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Discovering the causes of cancer and the means of prevention

Scientific Highlights November 2015 - February 2016

Posted on February 29, 2016

Cancer Topics

All Cancers

Microbiome

REVIEW: Vogtmann E, Goedert JJ. Epidemiologic studies of the human microbiome and cancer. Br J Cancer 2016;114:237-242.

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All Cause Mortality

Coffee Consumption

Data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial showed that coffee consumption at baseline, compared to no coffee consumption, was associated with lower hazard ratios for overall mortality (<1 cup/day: hazard ratio (HR) = 0.99; 1 cup/day: HR = 0.94; 2-3 cups/day: HR = 0.82; 4-5 cups/day: HR = 0.79; ≥6 cups/day: HR = 0.84). Similar findings were observed for decaffeinated coffee and coffee additives. Inverse associations were observed for deaths from heart disease, chronic respiratory diseases, diabetes, pneumonia and influenza, and intentional self-harm, but not cancer. Coffee may reduce mortality risk by favorably affecting inflammation, lung function, insulin sensitivity, and depression. (Loftfield E, Freedman ND, Graubard BI, et al. Association of coffee consumption with overall and cause-specific mortality in a large U.S. prospective cohort study. Am J Epidemiol 2015;182:1010-1022)

Physical Activity

A study of 165,087 adults in the NIH-AARP Diet and Health (aged 50-71 years) who completed questionnaires at two time-points and were followed until death or December 31, 2011, showed that prolonged television viewing time was associated with greater mortality in older adults and demonstrated for the first time that individuals who reduced the amount of time they spent watching television between the first and second questionnaires had lower mortality than those whose viewing patterns were the same or higher. (Keadle SK, Arem H, Moore SC, et al. Impact of changes in television viewing time and physical activity on longevity: A prospective cohort study. Int J Behav Nutr Phys Act 2015;12:156)

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Bladder

Genetic Susceptibility

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In a search for additional susceptibility variants, the investigators followed up on four promising single nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance. Using data for 6,911 cases and 11,814 controls from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 and rs4907479 within the MCF2L gene at 13q34. Imputation and fine-mapping analyses at the 13q34 region suggest a single signal marked by rs4907479 in the 13q34 region. In contrast, there were two signals in the 20p12.2 region – one marked by rs6104690 and the other marked by two moderately correlated SNPs, rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared to non-muscle-invasive (Ta, T1 stage) bladder cancer. (Figueroa JD, Middlebrooks CD, Banday AR, et al. Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry. Hum Mol Genet 2016; Epub Jan 4)

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Breast

Genetic Predisposition to DCIS

Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer and is considered to be a non-obligate precursor of invasive ductal carcinoma (IDC). Using data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip, most (67%) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer, with similar results for estrogen receptor positive DCIS and IDC. This provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. (Petridis C, Brook MN, Shah V, et al. Genetic predisposition to ductal carcinoma in situ of the breast. Breast Cancer Res 2016;18:22)

Insulin-Like Growth Factor

Terminal duct lobular units (TDLUs) are the primary structures from which breast cancers and their precursors arise. Decreased age-related TDLU involution and elevated mammographic density are both correlated and independently associated with increased breast cancer risk, suggesting that these characteristics of breast parenchyma might be linked to a common factor. A cross-sectional study of women with benign breast disease demonstrated that circulating levels of serum insulin-like growth factor-1 and insulin-like growth factor binding protein-3 are associated with TDLU count among women with benign breast disease, and that the strongest associations are found among women who have high mammographic density. The findings contribute to the body of knowledge that supports the evaluation of TDLU involution and mammographic density as possible intermediate endpoints in breast carcinogenesis. (Horne HN, Sherman ME, Pfeiffer RM, et al. Circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3 and terminal duct lobular unit involution of the breast: A cross-sectional study of women with benign breast disease. Breast Cancer Res 2016;18:24)

Luminal Breast Cancer Heterogeneity

Luminal A breast cancer, defined as hormone receptor positive and human epidermal growth factor receptor 2 (HER2) negative, is known to be heterogeneous. In this study, investigators observed that most established breast cancer risk factors were similar in basal-positive and basal-negative luminal A tumors. There were non-significant but suggestive of differences in tumor features and family history. (Sung H, Garcia-Closas M, Chang-Claude J, et al. Heterogeneity of luminal breast cancer characterised by immunohistochemical expression of basal markers. Br J Cancer 2015;114:298-304)

Terminal Duct Lobular Units

Elevated mammographic density (MD) is an established breast cancer risk factor. Reduced involution of terminal duct lobular units (TDLUs), the histologic source of most breast cancers, has been associated with higher MD and breast cancer risk. This study of the relationships of TDLU involution with area and volumetric MD, measured throughout the breast and surrounding biopsy targets (peri-lesional) indicated that TDLU involution and MD are correlated markers of breast cancer risk, suggesting that associations of MD with breast cancer may partly reflect amounts of at-risk epithelium. If confirmed, these results could suggest a prevention paradigm based on enhancing TDLU involution and monitoring efficacy by assessing MD reduction. (Gierach GL, Patel DA, Pfeiffer RM, et al. Relationship of terminal duct lobular unit involution of the breast with area and volume mammographic densities. Cancer Prev Res (Phila) 2015;9:149-158)

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Cervix

Screening

REVIEW: Wentzensen N, Schiffman M, Palmer T, Arbyn M. Triage of HPV positive women in cervical cancer screening. J Clin Virol 2015;Epub Nov 28.

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Endometrium

Estrogen Metabolites (Also appears under Ovary)

Within the Breast and Bone Follow-up to the Fracture Intervention Trial, investigators conducted a case-cohort study to evaluate 15 pre-diagnostic serum estrogens and estrogen metabolites with risk of incident endometrial and ovarian cancer among postmenopausal women not on hormone therapy. Estradiol was significantly associated with increased endometrial cancer risk, with 2-Hydroxyestrone and 16α-hydroxyestrone showing no associated after estradiol adjustment. Ratios of 2- and 4-pathway catechol-to-methylated estrogens remained positively associated with endometrial cancer after BMI or estradiol adjustment. Estrogens and estrogen metabolites were not associated with ovarian cancer risk. (Dallal CM, Lacey JV Jr, Pfeiffer RM, et al. Estrogen metabolism and risk of postmenopausal endometrial and ovarian cancer: The B∼FIT Cohort. Horm Cancer 2016;7:49-64)

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Esophagus

Gastroesophageal Reflux Disease

Using Cerner Health Facts(®), a database on 35 million patients, investigators found that rates of gastroesophageal reflux disease (GERD) increased approximately 50% and esophageal cancer (EC) rates more than doubled between 2001 and 2010. Barrett esophagus (BE) rates declined approximately 40%. These data indirectly support the idea that increased incidence of EC may be partially due to GERD and raise the provocative hypothesis that BE rates may be decreasing possibly as a forerunner of continued stabilization of esophageal adenocarcinoma rates and a possible subsequent decline. (Petrick JL, Nguyen T, Cook MB. Temporal trends of esophageal disorders by age in the Cerner Health Facts database. Ann Epidemiol 2015; Epub Dec 11)

MicroRNA Profiles

The tissue-specificity and robustness of miRNAs may aid risk prediction in individuals diagnosed with Barrett esophagus (BE). A case-control study of 150 esophageal adenocarcinoma cases and 148 matched BE cases provided evidence that miRNA profiles from formalin-fixed paraffin-embedded tissue can discriminate EA from BE. This large analysis has identified miRNAs that merit further investigation in relation to pathogenesis and diagnosis of EA. These candidate miRNAs may provide a means for improved risk stratification and more cost-effective surveillance. (Drahos J, Schwameis K, Orzolek LD, et al. MicroRNA profiles of Barrett esophagus and esophageal adenocarcinoma: Differences in glandular non-native epithelium. Cancer Epidemiol Biomarkers Prev 2015; Epub Nov 24)

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Inherited Bone Marrow Failure Syndromes

Novel FANCI Mutations

Fanconi anemia (FA) is an inherited bone marrow failure syndrome caused by mutations in DNA repair genes. The investigators characterized three patients with FA and the VACTERL association caused by autosomal recessive mutations in FANCI. Data from these patients and limited data from cases reported by others suggest that mutations in FANCI may be added to the FA genotypes in which the VACTERL association is unusually frequent. (Savage SA, Ballew BJ, Giri N, et al. Novel FANCI mutations in Fanconi anemia with VACTERL association. Am J Med Genet A 2016;170:386-391)

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Liver

Hepatitis C Virus Treatment

EDITORIAL: O'Brien TR, Feld JJ, Kottilil S, Pfeiffer RM. No scientific basis to restrict 8 weeks of treatment with ledipasvir/sofosbuvir to patients with hepatitis C virus RNA <6,000,000 IU/mL. Hepatology 2016;63:28-30.

Menopausal Hormone Therapy

Primary liver cancer occurs less commonly among women than men in almost all countries, suggesting that hormone levels and/or exogenous hormone use could play a role. A study of 339 liver cancer cases and 1318 matched controls was conducted within the United Kingdom's Clinical Practice Research Datalink. Menopausal hormonal therapy (MHT), especially estrogen-only MHT use, was associated with a significantly lower risk of liver cancer in an overall analysis and in a substudy of cases and controls with diabetes. (McGlynn KA, Hagberg K, Chen J, et al. Menopausal hormone therapy use and risk of primary liver cancer in the Clinical Practice Research Datalink. Int J Cancer 2015; Epub Dec 13)

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Lung

Alcohol Consumption

Using data from the National Institutes of Health-AARP Diet and Health Study, investigators found that alcohol consumption was associated with a modest reduction in the risk of total lung carcinoma at lower levels of consumption (for 0.5-<1 drink/day) and a modest increase in risk in the highest category (for ≥7 drinks/day), with some differences by histologic type. Alcohol was associated with an inverse association at all alcohol levels for squamous cell carcinoma and a modest increase in risk of adenocarcinoma among heavier drinkers. (Troche JR, Mayne ST, Freedman ND, et al. The association between alcohol consumption and lung carcinoma by histological subtype. Am J Epidemiol 2016;183:110-121)

Gene Expression and Smoky Coal

Non-smoking women living in rural China who burn smoky (bituminous) coal for heating and cooking had gene expression patterns in buccal epithelial cells similar to those present in the cheek cells of active cigarette smokers. These results shed new light on the molecular mechanisms by which smoky coal exposure increases the risk of lung cancer. (Wang TW, Vermeulen RC, Hu W, et al. Gene-expression profiling of buccal epithelium among non-smoking women exposed to household air pollution from smoky coal. Carcinogenesis 2015;36:1494-1501)

Polymorphisms in MicroRNAs

MicroRNAs (miRNAs) are suggested to be very important in the development of lung cancer. This case-control showed that MiR-16-1 rs1022960 may be associated with risk of lung cancer in a Chinese nonsmoking female population, however the gene-environment interaction between three miRNA single nucleotide polymorphisms and cooking oil fumes were not significant. (Yin Z, Li H, Cui Z, et al. Polymorphisms in pre-miRNA genes and cooking oil fume exposure as well as their interaction on the risk of lung cancer in a Chinese nonsmoking female population. Onco Targets Ther 2016 Jan 19 doi: 10.2147/OTT.S96870)

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Lymphoma

Polycyclic Aromatic Hydrocarbons

A case-control study demonstrated elevated risks for NHL overall and some B cell lymphoma subtypes in association with the concentration of polycylic aromatic hydrocarbons (PAHs) in residential carpet dust, but without a monotonic trend, and there was no association comparing the highest quartile or tertile to the lowest. In contrast, risk of T cell lymphoma was significantly increased among participants with the highest tertile of summed PAHs and benzo(k)fluoranthene compared with the lowest tertile. Predictors of PAH dust concentrations in homes included ambient air PAH concentrations and the proportion of developed land within 2 km of a residence. (DellaValle CT, Deziel NC, Jones RR, et al. Polycyclic aromatic hydrocarbons: Determinants of residential carpet dust levels and risk of non-Hodgkin lymphoma. Cancer Causes Control 2016;27:1-13)

Ultraviolet Radiation

Ground-based ambient ultraviolet radiation (UVR) estimates were linked to incidence rates of Hodgkin lymphoma (HL) subtypes from 15 population-based cancer registries in the United States from 2001 to 2010. HL incidence was lower in the highest UVR quintile for nodular sclerosis, mixed cellularity/lymphocyte-depleted, lymphocyte-rich, and nodular lymphocyte predominant HL, but 'not otherwise specified' HL. These findings support an inverse association between UVR and HL. (Bowen EM, Pfeiffer RM, Linet MS, et al. Relationship between ambient ultraviolet radiation and Hodgkin lymphoma subtypes in the United States. Br J Cancer 2016;114:826-831)

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Methods

Analysis of Tumor Mutations

The central challenges in tumor sequencing studies are to identify driver genes and pathways, investigate their functional relationships, and nominate drug targets. Efficiency, particularly for infrequently mutated genes, is compromised when subjects carry different combinations of driver mutations. Mutual exclusivity analysis helps address these challenges. To identify mutually exclusive gene sets (MEGS), investigators developed a powerful and flexible analytic framework based on a likelihood ratio test and a model selection procedure. Extensive simulations demonstrated that the method outperformed existing methods for both statistical power and the capability of identifying the exact MEGS, particularly for highly imbalanced MEGS. The method can be used for de novo discovery, for pathway-guided searches, or for expanding established small MEGS, and was applied successfully to data from The Cancer Genome Atlas (TCGA). (Hua X, Hyland PL, Huang J, et al. MEGSA: A powerful and flexible framework for analyzing mutual exclusivity of tumor mutations. Am J Hum Genet 2016;98:442-455)

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Ovary

Estrogen Metabolites (Also appears in Endometrium)

Within the Breast and Bone Follow-up to the Fracture Intervention Trial, investigators conducted a case-cohort study to evaluate 15 pre-diagnostic serum estrogens and estrogen metabolites with risk of incident endometrial and ovarian cancer among postmenopausal women not on hormone therapy. Estradiol was significantly associated with increased endometrial cancer risk, with 2-Hydroxyestrone and 16α-hydroxyestrone showing no associated after estradiol adjustment. Ratios of 2- and 4-pathway catechol-to-methylated estrogens remained positively associated with endometrial cancer after BMI or estradiol adjustment. Estrogens and estrogen metabolites were not associated with ovarian cancer risk. (Dallal CM, Lacey JV Jr, Pfeiffer RM, et al. Estrogen metabolism and risk of postmenopausal endometrial and ovarian cancer: The B∼FIT Cohort. Horm Cancer 2016;7:49-64)

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Pancreas

Genetic Susceptibility

REVIEW: Amundadottir LT. Pancreatic cancer genetics. Int J Biol Sci 2016;12:314-325.

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Prostate

Data on dermatologist-assessed hair loss and prostate cancer-specific mortality from the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study suggests that male patterned hair loss is associated with a higher risk of fatal prostate cancer and supports the hypothesis of overlapping pathophysiological mechanisms. (Zhou CK, Levine PH, Cleary SD, et al. Male pattern baldness in relation to prostate cancer-specific mortality: A prospective analysis in the NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 2016;183:210-217)

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Radiation

Pediatric CT Scans

To investigate whether underlying unreported conditions could have biased an earlier report of a dose-response relationship between radiation exposure from pediatric computed tomography (CT) scans and the risk of leukemia and brain tumors in a large U.K. cohort, investigators collected and reviewed additional clinical information from radiology information systems databases, underlying cause of death, and pathology reports. Although there was evidence of some bias in the original risk estimates, re-analysis of the cohort with additional clinical data still showed an increased cancer risk after low-dose radiation exposure from CT scans among young patients. (Berrington de Gonzalez A, Salotti JA, McHugh K, et al. Relationship between paediatric CT scans and subsequent risk of leukaemia and brain tumours: Assessment of the impact of underlying conditions. Br J Cancer 2016;114:388-394)

Tool to Estimate Exposure from CT Scans

Investigators used the International Commission on Radiological Protection (ICRP) reference pediatric and adult phantoms combined with the Monte Carlo simulation of a reference computed tomography (CT) scanner to establish comprehensive organ dose coefficients and organ absorbed dose per unit volumetric CT Dose Index. They also developed methods to estimate organ doses with tube current modulation techniques and size specific dose estimates. A graphical interface was designed to obtain user input of patient- and scan-specific parameters, and to calculate and display organ doses. The NCI Dosimetry System for DT (NCICT) provides more realistic anatomy based on the ICRP reference phantoms, higher age resolution, the most up-to-date bone marrow dosimetry, and several convenient features, compared to previous tools. (Lee C, Kim KP, Bolch WE, et al. NCICT: A computational solution to estimate organ doses for pediatric and adult patients undergoing CT scans. J Radiol Prot 2015;35:891-909)

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Skin

Exogenous Estrogens

Because external sources of estrogen increase photosensitivity, researchers evaluated whether oral contraceptives and menopausal hormone therapy (MHT) affect the risk of basal cell carcinoma (BCC). Data from a large, nationwide, prospective cohort of women geographically dispersed across the U.S. confirmed a previous finding of increased risk of BCC associated with MHT and demonstrated novel findings of increased BCC risk associated with MHT among women experiencing natural menopause and for late age at natural menopause. There was no increased risk associated with oral contraceptive use. (Cahoon EK, Kitahara CM, Ntowe E, et al. Female estrogen-related factors and incidence of basal cell carcinoma in a nationwide U.S. cohort. J Clin Oncol 2015;33:4058-4065)

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Testis

Etiology and Treatment

REVIEW: Meyts ER, McGlynn KA, Okamoto K, et al. Testicular germ cell tumours. Lancet 2015; Epub Dec 2.

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Thyroid

Anthropometric Factors

Greater height and body mass index have been associated with an increased risk of thyroid cancer, particularly papillary carcinoma, the most common and least aggressive subtype. This large, pooled analysis of 22 prospective studies (833,176 men and 1,260,871 women) observed that greater height and excess adiposity throughout adulthood are associated with higher incidence of most major types of thyroid cancer, including the least common but most aggressive form, anaplastic carcinoma, and higher thyroid cancer mortality. (Kitahara CM, McCullough ML, Franceschi S, et al. Anthropometric factors and thyroid cancer risk by histological subtype: Pooled analysis of 22 prospective studies. Thyroid 2016;26:306-318)

Nonsteroidal Anti-Inflammatory Drugs

Cyclooxygenase (COX-2) has been associated with tumor growth and metastasis in several cancers, including thyroid cancer. For this reason, it has been hypothesized that COX-2 inhibitors might have antineoplastic effects. Data from three large prospective population-based studies (the NIH-AARP Diet and Health Study; the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; and the U.S. Radiologic Technologists Study) showed that self-reported frequency of aspirin and nonaspirin NSAID use one year prior to baseline (no use, ≤2/week, >2-6/week, and ≥7/week) were not associated with a reduced risk of thyroid cancer. (Patel D, Kitahara CM, Park Y, et al. Thyroid cancer and nonsteroidal anti-inflammatory drug use: A pooled analysis of patients older than 40 years of age. Thyroid 2015;25:1355-1362)

Histopathological Features Related to I-131 Dose

There are limited data on the histopathology of papillary thyroid carcinomas (PTCs) diagnosed in irradiated populations. In a large thyroid screening cohort in Ukraine comprising individuals exposed to 131I from the Chernobyl accident during childhood or adolescence, investigators observed strong, significant trends in decreasing tumor size and invasive properties of PTCs with each subsequent screening after adjustment for increasing age at surgery. There was a borderline significant non-linear 131I dose response for the combined characteristics of tumor invasiveness, defined as the presence of extrathyroidal extension, lymphatic/vascular invasion, or metastases. In a subset of tumors for which somatic mutation profiling was performed, irrespective of 131I dose, there was a significantly increased risk with the presence of lymphatic/vascular invasion for cases with common chromosomal rearrangements relative to cases without chromosomal rearrangements or to cases with BRAF/RAS point mutations. (Bogdanova TI, Zurnadzhy LY, Nikiforov YE, et al. Histopathological features of papillary thyroid carcinomas detected during four screening examinations of a Ukrainian-American cohort. Br J Cancer 2015;113:1556-1564)

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