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Scientific Highlights March–June 2014

Posted on July 01, 2014

Cancer Topics

Bladder Cancer

Gene-Environment Interaction

A genome-wide interaction study based on primary scan data from 3,002 bladder cancer cases and 4,411 controls identified 10 single nucleotide polymorphisms (SNPs) that provided evidence of interaction with tobacco use. Included were two novel SNPs (rs1711973 [FOXF2] and rs12216499 [RSPH3-TAGAP-EZR] on 6p25.3) that showed strong evidence of association with bladder cancer in tobacco use subgroups and approached genome-wide significance. (Figueroa JD, Han SS, Garcia-Closas M, et al. Genome-wide interaction study of smoking and bladder cancer risk. Carcinogenesis 2014; May 10 [E-pub ahead of print])

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Brain Tumors

Benign Brain Tumor Risk Among Cancer Survivors

Using data from the NCI Surveillance, Epidemiology, and End Results (SEER) Program, the authors showed that the risk of second benign brain tumors, particularly meningioma, increases following first primary cancers of the brain/central nervous system, thyroid, prostate, and acute lymphoblastic leukemia. Radiation exposure likely contributes to these excess risks. (Kutsenko A, Berrington de González A, Curtis RE, Rajaraman P. Risk of second benign brain tumors among cancer survivors in the Surveillance, Epidemiology, and End Results Program. Cancer Causes Control 2014;25:659–668)

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Breast Cancer

Endometrial Thickness

Data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial suggest that endometrial thickness as assessed by transvaginal ultrasound is a biological marker of excess estrogen stimulation and is associated with postmenopausal breast cancer and endometrial cancer. (Felix AS, Weissfeld JL, Pfeiffer RM, et al. Endometrial thickness and risk of breast and endometrial carcinomas in the prostate, lung, colorectal and ovarian cancer screening trial. Int J Cancer 2014;134:954–960)

Estrogen Metabolism

The authors conducted a case-cohort study within the Breast and Bone Follow-up to the Fracture Intervention Trial to assess serum estrogens and estrogen metabolites in relation to breast cancer risk and found increased risk associated with elevated circulating estradiol and reduced risk associated with a higher ratio of the 2/16-hydroxylation pathways. (Dallal CM, Tice JA, Buist DS, et al. Estrogen metabolism and breast cancer risk among postmenopausal women: A case-cohort study within B~FIT. Carcinogenesis 2014;35:346–355)

Fertility Drugs

Follow-up of 9,892 women evaluated for infertility between 1965 and 1988 at five U.S. sites showed that overall, those who took clomiphene citrate (brand name Clomid) or gonadotropins were not at increased risk for breast cancer. The authors reported elevated breast cancer risk among a subset of women in the study: those who remained nulligravid after treatment with gonadotropins, which may be related to underlying causes of infertility; and women who had 12 or more cycles of clomiphene, a finding which warrants continued monitoring. (Brinton LA, Scoccia B, Moghissi KS, et al. Long-term relationship of ovulation-stimulating drugs to breast cancer risk. Cancer Epidemiol Biomarkers Prev 2014;23:584–593)

Genetic Predisposition to Lobular Carcinoma

A pooling study based on 6,023 breast cancer cases and 34,271 controls identified a novel lobular breast cancer–specific predisposition polymorphism at 7q34. This finding showed for the first time that common breast cancer polymorphisms predispose to lobular carcinoma in situ and that many of the estrogen receptor positive (ER+) breast cancer predisposition loci also predispose to invasive lobular breast cancer, although some heterogeneity exists between ER+ lobular and ER+ intraductal carcinomas. (Sawyer E, Roylance R, Petridis C, et al. Genetic predisposition to in situ and invasive lobular carcinoma of the breast. PLoS Genet 2014;10:e1004285)

Genetic Susceptibility

Using data from 38 case-control studies, the authors assessed 41 common non-synonymous single nucleotide polymorphisms (nsSNPs) for which some evidence of association with breast cancer risk had been previously reported. Strong evidence of association was observed for a novel susceptibility locus at 3p21 (rs1053338), a previously suggested locus rs6964587 at 7q21, and locus rs10510592 at 3p24, for which the association was substantially attenuated after adjustment for the known genome-wide association study hit. (Milne RL, Burwinkel B, Michailidou K, et al. Common non-synonymous SNPs associated with breast cancer susceptibility: Findings from the Breast Cancer Association Consortium. Hum Mol Genet 2014;Jun 18 [E-pub ahead of print])

Male Breast Cancer

Analyses within the Male Breast Cancer Pooling Project, a consortium of 11 case-control and 10 cohort investigations involving 2,405 cases and 52,013 controls, showed risk associated with weight, height, and body mass index (BMI), particularly recent BMI, Klinefelter syndrome, gynecomastia, diabetes, cryptorchidism, orchitis, and never having children. (Brinton LA, Cook MB, McCormack V, et al. Anthropometric and hormonal risk factors for male breast cancer: Male breast cancer pooling project results. J Natl Cancer Inst 2014;106:djt465)

Smoking

Data from the NIH-AARP Diet and Health Study showed an increased risk of postmenopausal breast cancer among women who smoke or have smoked in the past, particularly among those without a family history or late menarche. (Nyante SJ, Gierach GL, Dallal CM, et al. Cigarette smoking and postmenopausal breast cancer risk in a prospective cohort. Br J Cancer 2014;110:2339–2347)

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Cervical Cancer

Infection with Multiple Human Papillomavirus Genotypes

Using a population-based stratified sample of 59,664 cervical cytology specimens from women residing in New Mexico, the authors did not see more than additive effects of human papillomavirus types on the risk of high-grade squamous intraepithelial lesions among women infected with multiple types. (Wentzensen N, Nason M, Schiffman M, et al. No evidence for synergy between human papillomavirus genotypes for the risk of high-grade squamous intraepithelial lesions in a large population-based study. J Infect Dis 2014;209:855–864)

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Endometrial Cancer

Endometrial Thickness

Data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial suggest that endometrial thickness as assessed by transvaginal ultrasound is a biological marker of excess estrogen stimulation and is associated with postmenopausal breast cancer and endometrial cancer. (Felix AS, Weissfeld JL, Pfeiffer RM, et al. Endometrial thickness and risk of breast and endometrial carcinomas in the prostate, lung, colorectal and ovarian cancer screening trial. Int J Cancer 2014;134:954–960)

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Gallbladder Cancer

Helicobacter pylori

Seropositivity to H. pylori proteins was associated with an increased risk of biliary tract cancers in the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. (Murphy G, Michel A, Taylor PR, et al. Association of seropositivity to Helicobacter species and biliary tract cancer in the ATBC study. Hepatology 2014;May 2 [E-pub ahead of print])

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Gastrointestinal Cancer

Folate and the One-Carbon Metabolism Pathway

In a prospective study, the authors observed an association of low intake of folate with an elevated risk of esophageal squamous cell carcinoma but not with esophageal adenocarcinoma, gastric cardia adenocarcinoma, or non-cardia gastric adenocarcinoma. The intakes of methionine, vitamin B6, and vitamin B12 were not associated with esophageal and gastric cancer. (Xiao Q, Freedman ND, Ren J, et al. Intakes of folate, methionine, vitamin B6, and vitamin B12 with risk of esophageal and gastric cancer in a large cohort study. Br J Cancer 2014;110:1328–1333)

Gallstones and Cholecystectomy

Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, the authors observed that gallstones and cholecystectomy—which cause inflammation, altered bile flux, and changes in metabolic hormone levels—were associated with increased risk of noncardia gastric cancer, small-intestine carcinoid, liver cancer, and pancreatic cancer. (Nogueira L, Freedman ND, Engels EA, et al. Gallstones, cholecystectomy, and risk of digestive system cancers. Am J Epidemiol 2014;179:731–739)

Helicobacter pylori Treatment

The fifteen-year follow-up of a randomized clinical trial of Helicobacter pylori-seropositive subjects found that one-time treatment with amoxicillin-omeprazole was associated with a statistically significant decrease in gastric cancer incidence (odds ratio = 0.36) and mortality (hazard ratio = 0.26) among subjects aged 55 years or older at baseline, and a statistically significant decrease in incidence among those with intestinal metaplasia or dysplasia at baseline (odds ratio = 0.56). Treatment benefits for incidence and mortality among those with and without post-treatment infection were similar. The study suggests that H. pylori treatment can benefit an entire population, not just the young or those with mild histopathology. (Li WQ, Ma L, Zhang L, et al.  Effects of Helicobacter pylori Treatment on Gastric Cancer Incidence and Mortality in Subgroups. J Natl Cancer Inst 2014;Jun 12 [E-pub ahead of print])

Metabolic Syndrome

Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database compared with two control groups (Medicare population controls and endoscopy controls), the authors found that metabolic syndrome increased the risk of Barrett esophagus compared with population controls, but not the endoscopy controls, with the association driven by and confined to those without gastroesophageal reflux disease. (Drahos J, Ricker W, Parsons R, et al. Metabolic syndrome increases risk of Barrett esophagus in the absence of gastroesophageal reflux: An analysis of SEER-Medicare data. J Clin Gastroenterol 2014;Mar 25 [E-pub ahead of print])

Survival in Relation to Tumor Epstein-Barr Virus Positivity

In a follow-up study of 4,599 gastric cancer patients diagnosed between 1976 and 2010 in Asia, Europe, and Latin America, Epstein-Barr virus positivity of tumors was associated with lower mortality, even after adjusting for stage at diagnosis and other confounders. (Camargo MC, Kim WH, Chiaravalli AM, et al. Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: An international pooled analysis. Gut 2014;63:236–243)

Vitamin and Mineral Supplement Use

Data from the NIH-AARP Diet and Health Study showed no association of multivitamin use with reduced risk of four highly fatal upper gastrointestinal cancers (esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric noncardia adenocarcinoma, and gastric cardia adenocarcinoma), but there were some increases and decreases in risk with reported use of individual supplements. (Dawsey SP, Hollenbeck A, Schatzkin A, Abnet CC. A prospective study of vitamin and mineral supplement use and the risk of upper gastrointestinal cancers. PLoS One 2014;9:e88774)

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Kidney Cancer

Mitochondrial DNA Copy Number

High pre-diagnostic leukocyte mtDNA copy number, a suspected marker of oxidative DNA damage and mitochondrial dysfunction, was associated with increased future renal cell carcinoma risk among 252 cases and 504 controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. (Hofmann JN, Hosgood HD 3rd, Liu CS, et al. A nested case-control study of leukocyte mitochondrial DNA copy number and renal cell carcinoma in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Carcinogenesis 2014;35:1028–1031)

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Lung Cancer

Diesel Engine Exhaust

Combined data from three U.S. occupational cohort studies suggest that levels of diesel engine exhaust—recently classified as a known human carcinogen and common in the workplace and in outdoor air—appear to pose substantial excess lifetime risks of lung cancer above the usually acceptable limits in the United States and Europe, which are generally set at 1/1,000 and 1/100,000 based on lifetime exposure for the occupational and general population, respectively. (Vermeulen R, Silverman DT, Garshick E, et al. Exposure-response estimates for diesel engine exhaust and lung cancer mortality based on data from three occupational cohorts. Environ Health Perspect 2014;122:172–177)

Telomere Length

Using prediagnostic specimens from three prospective cohort studies, longer telomere length was associated with increased lung cancer risk and was particularly evident for female adenocarcinoma cases. Telomere length in white blood cell DNA may be a biomarker of future increased risk of lung cancer. (Seow WJ, Cawthon RM, Purdue MP, et al. Telomere length in white blood cell DNA and lung cancer: A pooled analysis of three prospective cohorts. Cancer Res 2014;May 22 [E-pub ahead of print])

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Lymphoma

HIV and Diffuse Large B-Cell Lymphoma Subtypes

Through a comparison of 51 HIV-infected and 116 HIV-uninfected diffuse large B-cell lymphoma cases diagnosed from 1977 to 2003, the authors found key differences in the molecular characteristics, cell of origin, and prognosis by HIV status in the pre–highly active antiretroviral therapy and pre-rituximab era, supporting biologic differences in lymphomagenesis in the presence of HIV. (Morton LM, Kim CJ, Weiss LM, et al. Molecular characteristics of diffuse large B-cell lymphoma in human immunodeficiency virus-infected and -uninfected patients in the pre-highly active antiretroviral therapy and pre-rituximab era. Leuk Lymphoma 2014;55:551–557)

Marginal Zone Lymphoma Incidence

A comprehensive assessment of incidence patterns of marginal zone lymphoma by anatomic site in the Surveillance, Epidemiology and End Results (SEER) Program population-based registry data supports the contention that this malignancy is characterized by etiological heterogeneity across sites and that susceptibility is probably influenced by intrinsic characteristics and environmental exposures. (Khalil MO, Morton LM, Devesa SS, et al. Incidence of marginal zone lymphoma in the United States, 2001-2009 with a focus on primary anatomic site. Br J Haematol 2014;165:67–77)

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Melanoma

Genetic Susceptibility

Using whole-exome sequencing, the authors identified a rare inherited mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. The authors also identified additional rare POT1 variants in all cases sequenced in two separate Italian families, one variant per family, as well as two rare recurrent POT1 variants in U.S. and French familial melanoma cases, suggesting that POT1 is a major susceptibility gene for familial melanoma in several populations. (Shi J, Yang XR, Ballew B, Rotunno M, et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet 2014;46:482–486)

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Methods

Leveraging Family History in Population-Based Case-Control Studies

The authors propose a simple approach to primary genetic association testing in population-based epidemiologic studies that incorporates family history information as a “phenotype” and increases efficiency by as much as 40%, depending on the type of design used for conducting the primary study, extent of family history, and accuracy and completeness of reporting. (Ghosh A, Hartge P, Kraft P, et al. Leveraging family history in population-based case-control association studies. Genet Epidemiol 2014;38:114–122)

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Ovarian Cancer

Aspirin Use

Pooled data from 12 population-based case-control studies of ovarian cancer, comprising 7,776 case patients and 11,843 control subjects accrued between 1992 and 2007, showed that aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin, suggesting that the same aspirin regimen proven to protect against cardiovascular events and several cancers could reduce the risk of ovarian cancer 20% to 34% depending on frequency and dose of use. (Trabert B, Ness RB, Lo-Ciganic WH, et al. Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: A pooled analysis in the Ovarian Cancer Association Consortium. J Natl Cancer Inst 2014;106:djt431)

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Pancreatic Cancer

Serum Transforming Growth Factor-β1

Using prediagnostic specimens from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, serum levels of transforming growth factor-β1, a potential marker of subclinical pancreatic inflammation, were associated with increased pancreatic cancer risk after 10 years of follow-up. (Jacobs EJ, Newton CC, Silverman DT, et al. Serum transforming growth factor-β1 and risk of pancreatic cancer in three prospective cohort studies. Cancer Causes Control 2014;Jun 10 [E-pub ahead of print])

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Prostate Cancer

Genetic Susceptibility Among West African Men

A genome-wide association study of prostate cancer among West African men found a promising association at 10p14 within an intron of a long non-coding RNA (lncRNA RP11-543F8.2) 360 kb centromeric of GATA3 (p = 1.29 × 10-7), as well as single nucleotide polymorphisms at 5q31.3 associated with high Gleason score (≥ 7) cancers. (Cook MB, Wang Z, Yeboah ED, et al. A genome-wide association study of prostate cancer in West African men. Hum Genet 2014;133:509–521)

Genetic Variants Among Men of African Ancestry

By resequencing a region on chromosome 8 containing several prostate cancer susceptibility loci, as well as a locus associated with chronic lymphocytic leukemia (CLL), among samples from men from Ghana and African Americans, 1,838 single nucleotide polymorphisms (SNPs) were identified, including 285 novel SNPs that had not previously been reported in any public database. These findings could be important for establishing priorities for future functional work designed to explain the biological basis of associations between SNPs and both prostate cancer and CLL. (Chung CC, Hsing AW, Yeboah E, et al. A comprehensive resequence-analysis of 250 kb region of 8q24.21 in men of African ancestry. Prostate 2014;74:579–589)

Genetic Variants Related to Vitamin E Status

A study of variants in vitamin E–related genes among participants in the Prostate, Lung, Colorectal and Ovarian  Cancer Screening Trial suggests that polymorphisms near BUD13/ZNF259/APOA5, involved in vitamin E transport and metabolism, may be associated with lower risk of prostate cancer. (Major JM, Yu K, Weinstein SJ, et al. Genetic variants reflecting higher vitamin e status in men are associated with reduced risk of prostate cancer. J Nutr 2014;144:729–733)

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Screen-Detected Prostate Cancer Among West African Men

In a relatively unscreened population in Ghana, the authors conducted a population-based prostate cancer screening study with biopsy confirmation and found that screen-detected prostate cancer prevalence is high, suggesting a possible role of genetics in both prostate cancer etiology and the disparity in prostate cancer risk between African Americans and Caucasian Americans. (Hsing AW, Yeboah E, Biritwum R, et al. High prevalence of screen-detected prostate cancer in West Africans: Implications for racial disparity of prostate cancer. J Urol 2014;Apr 17 [E-pub ahead of print])

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Renal Cancer

Vitamin D

A nested case-control analysis within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study observed a strong protective association between higher circulating vitamin D-binding protein concentration and kidney cancer risk, which was independent of circulating 25-hydroxyvitamin D [25(OH)D], the accepted measure of vitamin D status. (Mondul AM, Weinstein SJ, Moy KA, et al. Vitamin D-binding protein, circulating vitamin D and risk of renal cell carcinoma. Int J Cancer 2014;134:2699–2706)

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Testicular Cancer

Pathway-based Analysis of Sex Determination Genes

Genome-wide association studies (GWAS) of testicular germ cell tumor (TGCT) have identified 18 susceptibility loci containing genes that are important for male germ cell differentiation and maturation. One of these genes, DMRT1, plays crucial roles in male germ cell development and sex determination across the phylogenetic spectrum. The authors undertook pathway-based analyses of genes influencing sex determination to identify additional loci associated with the development of TGCT. They found evidence of a statistically significant association with a set of genes involved in sex determination, including DMRT1, with TGCT status in three independent TGCT GWAS datasets. Even after removing DRMT1 from the sex determination gene set, there were strong indications of a statistically significant association with TGCT in the datasets. These results suggest that the pathway-based finding is not solely driven by the associations of DMRT1 single nucleotide polymorphism markers and that variation in other genes included in this gene set are involved in the development of TGCT. (Koster R, Mitra N, D'Andrea K, et al. Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors. Hum Mol Genet 2014;Jun 18 [E-pub ahead of print])

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