Cancer Epidemiology Biomarkers & Prevention recent issues

Validation of Colorectal Cancer Screening Behaviors

Zapka, J. G. — 2008-04-08

Accuracy of Self-Reported Cancer-Screening Histories: A Meta-analysis

Rauscher, G. H., Johnson, T. P., Cho, Y. I., Walk, J. A. — 2008-04-08

Background: Survey data used to study trends in cancer screening may overestimate screening utilization while potentially underestimating existing disparities in use.

Methods: We did a literature review and meta-analysis of validation studies examining the accuracy of self-reported cancer-screening histories. We calculated summary random-effects estimates for sensitivity and specificity, separately for mammography, clinical breast exam (CBE), Pap smear, prostate-specific antigen testing (PSA), digital rectal exam, fecal occult blood testing, and colorectal endoscopy.

Results: Sensitivity was highest for mammogram, CBE, and Pap smear (0.95, 0.94, and 0.93, respectively) and lowest for PSA and digital rectal exam histories (0.71 and 0.75). Specificity was highest for endoscopy, fecal occult blood testing, and PSA (0.90, 0.78, and 0.73, respectively) and lowest for CBE, Pap smear, and mammogram histories (0.26, 0.48, and 0.61, respectively). Sensitivity and specificity summary estimates tended to be lower in predominantly Black and Hispanic samples compared with predominantly White samples. When estimates of self-report accuracy from this meta-analysis were applied to cancer-screening prevalence estimates from the National Health Interview Survey, results suggested that prevalence estimates are artificially increased and disparities in prevalence are artificially decreased by inaccurate self-reports.

Conclusions: National survey data are overestimating cancer-screening utilization for several common procedures and may be masking disparities in screening due to racial/ethnic differences in reporting accuracy. (Cancer Epidemiol Biomarkers Prev 2008;17(4):748–57)

Reliability and Validity of a Questionnaire to Measure Colorectal Cancer Screening Behaviors: Does Mode of Survey Administration Matter?

2008-04-08

Valid and reliable self-report measures of cancer screening behaviors are important for evaluating efforts to improve adherence to guidelines. We evaluated test-retest reliability and validity of self-report of the fecal occult blood test (FOBT), sigmoidoscopy (SIG), colonoscopy (COL), and barium enema (BE) using the National Cancer Institute colorectal cancer screening (CRCS) questionnaire. A secondary objective was to evaluate reliability and validity by mail, telephone, and face-to-face survey administration modes. Consenting men and women, 51 to 74 years old, receiving care at a multispecialty clinic for at least 5 years who had not been diagnosed with colorectal cancer were stratified by prior CRCS status and randomized to survey mode (n = 857). Within survey mode, respondents were randomized to complete a second survey at 2 weeks, 3 months, or 6 months. Comparing self-report with administrative and medical records, concordance estimates were 0.91 for COL, 0.85 for FOBT, 0.85 for SIG, and 0.92 for BE. Overall sensitivity estimates were 0.91 for COL, 0.82 for FOBT, 0.76 for SIG, and 0.56 for BE. Specificity estimates were 0.91 for COL, 0.86 for FOBT, 0.89 for SIG, and 0.97 for BE. Sensitivity and specificity varied little by survey mode for any test. Report-to-records ratio showed overreporting for SIG (1.1), COL (1.15), and FOBT (1.57), and underreporting for BE (0.82). Reliability at all time intervals was highest for COL; there was no consistent pattern according to survey mode. This study provides evidence to support the use of the National Cancer Institute CRCS questionnaire to assess self-report with any of the three survey modes. (Cancer Epidemiol Biomarkers Prev 2008;17(4):758–67)

Validation of Self-Reported Colorectal Cancer Screening Behavior from a Mixed-Mode Survey of Veterans

2008-04-08

Objective: The aim of the study was to validate self-reported colorectal cancer (CRC) screening using the National Cancer Institute Colorectal Cancer Screening questionnaire.

Materials and Methods: 890 patients, ages 50 to 75 years, from the Minneapolis Veterans Affairs (VA) Medical Center were surveyed by mail. Phone administration was attempted with mail nonresponders. VA and non-VA records were combined for the reference standard. Sensitivity, specificity, concordance, and report-to-records ratio (R2R) were estimated for overall and test-specific CRC adherence among respondents providing complete medical records. Secondary analyses examined variation in estimates by patient characteristics, treatment of missing and uncertain responses, and whether a strict or liberal time interval was used for assessing concordance.

Results: Complete medical records were available for 345 of the 686 survey responders. For overall adherence, sensitivity was 0.98, specificity was 0.59, concordance was 0.88, and R2R was 1.14. Sensitivity was 0.82 for fecal occult blood test (FOBT), 0.75 for sigmoidoscopy, 0.97 for colonoscopy, and 0.63 for double-contrast barium enema (DCBE). Specificity was 0.89 for FOBT, 0.76 for sigmoidoscopy, 0.72 for colonoscopy, and 0.85 for DCBE. Concordance was >0.80 for all tests other than sigmoidoscopy (0.76). R2R was 1.31 for FOBT, 1.33 for sigmoidoscopy, 1.42 for colonoscopy, and 6.13 for DCBE. The R2R was lower for a combined sigmoidoscopy and colonoscopy measure. Overreporting was more pronounced for older, less-educated individuals with no family history of CRC. Sensitivity and R2R improved using a liberal interval and treating uncertain responses as nonadherent (versus missing), but differences were not statistically significant.

Conclusions: Self-reported CRC screening validity is generally acceptable and robust across definitional decisions, but varies by screening test and patient characteristics. (Cancer Epidemiol Biomarkers Prev 2008;17(4):768–76)

Validity of Four Self-reported Colorectal Cancer Screening Modalities in a General Population: Differences over Time and by Intervention Assignment

Jones, R. M., Mongin, S. J., Lazovich, D., Church, T. R., Yeazel, M. W. — 2008-04-08

Little is known about the validity of self-reported colorectal cancer screening. To date, few published studies have validated all four screening modalities per recommended guidelines or included a general population-based sample, and none has assessed validity over time and by intervention condition. To estimate the validity of self-reported screening, a random sample of 200 adults, ages ≥50 years, was selected from those completing annual surveys on screening behavior as part of an intervention study. Approximately 60% of the validation sample authorized medical record review. Sensitivity, specificity, and positive and negative predictive values were calculated for baseline and year 1 follow-up reports for each test and for overall screening adherence. Sensitivity at baseline ranged from 86.9% (flexible sigmoidoscopy) to 100% (colonoscopy). Sensitivity at follow-up was slightly lower. Adjusting for validity measures, the sample overreported screening prevalence at baseline for each of the four modalities. At follow-up, overreporting was greatest for fecal occult blood test (13.0%). Overreporting across intervention conditions was highest for fecal occult blood test (10.8% for control; 24.8% for the most intense intervention) and overall screening adherence (10.9% for control; 14.3% for the most intense intervention). Sensitivity and specificity of self-reported colorectal cancer screening compared with medical records were high; however, adjusting self-reported screening rates based on relative error rates reduced screening prevalence estimates. Those exposed to more intense interventions to modify screening behavior seemed more likely to overestimate their screening rates compared with those who were not exposed. (Cancer Epidemiol Biomarkers Prev 2008;17(4):777–84)

The Effects of Survey Mode and Asking About Future Intentions on Self-Reports of Colorectal Cancer Screening

Beebe, T. J., Jenkins, S. M., Anderson, K. J., Davern, M. E., Rockwood, T. H. — 2008-04-08

Colorectal cancer (CRC) screening rates are often ascertained via self-reports but can be subject to overreporting bias. Asking about intention to get screened before asking about past screening may minimize overreporting of cancer screening. In a statewide survey conducted from July through October of 2005, we embedded an experiment that tested the effect of question ordering (asking about future intention to get screened before or after asking about past screening; "future first" and "future second," respectively), crossed with survey mode (mail versus telephone), on CRC screening rates. Weighted analysis focused on 752 respondents who were ages 50 years or older. We found (a) that asking about future intentions to get screened before asking about past screening (future first) statistically significantly lowers reports of past CRC screening [70.9% future second versus 58.0% future first; odds ratio (OR), 1.83; 95% confidence interval (95% CI), 1.08-3.13]; (b) that there was no main effect of survey mode; and (c) that the effect of the ordering of the future intentions item varies by survey mode. In the mailed survey, the odds of reporting past CRC screening were almost thrice greater in the future second condition compared with the future first condition (72.4% versus 49.0%, respectively; OR, 2.74; 95% CI, 1.22-6.17). In the telephone condition, the odds of reporting were only 28% higher in the future second (69.5%) condition than in the future first condition (63.9%; OR, 1.28; 95% CI, 0.64-2.57). The results suggest that asking about future intentions to get screened before the actual behavior elicits lower, and arguably more truthful reports of CRC screening but mainly in mailed surveys. (Cancer Epidemiol Biomarkers Prev 2008;17(4):785–90)

Validation of Self-reported Colorectal Cancer (CRC) Screening in a Study of Ethnically Diverse First-Degree Relatives of CRC Cases

2008-04-08

Background: Evidence about the accuracy of self-reports of colorectal cancer (CRC) screening is lacking. We conducted a validation protocol in a randomized trial to increase CRC screening among high-risk individuals.

Methods: First-degree relatives (n = 1,280) of CRC cases who were due for CRC screening were included in the parent trial. All subjects who completed the follow-up interview (n = 948) were asked to participate in validation activities. Self-reports of receipt of CRC screening during the 12-month study period were verified via physicians.

Results: Although 60% (n = 567) verbally agreed, only 171 subjects (18% of original sample) returned the signed validation form with the physician name and contact information and a medical information release statement. The signed forms were mailed to physicians with a $10 incentive and the request to list the dates of recent CRC screening tests. One hundred twenty-three physicians (72% of physicians contacted, 13% of original sample) returned completed validation forms. Rates of agreement were low across all three screening types with physicians verifying self-reported screening for 29% of fecal occult blood testing, 56% of sigmoidoscopy, 55% of colonoscopy, and 57% of any screening test.

Conclusion: Validation of self-report using the type of protocol we used for subjects receiving medical care in many community settings may be unfeasible and cost inefficient. Given the overall low participation rate in validation activities and considerable challenges in collecting high quality data, conclusions about the accuracy of self-reported CRC screening are difficult to make based on the results of this study. (Cancer Epidemiol Biomarkers Prev 2008;17(4):791–8)

Evaluation of Claims, Medical Records, and Self-report for Measuring Fecal Occult Blood Testing among Medicare Enrollees in Fee for Service

2008-04-08

Background: There is no agreement on the best data source for measuring colorectal cancer (CRC) screening. Medicare claims have been used to measure CRC testing but the validity of using claims to measure fecal occult blood tests (FOBT) has not been established.

Methods: We compared ascertainment of FOBT among three data sources: self-reports, Medicare claims, and medical records. Data were collected on FOBT use during the study window (1/1/1998 – 12/31/2002). Our study was conducted with North Carolina Medicare enrollees (N = 561) who had previously responded to a telephone survey on CRC tests. FOBT information was abstracted from respondents' physician office medical records and compared with self-reported FOBT use and Medicare claims for FOBT. Data sources were assessed for accuracy and completeness of FOBT reporting using sensitivity, specificity, positive predictive value, negative predictive value, and agreement.

Results: Reporting of FOBT use in the prior year in medical records and Medicare claims agreed 82% of the time [95% confidence interval (95% CI), 79-85%]. FOBT 1-year use rates from self-report agreed with test use found in medical records 70% of the time (95% CI, 66-74%). The lowest agreement was between self-reported 1-year FOBT use and Medicare claims, which agreed 67% of the time (95% CI, 63-71%).

Conclusions: No data source could be established as providing complete and valid information about FOBT use among Medicare enrollees, showing the difficulty of ascertaining test use rates for noninvasive, low-cost procedures conducted in multiple settings. Caution should be used when attempting to measure FOBT use with self-report, Medicare claims, or medical records. (Cancer Epidemiol Biomarkers Prev 2008;17(4):799–804)

The Case for a Gender-Neutral (Universal) Human Papillomavirus Vaccination Policy in the United States: Point

Giuliano, A. R., Salmon, D. — 2008-04-08

Human Papillomavirus Vaccination Should Be Offered to Young Males: Counterpoint

Trimble, C. L. — 2008-04-08

Human Papillomavirus in Cervical Cancer Screening: Important Role as Biomarker

Boulet, G. A.V., Horvath, C. A.J., Berghmans, S., Bogers, J. — 2008-04-08

Cervical cytology screening has reduced cervical cancer morbidity and mortality but shows important shortcomings in terms of sensitivity and specificity. Infection with distinct types of human papillomavirus (HPV) is the primary etiologic factor in cervical carcinogenesis. This causal relationship has been exploited for the development of molecular technologies for viral detection to overcome limitations linked to cytologic cervical screening. HPV testing has been suggested for primary screening, triage of equivocal Pap smears or low-grade lesions and follow-up after treatment for cervical intraepithelial neoplasia. Determination of HPV genotype, viral load, integration status and RNA expression could further improve the effectiveness of HPV-based screening and triage strategies. The prospect of prophylactic HPV vaccination stresses the importance of modification of the current cytology-based screening approach. (Cancer Epidemiol Biomarkers Prev 2008;17(4):810–7)

Intended Coping Responses to Cancer Symptoms in Healthy Adults: The Roles of Symptom Knowledge, Detection Behavior, and Perceived Threat

2008-04-08

Background: To date, the causal effects of the knowledge of cancer-related symptoms and detection behavior on coping with cancer-related symptoms have not been identified. Therefore, the current study explored the effects of active or passive detection of supposedly well-known or less-known cancer-related symptoms on intended coping responses. In addition, we were interested in the extent to which these effects are driven by heightened perceptions of threat.

Methods: In an experimental study using a 2 x 2 within-subject design, 221 Dutch adults from the general population responded to a survey study sent to their homes (18.4% response). They were asked to read scenario information about four cancer-related symptoms that were (a) well known or less known and (b) actively or passively detected (e.g., self-examination versus unusual blood loss). The authors measured intended coping responses to the detection of cancer-related symptoms as either adaptive (e.g., visiting a general practitioner) or maladaptive (e.g., denial of the symptom).

Results: As expected, the findings revealed that well-known symptoms resulted in more anticipated adaptive coping and less anticipated maladaptive coping than less-known symptoms. Unfortunately, the findings also suggest that the active as opposed to passive detection of cancer symptoms (e.g., self-examination versus unusual blood loss) is likely to result in more maladaptive coping. These effects were mediated by heightened perceptions of threat.

Conclusions: Future health education programs that aim to motivate people to be more active in the early detection of cancer symptoms should first focus on increasing people's knowledge about the early warning signs of cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(4):818–26)

Recruitment in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial: the First Phase of Recruitment at Henry Ford Health System

Lamerato, L. E., Marcus, P. M., Jacobsen, G., Johnson, C. C. — 2008-04-08

Objective: Recruitment of healthy subjects to long-term randomized controlled trials (RCTs) of cancer prevention or early detection has proven to be a difficult task. To quantify recruitment yield as well as characteristics of successfully recruited participants, we examined recruitment outcomes at 1 of the 10 centers participating in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, a National Cancer Institute–funded RCT of cancer screening modalities.

Materials and Methods: During the early recruitment phase of PLCO (1993-1997), data on recruitment outcome were collected at the Henry Ford Health System (HFHS) in Detroit, Michigan. In this phase, HFHS identified potential participants using patient databases. Records were used to assess recruitment success by age, sex, race, household income (using area-based U.S. Census data), and preexisting morbidity. Logistic regression was used to assess whether enrollment success differed significantly according to these factors.

Results: Of 74,139 persons ages 55 to 74 invited by HFHS to participate, 8,250 (11%) `enrolled. In multivariate analyses, the odds of enrolling were modestly but significantly higher for women, Caucasians, persons in their 60's, and persons living in census blocks with higher median household income. Persons with two or more preexisting morbidities had significantly lower odds of enrolling compared to those with one or no preexisting morbidities.

Conclusions: These data suggest that only a small fraction of persons invited to enroll in long-term RCTs of cancer screening modalities actually do so. In this urban, Midwestern setting, certain characteristics including age, race, and income influenced recruitment success, albeit modestly. (Cancer Epidemiol Biomarkers Prev 2008;17(4):827–33)

Health Insurance-Related Disparities in Colorectal Cancer Screening in Virginia

de Bosset, V., Atashili, J., Miller, W., Pignone, M. — 2008-04-08

Background: Colorectal cancer (CRC) screening rates remain low in the United States. The effect of health insurance on CRC screening is not clear. We assessed the association between having health insurance and being screened for CRC and the factors that modify this association.

Methods: We used data from the 2005 Virginia Behavioral Risk Factor Surveillance System to evaluate the association of self-reported insurance coverage on self-reported CRC screening among all men and women ages ≥50 years (N = 2,887). Prevalence odds ratios (POR) were estimated using unconditional logistic regression. All covariates were assessed for potential effect measure modification and confounding. All analyses accounted for the Behavioral Risk Factor Surveillance System complex survey sampling design.

Results: Overall, participants who reported having insurance coverage were more than twice as likely to report being screened for CRC compared with those who reported having none [crude POR, 2.16; 95% confidence interval (95% CI), 1.26-3.68]. This relationship differed between men and women (POR_males, 3.37; 95% CI, 1.63-6.96; POR_females, 1.46; 95% CI, 0.74-2.89). After adjusting for age and income, self-reported insurance coverage had a positive association with report of being screened among men (POR, 2.02; 95% CI, 0.96-4.23) but not among women (POR, 0.81; 95% CI, 0.34-1.93).

Conclusions: Men who reported having health insurance were more likely to report having CRC screening than those who reported not having insurance coverage. However, this effect was not observed in women. These findings, if confirmed in other study populations, indicate that improving CRC screening coverage may require not only insurance status specifications but also gender-explicit considerations. (Cancer Epidemiol Biomarkers Prev 2008;17(4):834–7)

Cancer High-Risk Subjects Identified by Serum Pepsinogen Tests: Outcomes after 10-Year Follow-up in Asymptomatic Middle-Aged Males

2008-04-08

Background: Gastric cancer screening using the pepsinogen filter test is receiving wide recognition in Japan owing to convenience, freedom from discomfort or risk, efficiency, and economy. Because the long-term outcomes of cancer development in extensive atrophic gastritis detected by pepsinogen test are unclear, test-positive and test-negative subjects were investigated in a longitudinal cohort study.

Methods: Subjects comprised 5,209 middle-aged men with measured serum pepsinogen levels who were followed for 10 years. Cancer development based on "atrophy-positive" and "atrophy-negative" criteria used for cancer screening was investigated.

Results: During the study, 63 cases of cancer developed in the cohort, representing an incidence rate of 125 per 100,000 person-years. Pepsinogen test screening using the most widely used atrophy-positive criterion (pepsinogen I, ≤70 ng/mL; pepsinogen I/II ratio, ≤3.0) displayed 58.7% sensitivity, 73.4% specificity, and 2.6% positive predictive value. Cancer incidence rate was 276 per 100,000 person-years for the atrophy-positive group and 70 per 100,000 person-years for the atrophy-negative group. Incidence rate was higher in groups fulfilling stricter positive criteria detecting more extensive atrophy, reaching 424 per 100,000 person-years. In addition, 9.2% of atrophy-negative subjects with pepsinogen I of >70 ng/mL and pepsinogen I/II ratio of ≤3.0 (reflecting putative inflammation-based high pepsinogen II level) are at high risk for cancer, particularly diffuse-type cancer, with a cancer incidence rate comparable with atrophy-positive subjects (216 per 100,000 person-years).

Conclusion: Atrophy-positive subjects by pepsinogen filter test, particularly those fulfilling stricter criteria, and atrophy-negative subjects with low pepsinogen I/II ratio reflecting putative extensive active inflammation constitute populations at high risk for gastric cancer, requiring thorough endoscopic examination. (Cancer Epidemiol Biomarkers Prev 2008;17(4):838–45)

Risk Factors for Hepatocellular Carcinoma in a Japanese Population: A Nested Case-Control Study

2008-04-08

Background: Epidemiologic studies have shown effects of lifestyle-related factors on risk for hepatocellular carcinoma. However, few cohort studies have incorporated, in a strict and in-depth manner, hepatitis B virus (HBV) and hepatitis C virus (HCV) infections or investigated synergism between such factors.

Methods: We conducted a nested case-control study using sera stored before hepatocellular carcinoma diagnosis in the longitudinal cohort of atomic bomb survivors. The study included 224 hepatocellular carcinoma cases and 644 controls that were matched to the cases on gender, age, city, time of serum storage, and method of serum storage, and countermatched on radiation dose.

Results: Univariate analysis showed that HBV and HCV infections, alcohol consumption, smoking habit, body mass index (BMI), and diabetes mellitus were associated with increased hepatocellular carcinoma risk, whereas coffee drinking was associated with decreased hepatocellular carcinoma risk. Multivariate relative risks of hepatocellular carcinoma (95% confidence interval) were 45.8 (15.2-138), 101 (38.7-263), 70.7 (8.3-601), 4.36 (1.48-13.0), and 4.57 (1.85-11.3), for HBV infection alone, HCV infection alone, both HBV and HCV infections, alcohol consumption of ≥40 g of ethanol per day, and BMI of >25.0 kg/m² 10 years before diagnosis, respectively. HBV and HCV infection and BMI of >25.0 kg/m² remained independent risk factors even after adjusting for severity of liver fibrosis. Among HCV-infected individuals, the relative risk of hepatocellular carcinoma for a 1 kg/m² increase in BMI was 1.39 (P = 0.003).

Conclusions: To limit the risk for hepatocellular carcinoma, control of excess weight may be crucial for individuals with chronic liver disease, especially those with chronic hepatitis C. (Cancer Epidemiol Biomarkers Prev 2008;17(4):846–54)

Impact of Estrogen Deprivation on Gene Expression Profiles of Normal Postmenopausal Breast Tissue In vivo

2008-04-08

Aromatase inhibitors play a key role in the clinical management of hormone receptor–positive breast cancer and have potential utility as chemopreventive agents. Further understanding of the molecular effects of estrogen and its deprivation in normal breast tissue may allow the development of biomarkers of risk of breast cancer and help to predict the value of chemoprevention with aromatase inhibitors. Core biopsies of normal breast tissue were taken before and after letrozole treatment from postmenopausal women in the LITMaS pilot prevention study. RNA was extracted from these samples and used for cDNA microarray analysis. Gene expression changes induced by letrozole treatment were much less extensive than observed in estrogen receptor–positive malignant tissue; however, overall, they correlated to a highly significant degree ( = 0.511; P < 10^–20). As well as some classically estrogen-associated genes, many genes associated with extracellular matrix remodeling were affected by estrogen deprivation in the normal breast in vivo. These data indicate for the first time that gene expression of normal breast tissue remains dependent on endogenous estrogens after the menopause. The modest degree of gene change suggests that intermediate markers of chemoprevention may be difficult to identify. (Cancer Epidemiol Biomarkers Prev 2008;17(4):855–63)

Prediagnostic Use of Hormone Therapy and Mortality After Breast Cancer

2008-04-08

Background: A few studies have observed reduced breast cancer mortality in women who used hormone therapy before diagnosis. Due to the high prevalence of past and current hormone use, it is important to investigate whether these preparations are related to breast cancer mortality.

Methods: To evaluate the influence of prediagnostic use of hormone therapy on breast cancer mortality, a prospective cohort of 12,269 women ages 50 years or more diagnosed with incident invasive breast cancer and residents of Wisconsin, Massachusetts, or New Hampshire were enrolled in three phases beginning in 1988. They were followed for death until December 31, 2005, using the National Death Index. Cumulative mortality and multivariable adjusted hazard rate ratios for breast cancer and other mortality causes were calculated for women according to any hormone therapy use, and for exclusive use of estrogen or estrogen-progestin (EP).

Results: During an average 10.3 years of follow-up, 1,690 deaths from breast cancer were documented. Cumulative mortality from breast cancer was lower among hormone therapy users, specifically current users at the time of diagnosis, and EP users, compared with nonusers. Adjusted survival varied by type and duration of hormone therapy before diagnosis. A reduced risk of death from breast cancer was associated with EP preparations (hazard rate ratio, 0.73; 0.59-0.91) and with ≥5 years of EP use (0.60; 0.43-0.84). No association was observed for women who were former or current users of E-alone preparations.

Conclusions: Although use of combined EP preparations increases breast cancer risk, in this study, use of these hormones before diagnosis was associated with reduced risk of death after a breast cancer diagnosis. The better survival among users, particularly of EP, persisted after adjustment of screening, stage, and measured confounders. (Cancer Epidemiol Biomarkers Prev 2008;17(4):864–71)

Association of Mammographic Density with the Pathology of Subsequent Breast Cancer among Postmenopausal Women

2008-04-08

Background: Limited studies have examined the associations between mammographic density and subsequent breast tumor characteristics.

Methods: Eligible women were part of a case-control study of postmenopausal breast cancer, were 40 years or older and had a routine mammogram 4 years or more before their diagnosis. Mammographic density (percent density, dense area, and nondense area) was estimated using a computer-assisted thresholding program. At the time of cancer diagnosis, cases were classified as asymptomatic or symptomatic based on medical record review and breast imaging workup. Pathologic review was done blinded to the density status. Linear regression models and tests for trend examined the association between pathologic characteristics of the breast tumor and the components of density for all participants, and stratified by symptom status at diagnosis.

Results: Of the 286 eligible cases, 77% were 60 years or older and mean percent density was 29.5% (SD, 14.6%). Density was not significantly associated with tumor size (P = 0.22), histologic type (P = 0.77), estrogen receptor (P = 0.11) or progesterone receptor (P = 0.37) status, mitotic activity (P = 0.12), or nuclear pleomorphism (P = 0.09; P values for percent density). An inverse association was suggested between tumor grade and percent density (32.0%, 30.3%, 26.7% for grades 1-3; P = 0.06 for trend). The inverse association with tumor grade and its components (nuclear pleomorphism and tubular differentiation) was only evident among the 97 symptomatic women; positive associations of estrogen receptor (P = 0.009) and progesterone receptor (P = 0.04) were also seen with percent density only in this subgroup.

Conclusions: The inverse association between tumor grade and percent density in the symptomatic population could inform the biology of the association between mammographic density and breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2008;17(4):872–9)

Genetic Polymorphisms Involved in Insulin-like Growth Factor (IGF) Pathway in Relation to Mammographic Breast Density and IGF Levels

Diorio, C., Brisson, J., Berube, S., Pollak, M. — 2008-04-08

The insulin-like growth factor (IGF) pathway is believed to play a role in carcinogenesis of the mammary gland. Single nucleotide polymorphisms (SNPs) of IGF-I, IGF-binding protein-3 (IGFBP-3), IGF receptor 1, insulin receptor substrate 1, and phosphoinositide-3-kinase, catalytic, β polypeptide genes, which are members of the IGF pathway, have been associated with risk of common cancers, breast density, and/or IGF levels but results remain inconclusive. Thus, we evaluated the association of 11 targeted IGF pathway SNPs with circulating IGF levels and mammographic breast density. Among 741 white premenopausal women, blood samples were collected at time of screening mammography, and plasma IGF-I and IGFBP-3 levels were measured by ELISA. Percent and absolute breast density were estimated using a computer-assisted method. Multivariate linear models were used to examine the associations. Women carrying increasing number of copies of the rare allele of IGF-I rs1520220 and rs6220 SNPs had increased percent breast density (P_trend = 0.04 and 0.06, respectively). Carriers of increasing number of copies of the rare allele of phosphoinositide-3-kinase, catalytic, β polypeptide rs361072 SNP had decreased percent (P_trend = 0.04) and absolute (P_trend = 0.02) breast density. An association of insulin receptor substrate 1 rs1801278 SNP with absolute density (P_trend = 0.03) was also observed. All four IGFBP-3 SNPs (including rs2854744) were associated with IGF-I and IGFBP-3 levels. This study shows that several components of the IGF pathway are associated with breast density or IGF levels. Our findings provide additional support for the idea that several components of the IGF pathway may affect breast cancer risk and that this effect on breast cancer development may be mediated, at least in part, through its influence on the morphogenesis of breast tissue. (Cancer Epidemiol Biomarkers Prev 2008;17(4):880–8)

Serum Levels of Vitamin D Metabolites and Breast Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

2008-04-08

Experimental and epidemiologic studies suggest that vitamin D metabolites (1,25-dihydroxyvitamin D [1,25(OH)₂D] and its precursor 25-hydroxyvitamin D [25(OH)D]) may reduce breast cancer risk. We examined subsequent breast cancer risk related to serum levels of these metabolites. In a cohort of women ages 55 to 74 years, who donated blood at baseline (1993-2001) in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we identified 1,005 incident breast cancer cases during follow-up through 2005 (mean time between blood draw and diagnosis, 3.9 years). Noncases (n = 1,005) were frequency matched to the cases based on age and year of entry. Sample weights that accounted for unequal probabilities of selecting cases and noncases were applied to make inferences that reflected the entire Prostate, Lung, Colorectal, and Ovarian cohort. Using Cox proportional hazards modeling, we computed breast cancer relative risks (RR) and 95% confidence intervals (95% CI) by quintile for each metabolite. The RR of breast cancer for the highest quintile of 25(OH)D concentration versus the lowest was 1.04 (95% CI, 0.75-1.45; P_trend = 0.81). Similarly, the breast cancer RR for the highest quintile of 1,25(OH)₂D compared with the lowest was 1.23 (95% CI, 0.91-1.68; P_trend = 0.14). Excluding the first 2 years of follow-up did not materially alter these estimates. There was also no evidence of inverse risk in older women (≥60 years) versus younger women (<60 years). In this prospective study of postmenopausal women, we did not observe an inverse association between circulating 25(OH)D or 1,25(OH)₂D and breast cancer risk, although we cannot exclude an association in younger women or with long-term or earlier exposure. (Cancer Epidemiol Biomarkers Prev 2008;17(4):889–94)

Coffee Consumption and CYP1A2*1F Genotype Modify Age at Breast Cancer Diagnosis and Estrogen Receptor Status

Bageman, E., Ingvar, C., Rose, C., Jernstrom, H. — 2008-04-08

CYP1A2 plays a key role in the metabolism of both estrogen and coffee. Women with higher coffee intake and the CYP1A2*1F A/A genotype have a ratio of high 2-hydroxyestrone (2-OHE1) to 16-OHE1. 2-OHE1 is a weak estrogen and may even block the estrogen receptor (ER), whereas 16-OHE1 is procarcinogenic. We hypothesized that moderate to high coffee consumption (≥2 cups per day) combined with the CYP1A2*1F A/A genotype would be associated with a later age at diagnosis and a greater proportion of ER-negative (ER–) tumors among patients with breast cancer. We genotyped 458 patients with breast cancer (age, 25-99 years) in Lund, Sweden, for CYP1A2*1F. Information on lifestyle factors and tumor characteristics were obtained from preoperative questionnaires and pathology reports. Among patients with CYP1A2*1F A/A (51.3%), moderate to high consumption was associated with a later age at diagnosis compared with low coffee consumption (59.8 versus 52.6 years, P = 0.0004). These patients were also more likely to have ER– tumors than patients with low consumption (14.7% versus 0%, P = 0.018). Coffee was not associated with ER status or age at diagnosis in patients with at least one C allele. Age at diagnosis was not associated with ER status in patients with CYP1A2*1F A/A, but younger patients (<50 years) with at least one C allele were more likely to have ER– tumors compared with older patients (odds ratio, 4.2; 95% confidence interval, 1.9-9.3; P = 0.0002). These findings raise the hypothesis that coffee slows the growth of ER-positive tumors in patients with CYP1A2*1F A/A and may have implications for breast cancer if confirmed. (Cancer Epidemiol Biomarkers Prev 2008;17(4):895–901)

Height, Body Mass Index, and Ovarian Cancer: A Pooled Analysis of 12 Cohort Studies

2008-04-08

Background: Although many studies have investigated the association between anthropometry and ovarian cancer risk, results have been inconsistent.

Methods: The associations of height, body mass index (BMI), and ovarian cancer risk were examined in a pooled analysis of primary data from 12 prospective cohort studies from North America and Europe. The study population consisted of 531,583 women among whom 2,036 epithelial ovarian cancer cases were identified. To summarize associations, study-specific relative risks (RR) were estimated using the Cox proportional hazards model and then combined using a random-effects model.

Results: Women with height ≥1.70 m had a pooled multivariate RR of 1.38 [95% confidence interval (95% CI), 1.16-1.65] compared with those with height <1.60 m. For the same comparison, multivariate RRs were 1.79 (95% CI, 1.07-3.00) for premenopausal and 1.25 (95% CI, 1.04-1.49) for postmenopausal ovarian cancer (P_interaction = 0.14). The multivariate RR for women with a BMI ≥30 kg/m² was 1.03 (95% CI, 0.86-1.22) compared with women with a BMI from 18.5 to 23 kg/m². For the same comparison, multivariate RRs were 1.72 (95% CI, 1.02-2.89) for premenopausal and 1.07 (95% CI, 0.87-1.33) for postmenopausal women (P_interaction = 0.07). There was no statistically significant heterogeneity between studies with respect to height or BMI. BMI in early adulthood was not associated with ovarian cancer risk.

Conclusion: Height was associated with an increased ovarian cancer risk, especially in premenopausal women. BMI was not associated with ovarian cancer risk in postmenopausal women but was positively associated with risk in premenopausal women. (Cancer Epidemiol Biomarkers Prev 2008;17(4):902–12)

BTF4/BTNA3.2 and GCS as Candidate mRNA Prognostic Markers in Epithelial Ovarian Cancer

2008-04-08

This study aims to identify reliable prognosis markers to predict patient outcome at surgery in high-grade serous epithelial ovarian cancer by a real-time quantitative PCR (RT-q-PCR)-based test. Seventeen tissue samples from serous epithelial ovarian cancer patients were screened by DNA microarray to identify genes differentially expressed between tumors from patients who relapsed within 18 months and tumors from patients showing no relapse or relapsed after 24 months after initial diagnosis. RNA expression of a subset of genes was validated by RT-q-PCR in the initial set of 17 samples. From these results, a refined list was selected and tested in independent samples from 41 serous. Expression was associated with time to relapse and clinical variables. Microarray analysis identified a profile of 34 differentially expressed genes. RT-q-PCR validated the expression profile of a subset of seven genes in the initial set of patients. Differential gene expression was also validated in an independent set of patients. Low BTF4 or GCS expression was strongly associated with poor outcome in Kaplan-Meier analysis (P < 0.05, log-rank test) and Cox univariate as well as in multivariate analyses with a higher hazard ratio than clinical variables, such as residual disease, age, stage, and grade. (Cancer Epidemiol Biomarkers Prev 2008;17(4):913–20)

A Prospective Evaluation of Insulin and Insulin-like Growth Factor-I as Risk Factors for Endometrial Cancer

2008-04-08

Obesity is a major risk factor for endometrial cancer, a relationship thought to be largely explained by the prevalence of high estrogen levels in obese women. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed whether insulin and/or insulin-like growth factor-I (IGF-I), a related hormone, are associated with endometrial cancer while accounting for estrogen levels. We therefore conducted a case-cohort study of incident endometrial cancer in the Women's Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. The study involved all 250 incident cases and a random subcohort of 465 subjects for comparison. Insulin, total IGF-I, free IGF-I, IGF-binding protein-3, glucose, and estradiol levels were measured in fasting baseline serum specimens. Cox models were used to estimate associations with endometrial cancer, particularly endometrioid adenocarcinomas, the main histologic type (n = 205). Our data showed that insulin levels were positively associated with endometrioid adenocarcinoma [hazard ratio contrasting highest versus lowest quartile (HR_q4-q1), 2.33; 95% confidence interval (95% CI), 1.13-4.82] among women not using hormone therapy after adjustment for age and estradiol. Free IGF-I was inversely associated with endometrioid adenocarcinoma (HR_q4-q1, 0.53; 95% CI, 0.31-0.90) after adjustment for age, hormone therapy use, and estradiol. Both of these associations were stronger among overweight/obese women, especially the association between insulin and endometrioid adenocarcinoma (HR_q4-q1, 4.30; 95% CI, 1.62-11.43). These data indicate that hyperinsulinemia may represent a risk factor for endometrioid adenocarcinoma that is independent of estradiol. Free IGF-I levels were inversely associated with endometrioid adenocarcinoma, consistent with prior cross-sectional data. (Cancer Epidemiol Biomarkers Prev 2008;17(4):921–9)

Dairy Product, Saturated Fatty Acid, and Calcium Intake and Prostate Cancer in a Prospective Cohort of Japanese Men

2008-04-08

Many epidemiologic studies have reported a positive association between dairy products and prostate cancer. Calcium or saturated fatty acid in dairy products has been suspected as the causative agent. To investigate the association between dairy products, calcium, and saturated fatty acid and prostate cancer in Japan, where both the intake of these items and the incidence of prostate cancer are low, we conducted a population-based prospective study in 43,435 Japanese men ages 45 to 74 years. Participants responded to a validated questionnaire that included 138 food items. During 7.5 years of follow-up, 329 men were newly diagnosed with prostate cancer. Dairy products were associated with a dose-dependent increase in the risk of prostate cancer. The relative risks (95% confidence intervals) comparing the highest with the lowest quartiles of total dairy products, milk, and yogurt were 1.63 (1.14-2.32), 1.53 (1.07-2.19), and 1.52 (1.10-2.12), respectively. A statistically significant increase in risk was observed for both calcium and saturated fatty acid, but the associations for these were attenuated after controlling for potential confounding factors. Some specific saturated fatty acids increased the risk of prostate cancer in a dose-dependent manner. Relative risks (95% confidence intervals) on comparison of the highest with the lowest quartiles of myristic acid and palmitic acid were 1.62 (1.15-2.29) and 1.53 (1.07-2.20), respectively. In conclusion, our results suggest that the intake of dairy products may be associated with an increased risk of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(4):930–7)

Consumption of Raw Cruciferous Vegetables is Inversely Associated with Bladder Cancer Risk

2008-04-08

Cruciferous vegetables contain isothiocyanates, which show potent chemopreventive activity against bladder cancer in both in vitro and in vivo studies. However, previous epidemiologic studies investigating cruciferous vegetable intake and bladder cancer risk have been inconsistent. Cooking can substantially reduce or destroy isothiocyanates, and could account for study inconsistencies. In this hospital-based case-control study involving 275 individuals with incident, primary bladder cancer and 825 individuals without cancer, we examined the usual prediagnostic intake of raw and cooked cruciferous vegetables in relation to bladder cancer risk. Odds ratios (OR) and 95% confidence intervals (CI) were estimated with unconditional logistic regression, adjusting for smoking and other bladder cancer risk factors. We observed a strong and statistically significant inverse association between bladder cancer risk and raw cruciferous vegetable intake (adjusted OR for highest versus lowest category = 0.64; 95% CI, 0.42-0.97), with a significant trend (P = 0.003); there were no significant associations for fruit, total vegetables, or total cruciferous vegetables. The associations observed for total raw crucifers were also observed for individual raw crucifers. The inverse association remained significant among current and heavy smokers with three or more servings per month of raw cruciferous vegetables (adjusted ORs, 0.46 and 0.60; 95% CI, 0.23-0.93 and 0.38-0.93, respectively). These data suggest that cruciferous vegetables, when consumed raw, may reduce the risk of bladder cancer, an effect consistent with the role of dietary isothiocyanates as chemopreventive agents against bladder cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(4):938–44)

Detection and Quantitation of N'-Nitrosonornicotine in Human Toenails by Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry

Stepanov, I., Hecht, S. S. — 2008-04-08

Specific biomarkers of tobacco carcinogen uptake are critical for investigations of the role of tobacco smoke exposure in human cancers. Two new biomarkers of human exposure to tobacco-specific carcinogens have been recently developed by our research group: urinary N'-nitrosonornicotine (NNN) and toenail 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). In this study, we report the presence of NNN in human toenails. Toenails of 17 smokers were analyzed for total NNN. Mean total NNN level in these samples was 4.63 ± 6.48 fmol/mg toenail and correlated with previously reported total NNAL (r = 0.96; P < 0.0001), total nicotine (r = 0.48; P < 0.05), and total cotinine (r = 0.87; P < 0.0001). An interesting finding was that amounts of NNN in smokers' toenails were generally higher than those of total NNAL. The ratio of toenail NNN to NNAL averaged 2.8, whereas the previously reported ratio between these biomarkers in smokers' urine was 0.1. NNN was also found in toenail samples from 12 nonsmokers, averaging 0.35 ± 0.16 fmol/mg and positively correlating with toenail cotinine (r = 0.58; P = 0.05). The results of this study show the feasibility of quantifying NNN in human toenails, providing a potentially useful new biomarker of tobacco carcinogen exposure. (Cancer Epidemiol Biomarkers Prev 2008;17(4):945–8)

Prognostic Significance of Cadherin-Based Adhesion Molecules in Cutaneous Malignant Melanoma

2008-04-08

Background: The need for novel molecular prognostic markers that can supplement validated clinicopathologic correlates for cutaneous malignant melanoma is well recognized. Proteins that mediate the epithelial-mesenchymal transition, the process by which a cancer cell disengages from its parent tumor, are important candidates.

Methods: The prognostic relevance of E-cadherin, N-cadherin, and P-cadherin, calcium-dependent transmembrane glycoproteins that regulate cell-cell adhesion, and their adaptors, -catenin, β-catenin, and p120-catenin, was evaluated on a cohort of 201 primary and 274 metastatic melanoma tumors using fluorescence-based immunohistochemical methods and Automated Quantitative Analysis of protein expression on digitally captured photomicrographs.

Results: Increasing levels of N-cadherin expression improved overall survival (log-rank = 7.31; P = 0.03) but did not retain significance following adjustment for established clinicopathologic correlates (P = 0.50). Higher levels of E-cadherin approached significance for favorable prognosis on both univariate (P = 0.13) and multivariable (P = 0.10) analyses. Hierarchical clustering of the composite profiles for all six markers identified four unique clusters that yielded differential overall survival (log-rank = 10.54; P = 0.01). Cluster 4, expressing high E-cadherin and N-cadherin levels, possessed the most favorable outcome and cluster 2, featuring low E-cadherin and -catenin but modest N-cadherin, showed least favorable outcomes. Cluster 2 remained significant on multivariable analysis (hazard ratio, 3.29; 95% confidence interval, 1.50-7.19; P = 0.003).

Conclusions: Although none of the cadherin-based adhesion molecules were independently prognostic, multimarker profiles were significant. Similar to epithelial-derived tumors, loss of E-cadherin correlates with poor outcome. In contrast, for neural crest–derived cutaneous malignant melanoma, N-cadherin overexpression can be associated with either a successful epithelial-mesenchymal transition or a favorably differentiated tumor. Additional cadherin profiles are needed to discriminate these distinctive phenotypes. (Cancer Epidemiol Biomarkers Prev 2008;17(4):949–58)

Family History of Cancer and Associated Risk of Developing Neuroendocrine Tumors: A Case-Control Study

Hassan, M. M., Phan, A., Li, D., Dagohoy, C. G., Leary, C., Yao, J. C. — 2008-04-08

Background: Carcinoids are rare neuroendocrine tumors (NET). Familial clusterings of NETs are rarely reported, except for a small proportion associated with multiple endocrine neoplasia syndrome type 1. We evaluated the effect of positive family history of NET as well as other cancers on the development of NETs arising at five different locations.

Methods: We conducted a retrospective, hospital-based, case-control study involving 740 patients with histologically confirmed NETs and 924 healthy controls. Information on family history of cancer was collected, and unconditional logistic regression analysis was used to determine adjusted odds ratios (AOR) and 95% confidence intervals (CI).

Results: The authors observed a significant relationship between first-degree relatives with cancers and the development of NETs arising at the small intestine, stomach, lung, and pancreas; AORs (95% CI) were 1.6 (1.1-2.4), 2.5 (1.1-6.3), 2.6 (1.5-4.5), and 1.8 (1.1-3.1), respectively. A first-degree family history of esophageal cancer was significantly associated with pancreatic NETs; AOR, 5.6 (95% CI, 1.1-29.6). There was a 70% and 130% increased risk of developing small intestinal NETs among subjects with family histories of colorectal cancer and prostate cancer, respectively. Moreover, individuals with a family history of lung cancer had a 2-fold increase in risk of developing pulmonary NETs.

Conclusions: Having a first-degree relative with any cancer in general, and NET in particular, was a risk factor for NETs. The elevated risk of developing NETs extended to individuals with a family history of other cancers (not NETs) among first-degree relatives. These results suggested that risk of NETs may be partially explained by genetic factors. (Cancer Epidemiol Biomarkers Prev 2008;17(4):959–65)

Line Region Hypomethylation Is Associated with Lifestyle and Differs by Human Papillomavirus Status in Head and Neck Squamous Cell Carcinomas

Furniss, C. S., Marsit, C. J., Houseman, E. A., Eddy, K., Kelsey, K. T. — 2008-04-08

Genomic hypomethylation is a hallmark of essentially all cancers, but the degree of this hypomethylation differs among individual tumors. Little work has explored what leads to these differences and or asked whether they are clinically meaningful. In this study of head and neck squamous cell carcinoma, we assessed hypomethylation in tumors using a semiquantitative fragment analysis approach to determine the relative methylation status of the line retroviral element LRE1 (Line-1.2). Because this is an established marker of genomic methylation status, we examined the relationship between the relative methylation, patient demographics, and other risk factors for head and neck squamous cell carcinoma. We determined relative methylation status for 303 patients, 193 of which had complete data for all variables of interest. Using a generalized linear model, we found that patient body mass index was significantly positively associated with tumor LRE1 methylation level. Smoking duration, particularly in tumors lacking human papillomavirus (HPV) DNA, was significantly negatively associated with relative methylation level. Having previously assessed relative methylation in blood-derived DNA, we compared tumor with the blood DNA methylation level and observed these to be independent. Finally, the lower LRE1 methylation in patients whose tumors were HPV DNA negative was associated with poorer patient survival (hazard ratio, 1.6; 95% confidence interval, 1.0-2.6). These findings suggest that HPV-associated tumors differ molecularly from those arising after heavy tobacco use and that this epigenetic alteration may affect survival in HPV-negative patients already exhibiting a more aggressive disease. (Cancer Epidemiol Biomarkers Prev 2008;17(4):966–71)

Polymorphisms in Angiogenesis-Related Genes and Prostate Cancer

2008-04-08

Background: Angiogenesis is required for development and progression of prostate cancer. Potentially functional single nucleotide polymorphisms (SNP) in genes important in prostate angiogenesis (VEGF, HIF1A, and NOS3) have previously been associated with risk or severity of prostate cancer.

Methods: Prostate cancer cases (n = 1,425) and controls (n = 1,453) were selected from the Cancer Prevention Study II Nutrition Cohort. We examined associations between 58 SNPs in nine angiogenesis-related candidate genes (EGF, LTA, HIF1A, HIF1AN, MMP2, MMP9, NOS2A, NOS3, VEGF) and risk of overall and advanced prostate cancer. Unconditional logistic regression was used to estimate odds ratios, adjusted for matching factors.

Results: Our results did not replicate previously observed associations with SNPs in VEGF, HIF1A, or NOS3, nor did we observe associations with SNPs in EGF, LTA, HIF1AN, MMP9, or NOS2A. In the MMP2 gene, three intronic SNPs, all in linkage disequilibrium, were associated with overall and advanced prostate cancer (for overall prostate cancer, P_trend = 0.01 for rs1477017, P_trend = 0.01 for rs17301608, P_trend = 0.02 for rs11639960). However, two of these SNPs (rs17301608 and rs11639960) were examined and were not associated with prostate cancer in a recent genome-wide association study using prostate cancer cases and controls from the Prostate, Lung, Colorectal, and Ovary study cohort. Furthermore, when we pooled our results for these two SNPs with those from the Prostate, Lung, Colorectal, and Ovary cohort; neither SNP was associated with prostate cancer.

Conclusion: None of the SNPs examined seem likely to be importantly associated with risk of overall or advanced prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(4):972–7)

Transcription Factor 7-like 2 Polymorphism and Colon Cancer

2008-04-08

Polymorphisms of the transcription factor 7–like 2 (TCF7L2) gene have been associated with insulin sensitivity and diabetes, and the TCF7L2 gene is involved in the Wnt/β-catenin signaling pathway, all factors thought to be important in the etiology of colon cancer. In this confirmatory study, we evaluated the rs7903146 TCF7L2 polymorphism with colon cancer using previously collected data on 1,578 cases and 1,966 controls. We did not observe a statistically significant association between the rs7903146 polymorphisms and risk of colon cancer [odds ratio (OR), 1.12; 95% confidence interval (95% CI), 0.98-1.28] when evaluating the total population. We did, however, observe a statistically significant interaction between the rs7903146 TCF7L2 polymorphism and recent use of aspirin/nonsteroidal anti-inflammatory drugs (NSAID; P = 0.001). Increased colon cancer risk associated with the T allele was restricted to those without recent use of aspirin/NSAIDs (OR, 1.65; 95% CI, 1.35-2.02, relative to recent aspirin users, i.e., use of aspirin/NSAIDS within the 2 years before diagnosis, with the CC genotype). Among individuals who reported recent use of aspirin/NSAIDs, the T allele reduced risk of colon cancer (OR, 0.78; 95% CI, 0.62-0.98) in a dose-response fashion (P for linear trend across genotypes = 0.03). These data suggest that colon cancer risk associated with the rs7903146 TCF7L2 polymorphism is modified by use of aspirin/NSAIDs. (Cancer Epidemiol Biomarkers Prev 2008;17(4):978–82)

MDM2 SNP309 Is Associated with Endometrial Cancer Risk

Terry, K., McGrath, M., Lee, I-M., Buring, J., De Vivo, I. — 2008-04-08

Mouse double-minute 2 homologue (MDM2) is a key negative regulator of p53, a tumor suppressor gene that initiates cell cycle arrest and apoptosis in response to DNA damage and other cellular stresses. A T > G polymorphism found in the promoter region of MDM2 (SNP309) increases MDM2 expression and thereby attenuates p53 activity. We genotyped the MDM2 polymorphism SNP309 in endometrial cancer case-control studies nested within the Nurses' Health Study (454 cases and 1,132 controls) and the Women's Health Study (137 cases and 411 controls). Due to a significant difference in genotype distribution by ethnicity, we restricted our analyses to Caucasians. We calculated odds ratios and 95% confidence intervals using conditional and unconditional logistic regression adjusted for age at menarche, parity and age at first birth, postmenopausal hormone use at diagnosis, age at menopause and menopausal status at diagnosis, first-degree family history of colon cancer, body mass index at diagnosis, and cigarette smoking status at diagnosis. Women with a heterozygous genotype had no greater risk whereas those with a homozygous variant genotype had a greater risk than women with a wild-type genotype for the MDM2 SNP309 (covariate-adjusted odds ratio, 1.87; 95% confidence interval, 1.29-2.73) for endometrial cancer. We observed no association between age at diagnosis and genotype. Women carrying two copies of the MDM2 SNP309 variant may be at greater risk of endometrial cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(4):983–6)

The Common D302H Variant of CASP8 Is Associated with Risk of Glioma

2008-04-08

Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and, hence, a defense against cancer. We tested the hypothesis that the CASP8 polymorphism D302H influences risk of glioma through analysis of five series of glioma case patients and controls (n = 1,005 and 1,011, respectively). Carrier status for the rare allele of D302H was associated with a 1.37-fold increased risk (95% confidence interval, 1.10-1.70; P = 0.004). The association of CASP8 D302H with glioma risk indicates the importance of inherited variation in the apoptosis pathway in susceptibility to this form of primary brain tumor. (Cancer Epidemiol Biomarkers Prev 2008;17(4):987–9)

No Evidence for Differences in DNA Damage Assessed before and after a Cancer Diagnosis

2008-04-08

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. (Cancer Epidemiol Biomarkers Prev 2008;17(4):990–4)

Differential Methylation of a Short CpG-Rich Sequence within Exon 1 of TCF21 Gene: A Promising Cancer Biomarker Assay

2008-04-08

Detection of cancer cells at early stages could potentially increase survival rates in cancer patients. Aberrant promoter hypermethylation is a major mechanism for silencing tumor suppressor genes in many kinds of human cancers. A recent report from our laboratory described the use of quantitative methylation-specific PCR assays for discriminating patients with lung cancer from those without lung cancer using lung biopsies as well as sputum samples. TCF21 is known to be essential for differentiation of epithelial cells adjacent to mesenchyme. Using restriction landmark genomic scanning, a recent study identified TCF21 as candidate tumor suppressor at 6q23-q24 that is epigenetically inactivated in lung and head and neck cancers. Using DNA sequencing technique, we narrowed down a short CpG-rich segment (eight specific CpG sites in the CpG island within exon 1) of the TCF21 gene, which was unmethylated in normal lung epithelial cells but predominantly methylated in lung cancer cell lines. We specifically targeted this short CpG-rich sequence and developed a quantitative methylation-specific PCR assay suitable for high-throughput analysis. We showed the usefulness of this assay in discriminating patients with lung cancer from those without lung cancer using biopsies and sputum samples. We further showed similar applications with multiple other malignancies. Our assay might have important implications in early detection and surveillance of multiple malignancies. (Cancer Epidemiol Biomarkers Prev 2008;17(4):995–1000)

Association between Genetic Polymorphisms of Macrophage Scavenger Receptor 1 Gene and Risk of Prostate Cancer in the Health Professionals Follow-up Study

Chen, Y.-C., Giovannucci, E., Kraft, P., Hunter, D. J. — 2008-04-08

Background: Macrophage scavenger receptor 1 (MSR1) is involved in chronic inflammation, which is a risk factor for prostate cancer. Association studies assessing the relationship between sequence variants of MSR1 and prostate cancer are inconsistent. We hypothesized that sequence variants of MSR1 were associated with prostate cancer risk.

Methods: In a nested case-control design within the Health Professionals Follow-up Study, we identified 700 participants with prostate cancer diagnosed after they had provided a blood specimen in 1993 and before January 2000. Controls were 700 age-matched men without prostate cancer who had had a prostate-specific antigen test after providing a blood specimen. We genotyped three common (>5%) single nucleotide polymorphisms (SNP) that have been reported previously to be associated with risk of prostate cancer.

Results: None of these MSR1 SNPs nor estimated haplotypes were associated with prostate cancer risk (P for the global test for haplotypes = 0.89). These MSR1 SNPs also did not appear to be associated with higher-grade or advanced-stage prostate cancer.

Conclusion: The association between these sequence variants of MSR1 and the risk of prostate cancer was null. Further study of aggressive prostate cancer may be warranted, as we had limited power to assess these. (Cancer Epidemiol Biomarkers Prev 2008;17(4):1001–3)

Lack of Association Between Physical Activity in Smokers and Plasma Glutathione Peroxidase Levels

Rundle, A., Richards, C., Tang, D., Perera, F. — 2008-04-08

Single Nucleotide Polymorphisms in Obesity-Related Genes and the Risk of Esophageal Cancers

2008-04-08

Rates of adenocarcinoma of the esophagus (EAC) and esophagogastric junction (EGJAC) have been rising rapidly in recent decades, in contrast to the declining rates of esophageal squamous cell carcinomas (ESCC). Obesity is a major risk factor for both EAC and EGJAC, but not ESCC, and there is speculation that obesity promotes adenocarcinoma development through endocrine and related pathways. We therefore compared the prevalence of 12 single nucleotide polymorphisms (SNPs) in nine candidate genes previously implicated in obesity pathways (LEP, LEPR, ADIPOQ, POMC, PPAR, PPAR, RXR, GHRL, and INSIG2) in a large Australian case-control study comprising DNA samples from 260 EAC cases, 301 EGJAC cases, 213 ESCC cases, and 1,352 population controls. No SNPs were associated with EGJAC or ESCC. Although several SNPs seemed to be associated with EAC on crude analysis [ADIPOQ (rs1501299), LEP (5'-untranslated region), PPAR (H447H), and GHRL (M72L)], effect sizes were modest and none of the associations was significant after correcting for multiple comparisons. Further, we found no consistent evidence that any of the genotypes were associated with risk of EAC or EGJAC within strata of body mass index (<25.0 kg/m², 25.0-29.9 kg/m², >30 kg/m²). In conclusion, our data suggest that these SNPs do not play a major role in esophageal carcinogenesis. (Cancer Epidemiol Biomarkers Prev 2008;17(4):1007–12)

The Ratio of Specific Polychlorinated Biphenyls as a Surrogate Biomarker of Cytochrome P4501A2 Activity--A Pharmaco-Metabonomic Study in Humans

Ye, X., Fitzgerald, E. F., Gomez, M. I., Lambert, G. H., Longnecker, M. P. — 2008-04-08

Polymorphisms in RAD51, XRCC2, and XRCC3 Are Not Related to Breast Cancer Risk

2008-04-08

Is Sunlight Important to Melanoma Causation?

Tucker, M. A. — 2008-03-18

Are We Overemphasizing Sun Avoidance in Protection from Melanoma?

Wartman, D., Weinstock, M. — 2008-03-18

The public health effect of melanoma in the United States is undeniable as ~60,000 diagnoses of invasive melanoma and 8,000 deaths from melanoma are expected in 2007. Due to the poor outcomes associated with treating advanced cases of melanoma, substantial public health resources have been devoted to prevention efforts. Of the various factors involved in the pathogenesis of melanoma, including genetic predisposition, immunosuppression, and UV radiation, decreasing UV exposure has attracted the most attention for decreasing the public health effect of melanoma. Although sun avoidance may be an important measure for reducing the public health effect of melanocytic and keratinocytic malignancies, educational and media campaigns to encourage sun avoidance have failed to achieve the desired behavior changes in young people, have had limited effect on elderly patients who have already experienced decades of damaging sun exposure, and most importantly have failed to decrease the incidence of melanoma. We believe the best method to reduce deaths from melanoma is to emphasize early detection and treatment of suspicious lesions through combined efforts of both patients and providers. (Cancer Epidemiol Biomarkers Prev 2008;17(3):469–70)

Ancestry Estimation and Correction for Population Stratification in Molecular Epidemiologic Association Studies

Barnholtz-Sloan, J. S., McEvoy, B., Shriver, M. D., Rebbeck, T. R. — 2008-03-18

Prostate Cancer, Serum Parathyroid Hormone, and the Progression of Skeletal Metastases

Schwartz, G. G. — 2008-03-18

Bony metastases from prostate cancer are a significant cause of morbidity and mortality. These metastases are predominantly blastic (bone-forming) and commonly cause increased serum levels of parathyroid hormone (PTH) as calcium ions are transferred from serum into blastic bone. The epidemiologic and clinical significance of secondary hyperparathyroidism in advanced prostate cancer have not been widely appreciated. Prostate cancer bony metastases show increased expression of the PTH receptor (PTH-IR) and PTH promotes the growth and invasiveness of prostate cancer cells in bone. Thus, blastic metastases appear to induce a "vicious cycle" in which PTH resorbs normal bone to support the growth of blastic bone. Recognition of the potential role of PTH in the progression of skeletal metastases suggests novel opportunities for prostate cancer secondary prevention. In particular, we propose that suppressing serum PTH in advanced prostate cancer may reduce morbidity by decreasing fractures and pain caused by bone resorption and may reduce mortality by retarding the progression of metastatic disease. (Cancer Epidemiol Biomarkers Prev 2008;17(3):478–83)