (a bioinformatics software package) was also used to predict microbial functional profiles. Compared to patients without family history of upper gastrointestinal (UGI) cancer in the non-malignant gastric tissue microbiota, patients with family history of UGI cancer had higher Helicobacter pylori (Hp) relative abundance and lower alpha diversity. Patients with higher tumor grade had higher Hp relative abundance, lower alpha diversity, altered beta diversity, and significant alterations in relative abundance of five KEGG functional modules in non-malignant gastric tissue microbiota. Patients without metastases had higher relative abundance of Lactobacillales than patients with metastases in non-malignant gastric tissue microbiota. (Yu G, Hu N, Wang L, et al. Gastric microbiota features associated with cancer risk factors and clinical outcomes: A pilot study in gastric cardia cancer patients from Shanxi, China. Int J Cancer 2017; Epub Mar 20)

Vitamin B12 and Gastric Cancer

An evaluation of one-carbon metabolism nutrients and upper gastrointestinal tract cancer was conducted using prediagnostic serum concentrations of several one-carbon metabolism nutrients in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Lower prediagnostic vitamin B12 concentrations at baseline were associated with a 5.8-fold increased risk of noncardia gastric adenocarcinoma (NCGA). In contrast, pepsinogen I, a known serologic marker of gastric atrophy, was not associated with NCGA in this population. As vitamin B12 absorption requires intact gastric mucosa to produce acid and intrinsic factor, the findings suggest vitamin B12 as a possible serologic marker for the atrophic gastritis that precedes NCGA, one more strongly associated with subsequent NCGA than pepsinogen.  (Miranti EH, Stolzenberg-Solomon R, Weinstein SJ, et al. Low vitamin B12 increases risk of gastric cancer: A prospective study of one-carbon metabolism nutrients and risk of upper gastrointestinal tract cancer. Int J Cancer 2017; Epub June 21)


Genetic Susceptibility

The international Testicular Cancer Consortium combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new susceptibility loci. Eight new loci mapping to 2q14.2, 3q26.2, 4q35.2, 7q36.3, 10q26.13, 15q21.3, 15q22.31, and Xq28 achieved genome-wide significance. Most loci harbor biologically plausible candidate genes. Investigators refined previously reported associations at 9p24.3 and 19p12 by identifying one and three additional independent SNPs, respectively. In aggregate, the 39 independent markers identified to date explain 37 percent of father-to-son familial risk, eight percent of which can be attributed to the 12 new signals reported here. (Wang Z, McGlynn KA, Rajpert-De Meyts E, et al. Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor. Nat Genet 2017; Epub June 12)

Mosaic Chromosome Y Loss

Studies have suggested mosaic loss of chromosome Y (mLOY) in blood-derived DNA is common in older men. This study investigated whether mosaic loss across the entire Y chromosome was associated with testicular germ cell tumors (TGCT) using blood- and buccal-derived DNA from two case-control studies. There was no significant overall relationship between mean chromosome Y target-to-reference (T/R) ratio and TGCT. However, when restricted to familial TGCT cases, a significantly lower T/R ratio was observed in cases compared with controls. (Machiela MJ, Dagnall CL, Pathak A, et al. Mosaic chromosome Y loss and testicular germ cell tumor risk. J Hum Genet 2017; Epub Mar 9)

Risk Factors

REVIEW: Gurney JK, McGlynn KA, Stanley J, et al. Risk factors for cryptorchidism. Nat Rev Urol 2017; Epub Jun 27.



Data from the Surveillance, Epidemiology, and End Results-9 (SEER-9) cancer registry program were used to evaluate thyroid cancer incidence in the United States, and whether the increasing incidence of papillary thyroid cancer has been related to thyroid mortality trends. Among patients in the United States diagnosed with thyroid cancer from 1974-2013, the overall incidence of thyroid cancer increased 3 percent annually; incidence rate and thyroid cancer mortality rate for advanced-stage papillary thyroid cancer also increased. These findings are consistent with a true increase in the occurrence of thyroid cancer in the United States. (Lim H, Devesa SS, Sosa JA, et al. Trends in thyroid cancer incidence and mortality in the United States, 1974-2013. JAMA 2017). For more information, read Increasing Thyroid Cancer Incidence and Mortality in the United States in Research News & Highlights.

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