Metabolic dysregulation and cancer risk program (MeDOC): a transdisciplinary approach to Obesity-Associated cancers.

With the escalating prevalence of obesity, the association between obesity and cancer is a growing public health concern. Obesity will soon surpass tobacco smoking as the most important preventable cause of cancer. Obesity-driven mechanisms can alter cell functions to induce metabolic changes, chronic inflammation, and insulin resistance that are believed to contribute to cancer risk and development; yet the specific underlying biological mechanisms of obesity-related cancer development are largely unknown. The Metabolic Dysregulation and Obesity Cancer Risk (MeDOC) Program is a trans-NCI research program supported by the Division of Cancer Control and Population Sciences, the Division of Cancer Biology, the Division of Cancer Prevention, and the Center to Reduce Cancer Health Disparities. The overall purpose of the MeDOC Program is to advance our understanding of the underlying mechanisms that connect obesity, metabolic dysregulation, and increased obesity cancer risk, as well as identify markers that will enhance cancer risk prediction, improve screening for high-risk individuals, and identify targets for preventive and therapeutic interventions for cancer interception or treatment. This report describes the funded research projects, the Coordinating Center, and the goals of the MeDOC Program.

Stakeholder assessment of the evidence for cancer genomic tests: insights from three case studies.

PURPOSE: Insufficient evidence on the net benefits and harms of genomic tests in real-world settings is a translational barrier for genomic medicine. Understanding stakeholders' assessment of the current evidence base for clinical practice and coverage decisions should be a critical step in influencing research, policy, and practice. METHODS: Twenty-two stakeholders participated in a workshop exploring the evidence of genomic tests for clinical and coverage decision making. Stakeholders completed a survey prior to and during the meeting. They also discussed if they would recommend for or against current clinical use of each test. RESULTS: At baseline, the level of confidence in the clinical validity and clinical utility of each test varied, although the group expressed greater confidence for epidermal growth factor receptor mutation and Lynch syndrome testing than for Oncotype DX. Following the discussion, survey results reflected even less confidence for Oncotype DX, intermediate levels of confidence for [corrected] epidermal growth factor receptor mutation testing and stable levels of confidence [corrected] for Lynch syndrome testing. The majority of stakeholders would consider clinical use for all three tests, but under the conditions of additional research or a shared clinical decision-making approach. CONCLUSION: Stakeholder engagement in unbiased settings is necessary to understand various perspectives about evidentiary thresholds in genomic medicine. Participants recommended the use of various methods for evidence generation and synthesis.

Use of Oncotype DX in Women with Node-Positive Breast Cancer.

Women with early stage breast cancer frequently receive adjuvant chemotherapy to prevent recurrence; however, not all patients benefit. Recently, gene expression marker panels, such as Oncotype DX, that may better predict risk of breast cancer recurrence have become commercially available and are being used to guide treatment decisions. Oncotype DX analyzes the expression of 21 genes within a tumor to determine a recurrence score that corresponds to a specific likelihood of breast cancer recurrence within 10 years of the initial diagnosis, as well as response to adjuvant treatment. We examined the published literature on the analytic validity, clinical validity, and clinical utility of Oncotype DX in guiding adjuvant treatment decisions in women with lymph node-positive breast cancer.

Use of epidermal growth factor receptor mutation analysis in patients with advanced non-small-cell lung cancer to determine erlotinib use as first-line therapy.

Lung cancer is the second most common cancer and the leading cause of cancer-related deaths in the United States. Moreover, advanced non-small-cell lung cancer (NSCLC) is considered an incurable disease and current treatment approaches provide marginal improvement in overall survival at the expense of substantial morbidity and mortality, highlighting the need for new, less toxic treatment approaches. Tyrosine kinase inhibitors, such as erlotinib (Tarceva®), have been developed and approved as maintenance, second- and third-line treatment options in unselected advanced NSCLC patients (2, 15). However, subgroup analyses from the initial clinical trials consistently showed that patients with epidermal growth factor receptor (EGFR) mutations who received erlotinib had higher rates of response and better progression-free and overall survival, leading to clinical trials specifically focused on the use of tyrosine kinase inhibitors as first-line therapy in these patients. We examined the published literature on the analytic validity, clinical validity, and clinical utility of EGFR mutational testing in guiding first-line therapy use of erlotinib to treat advanced NSCLC and we briefly summarized the current lung cancer screening guidelines. The primary goal was to provide a basic overview of EGFR mutational testing and use of erlotinib as first-line therapy and identify gaps in knowledge and evidence that affect the recommendation and adoption of the test in advanced NSCLC treatment management strategies.

Overview of the institute of medicine's committee search strategy and review process for gulf war and health: long-term consequences of traumatic brain injury.

OBJECTIVES: To examine the strength of the peer-reviewed literature on the evidence for an association between traumatic brain injury (TBI) and long-term health outcomes using the association categories established and used by previous Institute of Medicine Committees on Gulf War and Health. The health effects that were evaluated were neurologic, cognitive, social functioning, psychiatric, and other (eg, brain tumor, mortality) outcomes. PARTICIPANTS: Not applicable. DESIGN: A comprehensive search using Medline and PsycINFO databases and a critical review of the peer-reviewed literature on human TBI published between 1960 and 2008. PRIMARY MEASURES: Not applicable. RESULTS: A total of 14302 citations were identified, of which 1933 were reviewed for further scientific merit; of these, 152 studies met the inclusion/exclusion criteria that form the basis for the findings and recommendations contained in this topical issue. CONCLUSION: Based on this review, the committee concluded that there was sufficient evidence of a causal relationship for 3 health outcomes with TBI, sufficient evidence of an association for 13 outcomes, limited/suggestive evidence of an association for 10 outcomes, and inadequate/insufficient evidence to determine whether an association exists for 10 outcomes.

Risk of non-Hodgkin's lymphoma and family history of lymphatic, hematologic, and other cancers.

BACKGROUND: An elevated risk of developing non-Hodgkin's lymphoma (NHL) has been associated with a family history of NHL and several other malignancies, but the magnitude of risks and mechanisms are uncertain. METHODS: We used self-reported family history data from a recent multicenter U.S.-based case-control studies of NHL to evaluate familial aggregation of NHL with various hematolymphoproliferative and other cancers. Estimates of familial aggregation were obtained as hazard ratios (HR) that compare incidence of different cancers in first-degree relatives of NHL cases with that in the first-degree relatives of NHL controls. Limitations of the study included low participation rates (76% for cases and 52% for controls) and potential differential accuracy of recall. RESULTS: Risk of NHL was elevated in relatives of NHL cases [HR, 2.9; 95% confidence interval (95% CI), 0.95-8.53]; the aggregation seems to be stronger for siblings (HR, 7.6; 95% CI, 0.98-58.8) and for male relatives (HR, 6.2; 95% CI, 0.77-50.0). Risk of Hodgkin's lymphoma seems to be also elevated among relatives of early-onset (<50 years) NHL cases (HR, 3.2; 95% CI, 0.88-11.6). Evaluation of family history of other cancers provided modest evidence for an increased risk of melanoma of the skin (HR, 2.9; 95% CI, 1.08-7.75), pancreatic cancer (HR, 2.1; 95% CI, 0.96-4.43), stomach cancer (HR, 1.8; 95% CI, 0.91-3.63), and prostate cancer (HR, 1.3; 95% CI, 0.87-1.99). CONCLUSIONS: These results are consistent with previous findings of familial aggregation of NHL, Hodgkin's lymphoma, and a few other cancers. The pattern of male-specific and sibling-specific familial aggregation of NHL we observed, if confirmed, may shed new light on the possible mechanisms that underlie familial aggregation of the disease.

A genome scan of 18 families with chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) accounts for about 30% of all leukaemias and is most prevalent in older individuals. Significant familial aggregation has been demonstrated but the mode of inheritance is unknown. Recurrent cytogenetic abnormalities are frequently found in CLL tumour cells but no susceptibility genes have been confirmed. We have collected clinical data and biospecimens on families ascertained for having at least two living patients with CLL. The current study included DNA samples from 94 individuals (38 affected patients) in 18 families. We have carried out a genome scan using the ABI 28-panel medium density linkage mapping set (average spacing of 10 cM and average heterozygosity of 80%). Genotypes for 359 markers were scored. Multipoint limit of detection (lod) scores were calculated, assuming both dominant and recessive inheritance and allowing for increased penetrance with age and genetic heterogeneity. Non-parametric linkage scores were also calculated. Lod scores of 1.0 or greater were found on regions of chromosomes 1, 3, 6, 12, 13 and 17, but none of these loci achieved statistical significance. Four of these six regions (6q, 13q, 12 and 17p) coincide with areas where cytogenetic abnormalities are frequently observed in CLL tumour cells and are, therefore, strong candidate regions for containing germ line changes.

B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of familial B-cell chronic lymphocytic leukemia.

BACKGROUND: Among all hematologic malignancies, B-cell chronic lymphocytic leukemia (BCLL) has the highest familial clustering (three- to sevenfold increase), strongly suggesting a genetic component to its etiology. Familial BCLL can be used as a model to study the early pathogenesis of this disease. METHODS: We examined nine kindreds from the National Cancer Institute's Familial BCLL Registry, consisting of 19 affected members with BCLL and 33 clinically unaffected first-degree relatives. Flow cytometric immunophenotyping to detect a B-cell monoclonal lymphocytosis (BCML) was performed. Monoclonality was confirmed by polymerase chain reaction analysis of whole blood DNA. Cell cycle analysis for aneuploidy was conducted. RESULTS: In all affected individuals, we observed the classic BCLL CD5/CD19/CD20/CD23 immunophenotypic patterns. Six of the 33 unaffected individuals (18%) had evidence of BCML. Additional individuals (13/33, 39%) showed some other abnormality, whereas 14 individuals (42%) were normal. Based on an estimated prevalence of 0.7% for BCML in the general population, the finding of six subjects (18%) with clonal abnormalities in this relatively modest sample was significantly greater than expected (i.e., 18% vs. 0.7%, P < 5.7 x 10(-9)). CONCLUSIONS: Individual components of BCML and other B-cell abnormalities were observed in almost half of the apparently unaffected individuals. Our findings suggested that BCML may be an early detectable abnormality in BCLL. The spectrum of some of these observed abnormalities suggested the involvement of different B-cell subpopulations or different pathways in clonal evolution. Population-based, longitudinal studies will be required to determine the incidence of BCML and other B-cell abnormalities and their relation to disease progression in BCLL and other closely related B-cell lymphoproliferative disorders.

Polymorphisms in steroid hormone pathway genes and mammographic density.

Mammographic density has been linked with exposure to endogenous and exogenous steroid hormones, and increased breast cancer risk. Variation in breast density may be due, in part, to polymorphisms in steroid hormone biosynthesis, metabolism and signaling genes. We conducted cross-sectional analyses within the Nurses' Health Study (n = 538), to investigate variation in mammographic breast density, by 10 polymorphisms in eight candidate genes (CYP17, CYP19, CYP1A1, CYP1B1, COMT, UGT1A1, AR, and AIB1). Breast density was assessed using a computer-assisted technique. We evaluated whether associations between variant alleles of these genes and breast density differed by menopause and postmenopausal hormone (PMH) use. Polymorphisms in CYP17, CYP19, CYP1B1, COMT CYP1A1, or AR were not associated consistently with breast density among premenopausal or postmenopausal women. Premenopausal women with the 7/7 UGT1A1 genotype had lower breast density (difference compared to the 6/6 genotype of: -16.5% density; p = 0.04). In contrast, postmenopausal women with the 7/7 UGT1A1 genotype had greater breast density compared to those with the 6/6 genotype (+6.2% density; p = 0.05); this association was strongest among current PMH users (+13.0% density; p = 0.03). In analyses limited to postmenopausal women, breast density was also greater among women carrying short AIB1 alleles (< or = 26 glutamine repeats; +4.1% density; p = 0.04). Most of the variants in the candidate breast cancer genes evaluated in this study are not strong predictors of breast density. However, our findings of differences in associations for UGT1A1 and AIB1 genotypes with breast density by menopausal status needs additional corroboration.

Polychlorinated biphenyls, cytochrome P450 1A1, and breast cancer risk in the Nurses' Health Study.

There is concern that exposures to the environmental chemicals polychlorinated biphenyls (PCBs) may contribute to breast cancer risk. An individual's susceptibility to the effects of PCBs may be partially determined by polymorphisms in the gene encoding the biotransformation enzyme cytochrome P450 1A1 (CYP1A1). PCB exposure induces CYP1A1 activity, and PCBs themselves or other xenobiotics can be metabolized to carcinogenic intermediates in the presence of the variant genotype. A previous case-control study provided evidence of an interaction between high exposures to PCBs and the CYP1A1-exon 7 polymorphism (the A to G transition at nucleotide 4889), leading to a significant increase in postmenopausal breast cancer risk. We examined the interaction of PCBs with the CYP1A1-MspI (the T to C transition at nucleotide 6235) and exon 7 polymorphisms among 367 breast cancer case-control pairs (293 postmenopausal pairs) in the Nurses' Health Study. Although there was no independent association of either the CYP1A1 variants or PCBs with breast cancer risk, the relative risk among the postmenopausal women with plasma PCB levels in the highest third of the distribution in the control group and at least one exon 7 variant allele compared with women who were homozygous for the wild-type allele and who had PCB levels in the lowest third was 2.78 (95% confidence interval, 0.99-7.82). The majority of studies have concluded that exposure to PCBs is unlikely to be a major cause of breast cancer, but these findings indicate that further studies of genetically susceptible populations are warranted.

Association of prostate cancer with rapid N-acetyltransferase 1 (NAT1*10) in combination with slow N-acetyltransferase 2 acetylator genotypes in a pilot case-control study.

N-acetyltransferase-1 (NAT1) and N-acetyltransferase-2 (NAT2) are important in the metabolism of aromatic and heterocyclic amine carcinogens that induce prostate tumors in the rat. We investigated the association of genetic polymorphisms in NAT1 and NAT2, alone and in combination, with human prostate cancer. Incident prostate cancer cases and controls in a hospital-based case-control study were frequency-matched for age, race, and referral pattern. The frequency of slow acetylator NAT1 genotypes (NAT1*14, *15, *17) was 5.8% in controls but absent in cases. In contrast, in comparison with all other NAT1 genotypes the putative rapid acetylator NAT1 genotype (NAT1*10) was significantly higher in prostate cancer cases than controls (OR, 2.17; 95% CI, 1.08-4.33; P = 0.03). Combinations of NAT1*10 with NAT2 slow acetylator genotypes (OR, 5.08; 95% CI, 1.56-16.5; P = 0.008) or with NAT2 very slow (homozygous NAT2*5) acetylator genotypes (OR, 7.50; 95% CI, 1.55-15.4; P = 0.016) further increased prostate cancer risk. The results of this small pilot study suggest increased susceptibility to prostate cancer for subjects with combinations of NAT1*10 and slow (particularly very slow) NAT2 acetylator genotypes. This finding should be investigated further in larger cohorts and in other ethnic populations.

Telomere length and heavy-chain mutation status in familial chronic lymphocytic leukemia.

We examined whether telomere lengths of peripheral blood mononuclear cells are associated with immunoglobulin gene usage in 21 familial chronic lymphocytic leukemia (CLL) patients. Subjects with unmutated V genes tended to have shorter telomeres than those with somatic mutations, especially after adjusting for age. Unlike V(H) mutation status, telomere length was not predictive for survival. Our results suggest that telomere length is associated with V(H) gene mutation status and provides further evidence that the biological basis of familial B-CLL is similar to that of sporadic patients.

Genetic polymorphisms in heterocyclic amine metabolism and risk of colorectal adenomas.

High red meat intake has been linked with an increased risk of colorectal cancer and adenomas. During high temperature cooking of red meats, heterocyclic amines (HCAs) are generated; however, to be carcinogenic, they must be metabolized by enzymes including cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 1 (NAT1) and/or N-acetyltransferase 2 (NAT2). We have conducted a clinic-based case-control study of colorectal adenomas that focused on assessment of exposure to HCAs (estimated by use of a HCA database and meat cooking module) and modification of these exposures by genetic factors. We have previously reported that intake of MeIQx was associated with an increased risk of colorectal adenomas [overall association at 80th percentile, > 27.00 ng/day: odds ratio (OR) = 2.68, 95% confidence interval (CI) 1.58-4.55]. Here, we report our evaluation of whether variation in CYP1A2, NAT1 and/or NAT2 modify the association between HCAs and colorectal adenoma formation in 146 cases and 228 frequency-matched controls. The NAT1*10 allele was associated with a nonsignificant increased risk of colorectal adenomas (OR = 1.43; 95% CI 0.86-2.36). Further, when we analysed 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intake as a categorical variable, we observed a six-fold increase in adenoma risk among rapid NAT1 acetylators who consumed more than 27 ng a day (OR = 6.50; 95% CI 2.16-19.7), whereas among slow NAT1 acetylators, the increase in risk was two-fold (OR = 2.32; 95% CI 1.12-4.81). While suggestive, the results were not significantly different from each other on either an additive or multiplicative scale. In contrast, NAT2 genotype and CYP1A2 and NAT2 hepatic activity measured by caffeine urinary metabolites were not associated with adenoma risk, although an increase in risk with rapid CYP1A2 activity could not be ruled out (OR = 1.46; 95% CI 0.76-2.81). Moreover, there was no evidence that the effect of MeIQx was enhanced among subjects in any subgroup defined by variation in these measures. These results are compatible with the hypothesis that high HCA exposure is associated with an increased risk of colorectal adenomas, particularly in genetically susceptible subgroups. Further study of larger populations is needed to confirm and extend these observations.