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1.  Precursors to Lymphoproliferative Malignancies 
We review monoclonal B-cell lymphocytosis (MBL) as a precursor to chronic lymphocytic leukemia and monoclonal gammopathy of undetermined significance (MGUS) as a precursor to plasma cell disorders. These conditions are present in the general population and increase with age. These precursors aggregate with lymphoproliferative malignancies in families suggesting shared inheritance. MBL and MGUS may share some of the same risk factors as their related malignancies but data are limited. While these conditions are characterized by enhanced risk for the associated malignancy, the majority of individuals with these conditions do not progress to malignancy. A key focus for current work is to identify markers that predict progression to malignancy.
PMCID: PMC3616401  PMID: 23549397
2.  Dysplastic Nevi and Melanoma 
Dysplastic nevi (DN) are described as being on a continuum between common acquired nevi and melanoma because they are morphologically and biologically intermediate between these two entities. Since initially being reported as histologic lesions observed in melanoma-prone families, there has been considerable debate about the definition of dysplastic nevi, the histologic and clinical criteria used to define them, and their biological importance. Their role as precursor lesions for melanoma is not their primary role in their relationship to melanoma because of the rarity of transformation of any individual nevus to a melanoma. Although there is still no single universally agreed upon histologic or clinical definition or even name for these nevi, dysplastic nevi should be considered important because of their association with an increased risk for melanoma.
PMCID: PMC3616416  PMID: 23549396
3.  Acrylamide Hemoglobin Adduct Levels and Ovarian Cancer Risk: a nested case-control study 
Acrylamide is a probable human carcinogen formed during cooking of starchy foods. Two large prospective cohort studies of dietary acrylamide intake and ovarian cancer risk observed a positive association, although two other studies reported no association.
We measured acrylamide exposure using red blood cell acrylamide and glycidamide hemoglobin adducts among women in two large prospective cohorts: the Nurses’ Health Study and Nurses’ Health Study II. Between blood collection and 2010, we identified 263 incident cases of epithelial ovarian cancer, matching two controls per case. We used logistic regression models to examine the association between acrylamide exposure and ovarian cancer risk, adjusting for matching factors, family history of ovarian cancer, tubal ligation, oral contraceptive use, body mass index (BMI), parity, alcohol intake, smoking, physical activity, and caffeine intake.
The multivariate-adjusted relative risk (RR) of ovarian cancer comparing the highest versus lowest tertile of total acrylamide adducts was 0.79 (95% CI: 0.50–1.24, P trend = 0.08). The comparable RR of ovarian cancer among non-smokers at blood draw was 0.85 (95% CI: 0.57–1.27, P trend =0.14). The association did not differ by tumor histology (serous invasive versus not), P for heterogeneity=0.41. Individual adduct types (acrylamide or glycidamide) were not associated with risk.
We observed no evidence that acrylamide exposure as measured by adducts to hemoglobin is associated with an increased risk of ovarian cancer.
Our finding indicates that acrylamide intake may not increase risk of ovarian cancer.
PMCID: PMC3617048  PMID: 23417989
acrylamide; ovarian cancer; hemoglobin adducts; epidemiology; prospective
4.  HOXB13 Mutation and Prostate Cancer: Studies of Siblings and Aggressive Disease 
Recent work detected for the first time a high-risk prostate cancer mutation, in homeobox B13 (HOXB13) among European-Americans.
We further evaluated this G84E missense mutation (rs138213197) in two genetic association studies of prostate cancer: a family-based study of brothers and a case-control study of more aggressive disease (N=2,665 total). We then calculated overall impact of this mutation by pooling all published studies of European-Americans.
In our studies the mutation was found exclusively among men with prostate cancer (carrier frequency=1.48%) or unaffected brothers of cases carrying the mutation (frequency=0.34%), and carrying the mutation gave an odds ratio for disease=4.79 (P=0.01). The G84E mutation was more common among men with an earlier age of onset (≤55 years) or a family history of prostate cancer. We also observed for the first time an African-American case carrying the G84E mutation, although at HOXB13 both of his chromosomes were of European-American ancestry. The pooled analysis also indicated that carrying the G84E mutation results in an almost five-fold increase in risk of prostate cancer (P=3.5×10−17), and this risk is even higher among cases with an early age of prostate cancer onset (≤55 years) or a family history of disease: a test of heterogeneity across these strata gives P<1×10−5.
The HOXB13 mutation substantially increases risk of early onset, familial prostate cancer in European-American men. Impact: Testing for the G84E mutation in men with a positive family history may help distinguish those who merit more regular screening for prostate cancer.
PMCID: PMC3617049  PMID: 23396964
Familial Cancer; Genetic Association; Homeobox; Functional Mutation; Prostate Cancer
5.  A Review of NCI’s Extramural Grant Portfolio: Identifying Opportunities for Future Research in Genes and Environment in Cancer 
Genetic and environmental factors jointly influence cancer risk. The National Institutes of Health (NIH) has made the study of gene-environment (GxE) interactions a research priority since the year 2000.
To assess the current status of GxE research in cancer, we analyzed the extramural grant portfolio of the National Cancer Institute (NCI) from Fiscal Years 2007 to 2009. Publications attributed to selected grants were also evaluated.
From the 1,106 research grants identified in our portfolio analysis, a random sample of 450 grants (40%) was selected for data abstraction; of these, 147 (33%) were considered relevant. The most common cancer type was breast (20%, n=29), followed by lymphoproliferative (10%, n=14), colorectal (9%, n=13), melanoma/other skin (9%, n=13), and lung/upper aero-digestive tract (8%, n=12) cancers. The majority of grants were studies of candidate genes (68%, n=100) compared to genome-wide association studies (GWAS) (8%, n=12). Approximately one third studied environmental exposures categorized as energy balance (37%, n=54) or drugs/treatment (29%, n=43). From the 147 relevant grants, 108 publications classified as GxE or pharmacogenomic were identified. These publications were linked to 37 of the 147 grant applications (25%).
The findings from our portfolio analysis suggest that GxE studies are concentrated in specific areas. There is room for investments in other aspects of GxE research, including, but not limited to developing alternative approaches to exposure assessment, broadening the spectrum of cancer types investigated, and performing GxE within GWAS.
This portfolio analysis provides a cross-sectional review of NCI support for GxE research in cancer.
PMCID: PMC3617050  PMID: 23462918
Gene-Environment Interaction; Grants
6.  Relationship of Early Onset Baldness to Prostate Cancer in African-American Men 
Early onset baldness has been linked to prostate cancer (CaP), however, little is known about this relationship in African Americans (AA) who are at elevated CaP risk.
We recruited 219 AA controls and 318 AA CaP cases. We determined age-stratified associations of baldness with CaP occurrence and severity defined by high stage (T3/T4) or high grade (Gleason 7+.) Associations of androgen metabolism genotypes (CYP3A4, CYP3A5, CYP3A43, AR-CAG, SRD5A2 A49T, and SRD5A2 V89L), family history, alcohol intake, and smoking were examined by baldness status and age group by using multivariable logistic regression models.
Baldness was associated with odds of CaP (OR=1.69, 95% CI=1.05–2.74). Frontal baldness was associated with high stage (OR=2.61, 95% CI=1.10–6.18) and high grade (OR=2.20, 95% CI=1.05–4.61) tumors. For men diagnosed less than age 60, frontal baldness was associated with high stage (OR=6.51, 95% CI=2.11–20.06) and high grade (OR=4.23, 95% CI=1.47–12.14). We also observed a suggestion of an interaction among smoking, median age and any baldness (p=0.02).
We observed significant associations between early onset baldness and CaP in AA men. Interactions with age and smoking were suggested in these associations. Studies are needed to investigate the mechanisms influencing the relationship between baldness and CaP in AA.
AA men present with unique risk factors including baldness patterns that may contribute to CaP disparities.
PMCID: PMC3617056  PMID: 23532004
Prostate Cancer; African Americans; Baldness; Genotypes; Smoking
7.  The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race and sex 
Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine and carcinogen exposure. However a given cotinine level may not represent the same tobacco exposure; for example, African Americans have higher cotinine levels than Caucasians after controlling for exposure.
Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal which are both mediated by the enzyme CYP2A6. Since CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genotype, their effect on cotinine formation and removal were measured in non-smoking Caucasians (Study 1, n=181) infused with labeled nicotine and cotinine. The findings were then extended to ad libitum smokers (Study 2, n=163).
Study 1: Reduced CYP2A6 activity altered cotinine formation less than cotinine removal resulting in ratios of formation to removal of 1.31 and 1.12 in CYP2A6 reduced and normal metabolizers (P=0.01), or 1.39 and 1.12 in males and females (P=0.001), suggesting an overestimation of tobacco exposure in slower metabolizers. Study 2: Cotinine again overestimated tobacco and carcinogen exposure by ≥25% in CYP2A6 reduced metabolizers (≈2 fold between some genotypes) and in males.
In people with slower, relative to faster, CYP2A6 activity cotinine accumulates resulting in substantial differences in cotinine levels for a given tobacco exposure.
Cotinine levels may be misleading when comparing those with differing CYP2A6 genotypes within a race, between races with differing frequencies of CYP2A6 gene variants (i.e. African Americans have higher frequencies of reduced function variants contributing to their higher cotinine levels) or between the sexes.
PMCID: PMC3617060  PMID: 23371292
Tobacco; Cotinine; CYP2A6; Polycyclic aromatic hydrocarbons; NNAL
8.  Reproductive, lifestyle and anthropometric risk factors for cancer in elderly women 
With an increasing elderly population, the United States will experience an increased cancer burden in the coming years. We evaluated associations between anthropometric, lifestyle and reproductive factors and risk of breast, ovarian, and colorectal cancer in a prospective study of postmenopausal women with a focus on diagnoses occurring among very elderly women (≥75 years).
For each cancer type, we estimated associations with relevant exposures in two age bands (< vs. ≥75 years of age). During 22 years of follow-up, 322 ovarian, 1,311 colon, 315 rectal, and 2,664 breast cancers occurred among 37,459 postmenopausal women (mean age at baseline 62 years, range 55–71 years).
For ovarian cancer, we identified few significant associations in either age band. Colon cancer cases had a higher body mass index and were less likely to report estrogen or aspirin use than non-cases, yet these associations were consistent in both age bands. Few risk factors were identified for rectal cancer in women ≥75 years of age. For breast cancer, notably different patterns were revealed, with alcohol consumption associated with risk in the younger group and previous hysterectomy associated with risk only in the older group.
These analyses suggest some important differences in risk factors for cancer depending on age at diagnosis.
This study suggests that etiologic differences may exist in cancers occurring in the very elderly. The ongoing demographic shift in the United States provides a strong rationale for studies evaluating cancer etiology in the elderly.
PMCID: PMC3617066  PMID: 23429062
cancer risk; elderly; ovarian; colorectal; breast
9.  Metabolomics in Epidemiology: Sources of Variability in Metabolite Measurements and Implications 
Metabolite levels within an individual vary over time. This within-individual variability, coupled with technical variability, reduces the power for epidemiological studies to detect associations with disease. Here, the authors assess the variability of a large subset of metabolites and evaluate the implications for epidemiologic studies.
Using LC-MS and GC-MS platforms, 385 metabolites were measured in 60 women at baseline and year-1 of the Shanghai Physical Activity Study, and observed patterns were confirmed in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening study.
Although the authors found high technical reliability (median intra-class correlation = 0.8), reliability over time within an individual was low. Taken together, variability in the assay and variability within the individual accounted for the majority of variability for 64% of metabolites. Given this, a metabolite would need, on average, a Relative Risk of 3 (comparing upper and lower quartiles of “usual” levels) or 2 (comparing quartiles of observed levels) to be detected in 38%, 74% and 97% of studies including 500, 1000, and 5000 individuals. Age, gender, and fasting status, factors which are often of less interest in epidemiological studies were associated with 30%, 67%, and 34% of metabolites, respectively, but the associations were weak, and explained only a small proportion of the total metabolite variability.
Metabolomics will require large, but feasible, sample sizes to detect the moderate effect sizes typical for epidemiological studies.
We offer guidelines for determining the sample sizes needed to conduct metabolomic studies in epidemiology.
PMCID: PMC3617076  PMID: 23396963
metabolomics; power; variance components; measurement error
10.  Genetic Variation in the Vitamin D Pathway in Relation to Risk of Prostate Cancer – Results from Breast and Prostate Cancer Cohort Consortium (BPC3) 
Studies suggest that vitamin D status may be associated with prostate cancer risk, although the direction and strength of this association differs between experimental and observational studies. Genome-wide association studies have identified genetic variants associated with 25-hydroxyvitamin D (25(OH)D) status. We examined prostate cancer risk in relation to SNPs in four genes shown to predict circulating levels of 25(OH)D.
SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped in 10,018 cases and 11,052 controls from the NCI Breast and Prostate Cancer Cohort Consortium. Logistic regression was used to estimate the individual and cumulative association between genetic variants and risk of overall and aggressive prostate cancer.
We observed a decreased risk of aggressive prostate cancer among men with the allele in rs6013897 near CYP24A1 associated with lower serum 25(OH)D (per A allele, OR=0.86, 95%CI=0.80–0.93, p-trend=0.0002), but an increased risk for non-aggressive disease (per a allele: OR=1.10, 95%CI=1.04–1.17, p-trend=0.002). Examination of a polygenic score of the four SNPs revealed statistically significantly lower risk of aggressive prostate cancer among men with a greater number of low vitamin D alleles (OR for 6–8 vs. 0–1 alleles = 0.66, 95% CI = 0.44 – 0.98; p-trend=0.003).
In this large, pooled analysis, genetic variants related to lower 25(OH)D were associated with a decreased risk of aggressive prostate cancer.
Our genetic findings do not support a protective association between loci known to influence vitamin D levels and prostate cancer risk.
PMCID: PMC3617077  PMID: 23377224
Vitamin D; prostatic neoplasms; data pooling; genes; SNPs
11.  Dairy Intakes in Older Girls and Risk of Benign Breast Disease in Young Women 
Previous investigations found high dairy intakes in girls associated with rapid height growth and excess weight gain, which had opposite relationships with benign breast disease (BBD) in young women. We use data from the longitudinal Growing Up Today Study (GUTS) to investigate whether dairy intakes, in older children/adolescents, are associated with BBD risk in young women. GUTS includes 9039 females, aged 9–15yrs in 1996, who completed questionnaires annually through 2001, then in 2003, 2005, 2007, and 2010. Dietary food frequencies (1996–2001) obtained milk, yogurt, and cheese intakes. On 2005–2010 surveys, 7011 females (18–29yrs) reported whether a health care provider ever diagnosed them with BBD (n=250), and if confirmed by breast biopsy (n=105). Logistic regression models estimated associations between prevalent biopsy-confirmed BBD and dairy intakes, adjusted for age and energy. Multivariable-adjusted models additionally included menarche age, childhood adiposity, adolescent alcohol consumption, and pregnancy. Further analyses stratified by family history. Age-energy-adjusted models of dairy (milk, yogurt, cheese, total dairy servings, dairy protein, dairy fat) intakes at 14yr found no significant associations with BBD risk (milk OR=0.90/(serving/day), 95%CI:0.76–1.05; dairy protein OR=0.98/(10gm/day), 95%CI:0.82–1.17). Separate analyses of dairy intakes at 10yr, intakes before the growth spurt, during the growth spurt, before menses-onset, and after menses-onset provided no significant associations with BBD. Multivariable-adjustment, and family history stratification, did not alter the above findings. We conclude that dairy intakes by older girls have no strong relation with BBD risk in young women. Due to small number of cases, it is important to continue follow-up and re-examine later.
PMCID: PMC3617079  PMID: 23542805
adolescent; pre-teen; milk; cheese; yogurt; dairy protein; dairy fat; height growth spurt; BBD; breast cancer; prospective cohort; longitudinal
12.  Melanoma Genetic Testing, Counseling, and Adherence to Skin Cancer Prevention and Detection Behaviors 
Little is known about the impact of knowledge of CDKN2A and MC1R genotype on melanoma prevention behaviors like sun avoidance and skin examination in the context of familial melanoma.
73 adults with a family history of melanoma were randomly assigned to be offered individualized CDKN2A and MC1R genotyping results in the context of a genetic counseling session, or the standard practice of not being offered counseling or disclosure of genotyping results. Mixed effects or longitudinal logistic models were used to determine whether the intervention affected change in sun protection habits, skin examinations and perception and beliefs related to melanoma risk, prevention, and genetic counseling.
All participants in the intervention group who attended genetic counseling sessions chose to receive their test results. From baseline to follow-up, participants in the intervention group reported an increase in the frequency of skin self-examinations compared to a slight decrease in the control group (p=0.002). Participants in the intervention group reported a smaller decrease in frequency of wearing a shirt with long sleeves than did participants in the control group (p =0.047). No effect of the intervention was noted for other outcomes.
Feedback of CDKN2A and MC1R genotype among families without known pathogenic CDKN2A mutations does not appear to decrease sun protection behaviors.
While disclosure of CDKN2A and MC1R genotype did not have negative effects on prevention, the benefits of communicating this information remain unclear. The small number of families who tested positive for CDKN2A mutations in this study is a limitation.
PMCID: PMC3617083  PMID: 23392000
skin cancer; genetic testing; sun exposure; sun protection; surveys
13.  Transforming Epidemiology for 21st Century Medicine and Public Health 
In 2012, the National Cancer Institute (NCI) engaged the scientific community to provide a vision for cancer epidemiology in the 21st century. Eight overarching thematic recommendations, with proposed corresponding actions for consideration by funding agencies, professional societies, and the research community emerged from the collective intellectual discourse. The themes are (i) extending the reach of epidemiology beyond discovery and etiologic research to include multilevel analysis, intervention evaluation, implementation, and outcomes research; (ii) transforming the practice of epidemiology by moving towards more access and sharing of protocols, data, metadata, and specimens to foster collaboration, to ensure reproducibility and replication, and accelerate translation; (iii) expanding cohort studies to collect exposure, clinical and other information across the life course and examining multiple health-related endpoints; (iv) developing and validating reliable methods and technologies to quantify exposures and outcomes on a massive scale, and to assess concomitantly the role of multiple factors in complex diseases; (v) integrating “big data” science into the practice of epidemiology; (vi) expanding knowledge integration to drive research, policy and practice; (vii) transforming training of 21st century epidemiologists to address interdisciplinary and translational research; and (viii) optimizing the use of resources and infrastructure for epidemiologic studies. These recommendations can transform cancer epidemiology and the field of epidemiology in general, by enhancing transparency, interdisciplinary collaboration, and strategic applications of new technologies. They should lay a strong scientific foundation for accelerated translation of scientific discoveries into individual and population health benefits.
PMCID: PMC3625652  PMID: 23462917
big data; clinical trials; cohort studies; epidemiology; genomics; medicine; public health; technologies; training; translational research
14.  Association of AMP-activated Protein Kinase with Risk and Progression of Non-Hodgkin Lymphoma 
Metabolic dysregulation has been identified as an “emerging hallmark” of cancer. The heterotrimeric AMP-activated protein kinase (AMPK) complex is a central regulator of the metabolic system and an important component of the mTOR pathway and the p53 axis, making it uniquely positioned to influence carcinogenesis through its canonical functions in the metabolic arena, as well as through more traditional mechanisms such as regulation of apoptosis and angiogenesis.
We conducted a population-based genetic association study to examine the impact of mutations in AMPK subunit genes on risk of non-Hodgkin’s lymphoma (NHL). We also analyzed public microarray data to determine the expression of AMPK in NHL cells and to assess the influence of AMPK expression on overall survival in NHL patients.
We identified an AMPK subunit haplotype which was significantly associated with NHL (OR=5.44, 95%CI: 2.15–13.75) in women with no family history of cancer. Haplotypes in two subunits, PRKAA2 and PRKAG3, were nominally associated with the follicular and diffuse large B cell lymphoma histologic subtypes, respectively, although these associations did not retain statistical significance after correction for multiple comparisons. Further, both of these subunits were differentially expressed (p<0.05) in one or more lymphoma cell type, and higher expression of two versions of the AMPK-β subunit were significantly associated with increased five-year survival among NHL patients (p=0.001 and p=0.021).
These results provide evidence for AMPK involvement in the pathogenesis and progression of NHL.
These findings may lead to a novel area of research into NHL treatment and chemoprevention.
PMCID: PMC3631103  PMID: 23396962
AMPK; metabolism; lymphoma
15.  Bridging the Gap between Biologic, Individual, and Macroenvironmental Factors in Cancer: A Multilevel Approach 
To address the complex nature of cancer occurrence and outcomes, approaches have been developed to simultaneously assess the role of two or more etiological agents within hierarchical levels including the: 1) macro-environment level (e.g., health care policy, neighborhood, or family structure); 2) individual level (e.g., behaviors, carcinogenic exposures, socioeconomic factors and psychological responses); 3) biological level (e.g., cellular biomarkers and inherited susceptibility variants). Prior multilevel approaches tend to focus on social and environmental hypotheses, and are thus limited in their ability to integrate biological factors into a multilevel framework. This limited integration may be related to the limited translation of research findings into the clinic. We propose a “Multi-level Biological And Social Integrative Construct” (MBASIC) to integrate macro-environment and individual factors with biology. The goal of this framework is to help researchers identify relationships among factors that may be involved in the multifactorial, complex nature of cancer etiology, to aid in appropriate study design, to guide the develop statistical or mechanistic models to study these relationships, and to position the results of these studies for improved intervention, translation, and implementation. MBASIC allows researchers from diverse fields to develop hypotheses of interest under a common conceptual framework, to guide transdisciplinary collaborations, and to optimize the value of multilevel studies for clinical and public health activities.
PMCID: PMC3645448  PMID: 23462925
Multilevel Model; Cancer Etiology; Translation; Implementation
16.  Cancer Survivors in the United States: Prevalence across the Survivorship Trajectory and Implications for Care 
Cancer survivors represent a growing population, heterogeneous in their need for medical care, psychosocial support, and practical assistance. To inform survivorship research and practice, this manuscript will describe the prevalent population of cancer survivors in terms of overall numbers and prevalence by cancer site and time since diagnosis.
Incidence and survival data from 1975–2007 were obtained from the Surveillance, Epidemiology, and End Results Program and population projections from the United States (US) Census Bureau. Cancer prevalence for 2012 and beyond was estimated using the Prevalence Incidence Approach Model, assuming constant future incidence and survival trends but dynamic projections of the US population.
As of January 1, 2012, approximately 13.7 million cancer survivors were living in the US with prevalence projected to approach 18 million by 2022. Sixty-four percent of this population have survived ≥ 5 years; 40% have survived ≥ 10 years; and 15% have survived ≥ 20 years after diagnosis. Over the next decade, the number of people who have lived ≥ 5 years after their cancer diagnosis is projected to increase approximately 37% to 11.9 million.
A coordinated agenda for research and practice is needed to address cancer survivors’ long-term medical, psychosocial, and practical needs across the survivorship trajectory.
Prevalence estimates for cancer survivors across the survivorship trajectory will inform the national research agenda as well as future projections about the health service needs of this population.
PMCID: PMC3654837  PMID: 23535024
17.  Squamous dysplasia – the precursor lesion for esophageal squamous cell carcinoma 
Esophageal squamous cell carcinoma (ESCC) accounts for 80% of all esophageal cancers worldwide, and esophageal squamous dysplasia (ESD) is the only histopathology that predicts the development of ESCC. The prevalence of ESD parallels rates of invasive ESCC, and is typically found in 25% or more of adults above the age of 35 years in populations in north central China, where risk for ESCC is among the highest in the world. Results of chemoprevention and early detection studies to prevent progression of ESD suggest that these approaches, coupled with emerging endoscopic therapies, offer promise for the prevention of esophageal cancer mortality in high-risk populations. Future research on ESD and ESCC should focus on finding additional modifiable risk factors and on identifying biomarkers to incorporate into early detection strategies.
PMCID: PMC3681095  PMID: 23549398
18.  Human papillomavirus (HPV) infection and the multi-stage carcinogenesis of cervical cancer 
This short review outlines our understanding of cervical cancer precursors, concentrating on the central etiologic role of persistent human papillomavirus (HPV) infection. The stages of cervical carcinogenesis are better understood than for most other major cancers, providing a successful cancer etiology and prevention model.
PMCID: PMC3711590  PMID: 23549399
19.  Precursors in cancer epidemiology: aligning definition and function 
A precursor of a disease is a definable pathologic state that progresses directly to disease without a known intermediate step, and whose presence substantially increases the likelihood of disease. Precancers, or precursors of cancer, can help provide detail about the dynamic pathogenesis process before clinical disease. Thereby, ascertainment of properly defined precancers can increase precision of estimates and power in epidemiologic and clinical studies. Besides providing targets for direct treatment and improving tools for risk assessment in screening programs, precancers can help establish temporal ordering of cause and effect; can identify relatively homogeneous subsets of cancer that have passed through a given precancer state; and provide a basis for choosing high-risk individuals for detailed longitudinal study. Although the most appropriate definition of the precancer will vary with its function in particular research or clinical applications, the proportion of cancers that progress from the precancer and risk of cancer progressing from the precancer can be important measures of the value of a precancer in translational efforts.
PMCID: PMC3738010  PMID: 23549395
20.  Drinking water arsenic in northern Chile: high cancer risks 40 years after exposure cessation 
Millions of people worldwide are exposed to arsenic-contaminated water. In the largest city in northern Chile (Antofagasta) >250,000 people were exposed to high arsenic drinking water concentrations from 1958 until 1970 when a water treatment plant was installed. Because of its unique geology, limited water sources, and good historical records, lifetime exposure and long-term latency patterns can be assessed in this area with better accuracy than in other arsenic-exposed areas worldwide.
We performed a population-based case-control study in northern Chile from October 2007 to December 2010 involving 232 lung and 306 bladder cancer cases and 640 age- and gender-matched controls, with detailed information on past exposure and potential confounders, including smoking and occupation.
Bladder cancer odds ratios for quartiles of average arsenic concentrations in water before 1971 (<11, 11–90, 91–335, and >335 µg/L) were 1.00, 1.36 (95% confidence interval, 0.78 to 2.37), 3.87 (2.25 to 6.64), and 6.50 (3.69 to 11.43), respectively. Corresponding lung cancer odds ratios were 1.00, 1.27 (0.81 to 1.98), 2.00 (1.24 to 3.24), and 4.32 (2.60 to 7.17). Bladder and lung cancer odds ratios in those highly exposed in Antofagasta during 1958–70 but not thereafter were 6.88 (3.84 to 12.32) and 4.35 (2.57 to 7.36), respectively.
The lung and bladder cancer risks that we found up to 40 years after high exposures have ended are very high.
Our findings suggest that prevention, treatment, and other mortality reduction efforts in arsenic-exposed countries will be needed for decades after exposure cessation.
PMCID: PMC3848421  PMID: 23355602
Smoking has been associated with cervical cancer. We examined whether smoking increases the risk for high-grade cervical lesions in women with high-risk human papillomavirus (HPV) infection.
In a population-based cohort study, 8,656 women underwent a structured interview, and subsequently cervical cells were obtained for HPV DNA testing. Women with high-risk HPV infection and no prevalent cervical disease at baseline (n=1,353) were followed through the Pathology Data Bank for cervical lesions for up to 13 years. Separate analyses of women with persistent high-risk HPV infection were also conducted. Hazard ratios (HRs) for a diagnosis of cervical intraepithelial neoplasia grade 3 or worse/high-grade squamous intraepithelial lesions or worse (CIN3+) and the corresponding 95% confidence intervals (CIs) were calculated in the 2 groups.
Among high-risk HPV positive women an increased risk for CIN3+ was associated with long-term smoking (≥10 years) and heavy smoking (≥20 cigarettes/day). In the subgroup of women with persistent HPV infection heavy smoking was also associated with a statistically significantly higher risk for CIN3+ than never smoking (HR, 1.85; 95% CI, 1.05–3.22, adjusted for length of schooling, parity and HPV type at baseline). The average number of cervical cytology screening tests per year during follow-up did not explain the differences in risk in relation to smoking (p=0.4).
Smoking is associated with an increased risk for subsequent high-grade cervical lesions in women with persistent high-risk HPV infection.
Our study adds to the understanding of the role of smoking in the natural history of HPV and cervical carcinogenesis.
PMCID: PMC3970163  PMID: 23019238
cervical intraepithelial lesions; smoking; human papillomavirus
22.  Combined and interactive effects of environmental and GWAS-identified risk factors in ovarian cancer 
There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied.
Data from 14 ovarian cancer case-control studies were pooled, and stratified analyses by each environmental risk factor with tests for heterogeneity were conducted to determine the presence of interactions for all histological subtypes. A genetic “risk score” was created to consider the effects of all six variants simultaneously. A multivariate model was fit to examine the association between all environmental risk factors and genetic risk score on ovarian cancer risk.
Among 7,374 controls and 5,566 cases, there was no statistical evidence of interaction between the six SNPs or genetic risk score and the environmental risk factors on ovarian cancer risk. In a main effects model, women in the highest genetic risk score quartile had a 65% increased risk of ovarian cancer compared to women in the lowest (95% CI 1.48-1.84). Analyses by histological subtype yielded risk differences across subtype for endometriosis (phet<0.001), parity (phet<0.01), and tubal ligation (phet=0.041).
The lack of interactions suggests that a multiplicative model is the best fit for these data. Under such a model, we provide a robust estimate of each risk factor's effect, which sets the stage for absolute risk prediction modeling that considers both environmental and genetic risk factors. Further research into the observed differences in risk across histological subtype is warranted.
PMCID: PMC3963289  PMID: 23462924
Gene-environment interactions; ovarian cancer; epidemiology; histological subtype; pooled analysis
23.  Familial and Perceived Risk of Breast Cancer in Relation to Use of Complementary Medicine 
To examine use of complementary and alternative medicine (CAM) by women with varying levels of familial and perceived risk of breast cancer with the goal of preventing breast cancer.
Cross-sectional data on CAM use were collected on 2198 women (mean age 63) personally unaffected by breast cancer in the Minnesota Breast Cancer Family Study. CAM use was compared across women at high, moderate, or average risk based on family history, as well as across categories of perceived risk of breast cancer. CAM use was also examined in relation to screening and general health behaviors, worry about breast cancer, and optimism.
Half (49.5%) of the women reported using at least one CAM modality with the intent of preventing breast cancer. Univariate analyses indicated that greater overall CAM use was related to greater perceived risk (p = .018), more general health behaviors (p < .0001), more breast cancer screening behaviors (p = .0002), greater optimism (p = .0002) and higher educational attainment (p < .0001). Multivariate analysis revealed that general health behaviors (p < .0001), education (p = .0027), and optimism (p = .037) were significant predictors of CAM use when in the same model with perceived risk and breast cancer screening behaviors.
Many women use CAM with the goal of preventing breast cancer. General health promoting behaviors, education, and optimism predict CAM use. Evidence-based guidance is needed for the public and health care providers on the potential and limitations of specific CAM approaches to impact cancer risk.
PMCID: PMC3959885  PMID: 18541615
24.  Assessment of the Effects of Severe Obesity and Lifestyle Risk Factors On Stage of Endometrial Cancer 
Lifestyle risk factors, including obesity, have been associated with increased risk of endometrial cancer (EC). Women with higher obesity tend to have less aggressive EC disease stage and histology. This study further investigated the associations of non-modifiable risk factors, such as age, race and grade, and modifiable lifestyle factors, such as diet and physical activity expenditure, in relation to severe obesity and early versus late stage EC diagnosis.
Demographic, anthropometric and lifestyle surveys were administered to 177 women with histologically confirmed EC. Logistic regression analyses were used to assess the relationship between obesity and risk factors on EC stage at diagnosis.
In multivariate models, body mass index (BMI) was not significantly associated with late EC stage at diagnosis (OR=1.67, p=0.219) when adjusting for grade and age. Grade was significantly associated with EC stage when controlling for BMI and age (OR=8.48, p=0.000). Women over age 60 had a 4-fold increased risk of being diagnosed at late versus early EC stage when adjusting for other risk factors. Age had a confounding effect on the obesity-EC stage association.
Our results corroborate those of past studies showing that BMI is not an independent risk factor for EC stage and that age may have confounded the obesity-EC stage association. Due to mixed results and implications for treatment outcomes, however, further research examining these variables is warranted.
Our results provide further insight into the obesity EC-stage association, especially the confounding effect of age. Future studies should examine modifiable lifestyle factors in larger and more diverse populations.
PMCID: PMC3954974  PMID: 23118146
Obesity; Endometrial Cancer; Stage; Grade; Diet; Physical Activity
25.  No Evidence for Differences in DNA Damage Assessed before and after a Cancer Diagnosis 
The overwhelming majority of studies that have found increased cancer risk associated with functional deficits in DNA repair used a case-control design, in which measurements were made after cancer diagnosis. However, there are concerns about whether the cancer itself or cancer treatment affected the conclusions (reverse causation bias). We assessed the effect of cancer diagnosis among 26 breast cancer controls who had blood collected during 2001 to 2003 and again in 2005 to 2006 after being diagnosed with cancer. Using the alkaline comet assay, we quantified DNA damage in untreated lymphoblastoid cell lines. Comet distributed moment, olive tail moment, percentage of DNA in tail, and comet tail length were summarized as the geometric mean of 100 cells. For comet distributed moment, olive tail moment, tail DNA, and tail length, the proportions of women with before diagnosis values higher than after diagnosis were 65%, 50%, 50%, and 46%, respectively. We found no significant differences in the before or after diagnosis mean comet values. Median cut-points were determined from the before diagnosis distribution, and we used conditional logistic regression to calculate odds ratios (OR) and upper 95% bounds of the confidence intervals. ORs ranged from 0.6 to 0.9 with upper confidence interval bounds of 1.9 and 2.6, meaning biased ORs above 2.6 are unlikely. We found no evidence that reverse causation bias is an important concern in case-control studies using the comet assay applied to cell lines collected after cancer diagnosis. More work is needed to characterize the effect of cancer diagnosis on other phenotypic assays.
PMCID: PMC3950930  PMID: 18398043

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