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Purpose: Germ-line mutations in DICER1 increase the risk of various tumors, including pleuropulmonary blastoma. Macrocephaly and symmetric overgrowth have been reported in some, but not all, patients with mosaic DICER1 RNase IIIb mutations. The prevalence of these features in individuals with constitutional germ-line DICER1 mutations is unknown., Methods: We analyzed prospectively collected auxology data from 67 DICER1 mutation carriers and 43 family controls. We assessed differences between groups using an exact test for proportions and generalized estimating equations for continuous dependent variables., Results: Twenty-eight DICER1 mutation carriers (42%) were macrocephalic, and none had an occipitofrontal circumference (OFC) below the third centile, which significantly differed from family controls, of whom five were macrocephalic (12%) and two had OFC below the third centile (5%) (P < 0.001). DICER1 mutation carriers were taller than familial controls after controlling for gender (P = 0.048), but similar proportions of both groups were above the 97th centile of population norms. Head circumference remained increased after adjusting for differences in height., Conclusion: For the first time, we establish macrocephaly as a common finding in the DICER1 syndrome. Like some other tumor-predisposition disorders, macrocephaly may be a useful, albeit a subtle, clinical clue to the DICER1 syndrome diagnosis.Genet Med 19 2, 244-248., Competing Interests: Statement: The authors have no conflicts of interest to disclose.

Background: We developed an algorithm for the identification of patients with type 2 diabetes and ascertainment of the date of diabetes onset for examination of the temporal relationship between diabetes and cancer using data in the electronic medical record (EMR)., Methods: The Marshfield Clinic EMR was searched for patients who developed type 2 diabetes between January 1, 1995 and December 31, 2009 using a combination of diagnostic codes and laboratory data. Subjects without diabetes were also identified and matched to subjects with diabetes by age, gender, smoking history, residence, and date of diabetes onset/reference date., Results: The final cohort consisted of 11,236 subjects with and 54,365 subjects without diabetes. Stringent requirements for laboratory values resulted in a decrease in the number of potential subjects by nearly 70%. Mean observation time in the EMR was similar for both groups with 13-14 years before and 5-7 years after the reference date. The two cohorts were largely similar except that BMI and frequency of healthcare encounters were greater in subjects with diabetes., Conclusion: The cohort described here will be useful for the examination of the temporal relationship between diabetes and cancer and is unique in that it allows for determination of the date of diabetes onset with reasonable accuracy.

Type 2 diabetes mellitus is characterized by prolonged hyperinsulinemia, insulin resistance, and progressive hyperglycemia. Disease management relies on glycemic control through diet, exercise, and pharmacological intervention. The goal of the present study was to examine the effects of glycemic control and the use of glucose-lowering medication on the risk of breast, prostate, and colon cancer. Patients diagnosed with type 2 diabetes mellitus (N=9486) between 1 January 1995 and 31 December 2009 were identified and data on glycemic control (hemoglobin A1c, glucose), glucose-lowering medication use (insulin, metformin, sulfonylurea), age, BMI, date of diabetes diagnosis, insurance status, comorbidities, smoking history, location of residence, and cancer diagnoses were electronically abstracted. Cox proportional hazards regression modeling was used to examine the relationship between glycemic control, including medication use, and cancer risk. The results varied by cancer type and medication exposure. There was no association between glycemic control and breast or colon cancer; however, prostate cancer risk was significantly higher with better glycemic control (hemoglobin A1c ≤ 7.0%). Insulin use was associated with increased colon cancer incidence in women, but not with colon cancer in men or breast or prostate cancer risk. Metformin exposure was associated with reduced breast and prostate cancer incidence, but had no association with colon cancer risk. Sulfonylurea exposure was not associated with risk of any type of cancer. The data reported here support hyperinsulinemia, rather than hyperglycemia, as a major diabetes-related factor associated with increased risk of breast and colon cancer. In contrast, hyperglycemia appears to be protective in the case of prostate cancer.

An association between type 2 diabetes mellitus (DM) and cancer has long been postulated, but the biological mechanism responsible for this association has not been defined. In part one of this review, we discussed the epidemiological evidence for increased risk of cancer, decreased cancer survival, and decreased rates of cancer screening in diabetic patients. Here we review the risk factors shared by cancer and DM and how DM medications play a role in altering cancer risk. Hyperinsulinemia stands out as a major factor contributing to the association between DM and cancer, and modulation of circulating insulin levels by DM medications appears to play an important role in altering cancer risk. Drugs that increase circulating insulin, including exogenous insulin, insulin analogs, and insulin secretagogues, are generally associated with an increased cancer risk. In contrast, drugs that regulate insulin signaling without increasing levels, especially metformin, appear to be associated with a decreased cancer risk. In addition to hyperinsulinemia, the effect of DM medications on other shared risk factors including hyperglycemia, obesity, and oxidative stress as well as demographic factors that may influence the use of certain DM drugs in different populations are described. Further elucidation of the mechanisms behind the association between DM, cancer, and the role of DM medications in modulating cancer risk may aid in the development of better prevention and treatment options for both DM and cancer. Additionally, incorporation of DM medication use into cancer prediction models may lead to the development of improved risk assessment tools for diabetic patients.

Type 2 diabetes mellitus (DM) and cancer are common diseases that are frequently diagnosed in the same individual. An association between the two conditions has long been postulated. Here, we review the epidemiological evidence for increased risk of cancer, decreased cancer survival, and decreased rates of cancer screening in diabetic patients. The risk for several cancers, including cancers of the pancreas, liver, colorectum, breast, urinary tract, and endometrium, is increased in patients with DM. In a pooled risk analysis weighting published meta-analytic relative risk (RR) for individual cancer by differences in their incidence rates, we found a population RR of 0.97 (95 % CI, 0.75-1.25) in men and 1.29 (95 % CI, 1.16-1.44) in women. All meta-analyses showed an increased relative risk for cancer in diabetic men, except studies of prostate cancer, in which a protective effect was observed. The relationship between diabetes and cancer appears to be complex, and at present, a clear temporal relationship between the two conditions cannot be defined. DM also impacts negatively on cancer-related survival outcomes and cancer screening rates. The overwhelming evidence for lower cancer screening rates, increased incidence of certain cancers, and poorer prognosis after cancer diagnosis in diabetic patients dictates a need for improved cancer care in diabetic individuals through improved screening measures, development of risk assessment tools, and consideration of cancer prevention strategies in diabetic patients. Part two of this review focuses on the biological and pharmacological mechanisms that may account for the association between DM and cancer.

The assessment of human cancer risk from chemical exposure requires the integration of diverse types of data. Such data involve effects at the cell and tissue levels. This report focuses on the specific utility of one type of data, namely DNA adducts. Emphasis is placed on the appreciation that such DNA adduct data cannot be used in isolation in the risk assessment process but must be used in an integrated fashion with other information. As emerging technologies provide even more sensitive quantitative measurements of DNA adducts, integration that establishes links between DNA adducts and accepted outcome measures becomes critical for risk assessment. The present report proposes an organizational approach for the assessment of DNA adduct data (e.g., type of adduct, frequency, persistence, type of repair process) in concert with other relevant data, such as dosimetry, toxicity, mutagenicity, genotoxicity, and tumor incidence, to inform characterization of the mode of action. DNA adducts are considered biomarkers of exposure, whereas gene mutations and chromosomal alterations are often biomarkers of early biological effects and also can be bioindicators of the carcinogenic process.

The distinction between carcinogens with DNA-reactive and epigenetic modes of action and the application of mode-of-action considerations to risk assessment is reviewed. A bioindicator-based risk assessment strategy is described. This approach involves the use of mechanistic data to establish a "toxicologically insignificant daily intake".

Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of cancer, mainly in the context of chronic inflammation. Recent publications, however, have reported an increased risk of lymphoma in rheumatoid arthritis patients treated with immunomodulatory TNF-alpha blockers. To assess the role of TNF-alpha in neoplasia, a review of TNF-alpha effects on experimental and human cancer and the influence of anti-TNF-alpha therapy on cancer development was conducted. TNF-alpha produces a variety of cellular responses which, with sustained increased levels of activity, could either facilitate or inhibit tumorigenesis. In experimental models, most evidence supports the potential enhancement of neoplasia by TNF-alpha. The increased frequency of lymphoma that has been reported in patients with rheumatoid arthritis treated with anti-TNF-alpha therapy may reflect the severity of the disease, which could be associated with greater TNF-alpha activity. Skin cancer is also reported to be increased in some studies. Other findings, to the contrary, suggest that TNF-alpha inhibition could impede tumorigenesis. It is concluded that the presently available data do not permit a robust conclusion on the potential effects of anti-TNF-alpha therapy on the risk of human neoplasia, but reduction in neoplasia seems probable. Further investigation of this important topic is clearly warranted.

BAY 12-9566N (BAY), which is a substituted 4-biarylbutyric acid and has the properties of a matrix metalloproteinase (MMP) inhibitor, was tested in the accelerated cancer bioassay (ACB). In the ACB, three different genotoxic carcinogens were administered individually to groups of male and female Wistar rats, in initiation (IN) segments lasting 10 weeks, followed by BAY in promotion segments lasting 42 weeks, for a total of 52 weeks of treatment, followed by 12 weeks of recovery. The IN target organs in males were the liver using diethylnitrosamine (DEN), and the lungs, using N-nitrosodimethylamine (NDA), and in females, the mammary gland using 7,12-dimethylbenz(a)anthracene (DMBA). The study consisted of eight groups of 24 rats each as follows: controls (male and female), DEN alone (male), DEN/BAY (male), NDA (male), NDA/BAY (male), DMBA (female), and DMBA/BAY (female). The daily dose of BAY was 240 mg/kg in the diet, yielding a cumulative dose of 70,560 mg/kg. The cumulative doses of carcinogens were 220 mg/kg DEN, 150 mg/kg NDA, or 15 mg/kg DMBA. No significant difference in body-weight gain pattern was evident between any of the groups at 52 or 64 weeks. Rather, in males, DEN-induced hepatocellular adenomas were reduced with BAY treatment from 29% to 21% (p < 0.05) and carcinomas from 42% to 29% (p < 0.01). Also, in males, NDA-induced pulmonary adenomas were reduced with BAY treatment from 38% to 21% (p < 0.01) and carcinomas from 21% to 4% (p < 0.01). In females, DMBA-induced mammary gland adenomas were reduced from 13% to 4% (p < 0.01) and carcinomas from 54% to 42% (p < 0.05). Thus, BAY produced a consistent and significant reduction of neoplasm development in both genders in three target tissues of carcinogenicity in which neoplasms were induced by three different DNA-reactive initiators. This inhibition may be due to inhibition of MMP, leading to reduced neoplastic growth and development.

It has been known for decades that mutagenicity plays an important role in the activity of most carcinogens. This mutagenicity can result from direct damage to DNA through a chemical being DNA reactive or from indirect effects, such as through the production of oxygen radicals that then react with DNA. This article presents a set of key events whereby DNA reactivity initiates the process of carcinogenicity that leads to the subsequent mutation induction and enhanced cell proliferation that ultimately results in tumor development. This set of key events for DNA-reactive chemicals was applied to two case studies (aflatoxin B1 and dichloromethane) with the aim of assessing the utility of the Human Relevance Framework (HRF) for this class of chemicals. The conclusions were that the HRF was a viable approach for the use of mechanistic data for DNA-reactive chemicals obtained from both laboratory animals and human cells in vivo and in vitro for predicting human carcinogenicity. In the case of aflatoxin B1, the HRF could be used to predict that carcinogenicity in humans was a likely outcome. In contrast, the HRF predicted that the human carcinogenic potential of dichloromethane was at best less likely than in rodents; this conclusion was supported by the available epidemiological data.

The synthetic monocyclic phenolics (MPs), acetaminophen (APAP), butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT) are antimutagenic or anticarcinogenic against a diversity of chemical carcinogens affecting a variety of tissues in experimental animals. In studies in this laboratory of the anticarcinogenicity of MPs, the focus has been on delineating efficacy at low levels of MPs that do not elicit adaptive or toxic responses. To accomplish this, we are studying anticarcinogenicity against the neoplastic initiating activity of lower doses of carcinogens than have previously been studied and which are closer to human environmental exposures. In these studies, we have investigated anticarcinogenicity of BHT against liver cancer in rats induced by either 2-acetylaminofluorene (AAF) or aflatoxin B1 (AFB1) and anticarcinogenicity of APAP against colon cancer induced in rats by 3,2'-dimethyl-4-aminobiphenyl (DMAB). BHA and BHT at 100-125 ppm in the diet inhibited the initiation phase of AAF and AFB1 hepatocarcinogenesis and therefore may act intracellularly to block effects of the carcinogen. Likewise, with APAP in colon anticarcinogenicity, at 1000 ppm it reduced DNA binding and exerted a cytoprotective effect against DMAB. Thus, APAP also shows evidence of producing a blocking effect. We conclude that these MPs appear to be anticarcinogenic through a mechanism different from that of most other chemopreventive agents, possibly involving interception of the reactive chemical species of the carcinogen. Accordingly, they have promise as cancer prophylactics, including in combination with agents operating through other mechanisms.

The distinction between DNA-reactive and epigenetic carcinogens and their roles in oncogenesis is reviewed. An approach to cancer hazard assessment based upon mechanisms is described.

Diet can play a major role in cancer prevention. The international differences in cancer incidence are largely accounted for by lifestyle practices that include nutrition, exercise, and alcohol and tobacco use. About 50% of cancer incidence and 35% of cancer mortality in the U.S., represented by cancers of the breast, prostate, pancreas, ovary, endometrium, and colon, are associated with Western dietary habits. Cancer of the stomach, currently a major disease in the Far East, relates to distinct, specific nutritional elements such as excessive salt intake. For these cancers, information is available on possible initiating genotoxic factors, promoting elements, and prophylactic agents. In general, the typical diet in the United States contains low levels of the potent carcinogenic agents, heterocyclic amines, formed during the cooking of meats. It provides only about half the potent appropriate fiber intake and is high in calories. About twice as many calories as would be desirable come from fat, certain kinds of which enhance the development of cancers. Other foods with functional properties, such as soy products and tea, can be beneficial. To achieve reduction in risk of certain cancers, diet must be optimized, primarily to reduce caloric intake and the fat component. The latter should be 20% or less of total caloric intake and fiber should be increased to 25-35 g per day for adults. One approach to achieving these goals is the Fiber First Diet, a diet designed around adequate fiber intake from grains, especially cereals, vegetables, legumes, and fruits, which thereby reduces both calorie and fat intake. Such dietary improvements will not only reduce cancer and other chronic disease risks, but will contribute to a healthy life to an advanced age. A corollary benefit is a lower cost of medical care.

Chronic exposure to high doses of phenobarbital (PB) causes hepatocellular adenomas in both mice and rats and hepatocellular carcinomas in some strains of mice. Long-term PB therapy has not been found to cause human tumors. PB is not DNA reactive, and most genotoxicity tests have yielded negative results. PB has been extensively studied as an epigenetic, rodent liver tumor promoter. At exposures causing rodent liver tumors, PB has measurable effects on hepatocytes: PB inhibits cell-to-cell communication; PB induces enzymes, including P450 cytochromes; PB stimulates proliferation and inhibits apoptosis of hepatocytes in neoplastic foci. Threshold exposures for some of these endpoints coincide with the threshold exposure for tumorigenesis.

Vinyl chloride produced several tumor types among species. Angiosarcoma of the liver is found in all tested species, including humans with occupational exposures. Vinyl chloride is biotransformed by CYP2E1 to DNA-reactive chloroethylene oxide producing cyclic etheno adducts, which are mutagenic. The dose-response for angiosarcoma of the liver formation in rodents is supralinear, which is consistent with saturation of metabolic activation, and the tumor rate in humans at occupational exposure levels is similar to that for equivalent exposures in rodents.

The aromatic amine 2-acetylaminofluorene (AAF) produced neoplasms in diverse target organs of many animal species. AAF was DNA-reactive after N-hydroxylation by CYP1A2 in the liver and nitrenium ion formation at the target site. In mouse bladder, AAF-DNA adducts were proportional to dose. An epigenetic component for tumor formation was also present since tumor incidence and hyperplasia showed a threshold dose and decreased following discontinuation of AAF exposure. In contrast, both adduct and tumor formation in the liver were proportional to dose, and discontinuation of AAF did not reduce tumor incidence.

The aromatic amine benzidine (BZ) has produced various tumors, including liver tumors, in mice, rats and hamsters. BZ forms DNA adducts in rodent liver, and it is positive in most genotoxicity tests. Only bladder tumors are produced in dogs and in humans who have been occupationally exposed, possibly related to the slow rate of liver detoxification by acetylation, allowing activation of BZ or its metabolites in urine. Despite these differences, risk assessment for humans, based on liver tumors in mice, was approximately predictive of the incidence of bladder tumors observed in industrially exposed humans.

Exposures of rodents to airborne formaldehyde (FA) produce dose-related toxicity, enhanced cell proliferation and squamous cell carcinomas in the nasal passages. The mechanism of FA-induced tumor formation involves DNA-protein crosslink formation and enhanced cell proliferation secondarily to cytotoxicity. The mucociliary apparatus and glutathione protect against low-dose FA-induced effects. Consequently, the mechanistic information is consistent with a very sublinear dose-response curve for tumor formation. The sublinear dose-response of nasal DNA-protein crosslinks levels in rodents and monkeys has been used in the risk assessment of FA.

Butylated hydroxyanisole (BHA), at high doses, has been found to induce forestomach squamous cell carcinomas in rodents, but not glandular cell or other types of neoplasms. BHA is not DNA-reactive, and the epigenetic mechanism of tumor formation involves cytotoxicity and enhanced cell proliferation, which are mostly reversible. Humans lack a forestomach and, therefore, are predicted to be much less sensitive than rodents to the effects of BHA. Also, the exposures to humans are well below doses producing the epigenetic effects in rodents. It has been concluded that BHA is an agent whose rodent carcinogenicity is conditionally species-specific and not relevant to humans.

N-Nitrosodiethylamine (NDEA) is DNA reactive after bioactivation and produces tumors in every animal species tested. Bioactivation is effected by several P450 isozymes including CYP2E1, which is ethanol inducible. Tumor formation in rat liver was proportional to O4-ethyldeoxythymidine formation in DNA, which was generally proportional to NDEA dose. At low doses in the 0.033-1.1 ppm range, the dose-response for esophageal tumor formation was sublinear, possibly due to DNA repair. Although no epidemiological studies have specifically evaluated NDEA, sufficient exposure levels would be expected to cause cancer in humans.

The Environmental Health and Safety Council of the American Health Foundation has examined current estimates of cancer risks associated with the presence of asbestos-containing materials (ACM) in public buildings. The Council finds that even complete removal of asbestos from all of these buildings will provide no measurable benefit to public health. The removal of nonfriable ACM only can be postulated to protect the public against a small hypothetical risk that cannot be measured epidemiologically. Moreover, examination of the assumptions used in the risk assessment calculations leads to the conclusion that these small calculated risks are likely to represent overestimates. In recent surveys, the measured asbestos levels in indoor air cast some doubt on whether occupant exposure to asbestos levels are contributed to significantly by ACM even when some of the material is friable or in bad condition. Furthermore, the models used for cancer risk estimates assume no threshold level for cancer and conclude that any exposure is carcinogenic. This may be unjustified in light of information on the mechanisms for some asbestos-caused disease. Based on the best available data, it is very unlikely that cancer will result from indoor asbestos exposure, especially where ACM is well maintained.

The potential relationships between aging and cancer have received considerable attention in the scientific literature in recent years. While it is clear that the rates of most types of cancer increase with advancing age and that both the processes of aging and those of cancer are time dependent, an unequivocal relationship between the etiology of cancers and the mechanistic processes of aging has yet to be established. This article discusses the potential causal relationships between the processes of aging and the etiologies of most cancers.

The use of risk assessment by different governments and agencies varies widely in theory and practice. One major difference is in the consideration given to the biologic mechanisms of cancer causation. U.S. government agencies consider all animal carcinogens to be presumptive human carcinogens and to act in a similar manner without regard to available knowledge on the mechanism of carcinogenicity. Accordingly, standardized models that give linear dose-response at low doses without a threshold are used for predicting human cancer risk from animal studies. Accumulated evidence on biologic mechanisms reveals that some animal carcinogens should not cause cancer in humans at low exposures; other should not at any exposure level. The Netherlands has included such considerations in their cancer classification and risk assessment process. Other governments evaluate each chemical on a case-by-case basis or do not use standardized risk assessment methods for regulatory decisions. To address these issues, the American Health Foundation has convened an International Expert Panel on Carcinogen Risk Assessment.

Cancer accounts for 22 percent of all deaths in the United States and it remains the second leading cause of death across this country. The majority of these deaths are cancers of six major sites, i.e., lung, prostate, large intestine, urinary bladder, uterus and female breast. Experimental, clinical and epidemiological research indicate that approximately three-fourths of all cancer deaths are attributable to lifestyle factors. For this reason some specific cancers are, indeed, preventable. With a few straightforward changes in lifestyle behaviors such as smoking cessation, increasing fiber content and decreasing fat content of diet, reductions in certain cancers can be attained. National cancer prevention priorities should center around efforts to control and/or reduce those cancers that are pervasive and for which the evidence for preventive potential is indisputable.

The antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) were fed in the diet to male F344 rats in two chronic feeding studies. In one study, feeding BHT for 76 wk at concentrations ranging from 100 to 6000 ppm produced no increase in neoplasms at any site. In a second study, feeding 12,000 ppm BHT for 110 wk had no neoplastic effect at any site, whereas feeding BHA at 12,000 ppm resulted in a small increase in squamous cell papillomas of the non-glandular squamous portion of the stomach.

Liver cultures offer several special advantages for the study of chemical carcinogenesis in cell culture; these include the sensitivity of the cells to procarcinogens requiring enzymatic activation, the epithelial nature of the cells which qualifies them as a model for epithelial carcinogenesis, and the opportunity to compare culture findings with the extensive information available on the effects of carcinogens on liver. The actions of chemical carcinogens have been studied in primary and long-term rat liver cell cultures. A variety of procarcinogens induced DNA repair in primary cultures, indicating the usefulness of this system for studying carcinogen metabolism, the interaction of carcinogens with DNA, and the repair of carcinogen-induced DNA damage. In addition, this system may provide a screen for chemical carcinogens in which metabolic activation occurs in the target cell. Carcinogen treatment of long-term cultures initiated from the primary cultures resulted in morphologic transformation accompanied by an increased growth in soft agar and an increased frequency of 8-azaguanine-resistant mutants. Cultures with a high fraction of cells in S phase were found to be most sensitive to the induction of 8-azaguanine-resistant mutants.

The occurrence of cancer involves the effects of two types of agents: those that alter the genetic material to give rise to neoplasms and others that modulate tumor development through epigenetic effects. In the etiology of some of the major cancers in the North American population--cancers of the upper alimentary tract, stomach, large bowel, pancreas, breast, and prostate--food can contribute elements of both types. Thus, dietary modification has the potential both to prevent the occurrence of cancers at these sites and to control recurrences in treated patients.

Xenobiotics enhance and inhibit chemical carcinogenesis by a variety of mechanisms through effects at different steps in the overall process, including modification of carcinogen availability, biotransformation, reactive interactions, expression of cellular alteration, and neoplastic development. Importantly, the same agent can be both an enhancer or an inhibitor depending upon the circumstance of its interaction with the carcinogen.