We have recently investigated effects of hormone replacement therapy on the serum proteome, and found a high proportion of proteins with altered levels associated with oral estrogen and/or estrogen + progesterone treatment. Given this finding, we have investigated the extent to which exposure to hormone replacement therapy (HRT) may have a confounding effect in the assessment of circulating proteins as cancer biomarkers.
We utilize mass spectrometry data collected from the HRT serum proteome studies to estimate the overall effect of post-menopausal hormone therapy on candidate ovarian cancer biomarkers that have been previously reported.
Levels of approximately half of the proteins reported as potential ovarian cancer biomarkers were found to be affected by HRT. The impact of HRT on levels of insulin-like growth factor and inhibin protein families was found to be substantial.
We conclude that the potential confounding effect of HRT and other types of exposures should be taken into consideration in cancer biomarker study design.
Hormone replacement therapy significantly affects the serum proteome and should be taken into account as part of biomarker study design and data analysis.
Lead is a toxic non-essential metal with widespread exposure starting in utero. Lead has been reclassified in 2004 by the International Agency for Research on Cancer Working Group from a “possible” to “probably” human carcinogen. Lead may be a facilitative or permissive carcinogen which means that lead may permit or augment the genotoxic effects of other exposures.
This population-based study in Wisconsin gathered survey data and home-collected urine specimens from 246 women, aged 20–69 years, with incident invasive breast cancer identified from the Wisconsin state registry and 254 age-matched control subjects from population lists from September 2004 to February 2005. We measured urinary lead concentrations by inductively-coupled plasma mass spectrometry, adjusted the values by specific gravity and conducted interviews by telephone to obtain information on known and suspected breast cancer risk factors.
Women in the highest quartile of specific gravity-adjusted lead level (≥1.10 μg/L) had twice the breast cancer risk of those in the lowest quartile (<0.42 μg/L; OR = 1.99, 95% CI = 1.1 to 3.6) after adjustment for established risk factors. Excluding women who were currently taking nonsteroidal aromatase inhibitors (n=52), we did not observe any increased breast cancer risk after adjustment for established risk factors.
Our population-based case-control study suggests that lead exposure, as determined by specific gravity-adjusted urinary lead concentrations, is not associated with a significant increased risk for breast cancer.
breast cancer; lead exposure; urine samples
The age-specific of occurrence of cervical cancer related to human papillomavirus genotypes HPV16 and HPV18, the two targeted by current HPV vaccines, is not well described. We therefore used data from two large, tissue-based HPV genotyping studies of cervical cancer, one conducted in New Mexico (USA) (n = 744) and an international study restricted to cancers (n = 1,729) from Europe, North America, and Australia to represent those regions with widely available cervical cancer screening facilities. HPV results were categorized as HPV16 or HPV18 positive (HPV16/18) versus other HPV genotype. We observed a decreasing proportion of HPV16/18-positive cancers with increasing age in the international study (ptrend < 0.001) and New Mexico study (ptrend < 0.001). There was no heterogeneity in the relationship between age of diagnosis and the proportion of HPV16/18-positive cancers between studies (p = 0.8). Combining results from the two studies (n = 2,473), the percentages of HPV16/18-positive cases were 77.0% (95%CI: 75.1%-78.9%) for women less than 65 years old and 62.7% (95%CI: 58.4%-66.9%) for women aged 65 and older (p < 0.001). In women who are under the age of 25 and have been vaccinated before becoming sexually active, the cervical cancer incidence is expected to be approximately 3.5 per million by 2020. HPV vaccination against HPV16/18 may have a greater impact on cervical cancers in women under 65 than in women aged 65 and older. These data will inform the age-specific impact of HPV vaccination and its integration with cervical cancer screening activities.
Recently, we identified a novel breast cancer (BC) susceptibility locus at 6q22.33 following a genome-wide association study (GWAS) in the Ashkenazi Jewish (AJ) genetic isolate. To replicate these findings, we performed case-control association analysis on 6q22.33 (rs2180341) in additional 487 AJ BC cases and in an independent non-Jewish (non-AJ), predominantly European-American (EU-Am), populations of 1,466 BC cases and 1,467 controls. We have confirmed the 6q22.33 association with BC risk in the replication cohorts (per-allele OR=1.18, 95%CI 1.04–1.33, p=0.0083) with the strongest effect in the aggregate meta-analysis of 3,039 BC cases and 2,616 AJ and non-AJ controls (per-allele OR=1.24, 95%CI 1.13–1.36, P=3.85×10−7).
We have also shown that the association was slightly stronger with ER positive tumors (per-allele OR=1.35, 95%CI 1.20–1.51, p=2.2×10−5) compared to ER negative tumors (per-allele OR=1.19, 95%CI 0.97–1.47, p=0.1). Furthermore, this study provides a novel insight into the functional significance of 6q22.33 in BC susceptibility. Due to stronger association of 6q22.33 with ER-positive BC we examined the effect of candidate genes on ER response elements (ERE). Upon transfection of overexpressed RNF146 in the MCF-7 BC cell line, we observed diminished expression of an ERE reporter construct. This study confirms the association of 6q22.33 with BC, with slightly stronger effect in ER positive tumors. Further functional studies of candidate genes are in progress and a large replication analysis is being completed as part of an international consortium.
Ashkenazi Jews; Breast Cancer; Genome-wide association studies; SNPs; estrogen receptor
While tobacco is a well-established causal agent for many human cancers, less emphasis has been placed on translating this evidence by evaluating the effects of continued tobacco use after a cancer diagnosis. A broad assessment of the effects of continued tobacco use demonstrates that tobacco increases cancer treatment toxicity, recurrence, second primary tumors, and mortality in cancer patients. Few studies report the potential benefits of cessation after a cancer diagnosis, but data suggest improved treatment outcomes in cancer patients who quit smoking. Improving tobacco cessation treatment efficacy and access to cessation support has been sparsely researched in the oncology setting compared with the general population; however, cancer patients are receptive to standard evidence based tobacco cessation guidelines. Several studies demonstrate moderate tobacco cessation success in cancer patients using the general principles of evidence based tobacco cessation support. Several systems level issues and research efforts are needed to standardize tobacco use definitions, increase access to tobacco cessation support, improve tobacco cessation efficacy, understand the time dependent effects of tobacco and cessation on cancer biology, and realize the potential benefits of tobacco cessation for cancer patients.
Tobacco use behaviors have changed significantly over the past century. After a steep increase in cigarette use rates over the first half of the 20th century, adult smoking prevalence rates started declining from their peak reached in 1964. Improved understanding of the health risks of smoking has been aided by the United States Surgeon General’s Reports, issued on a nearly annual basis starting in 1964. Among the many forces driving down smoking prevalence were the recognition of tobacco use as an addiction and cause of cancer, along with concerns about the ill-effects of breathing secondhand smoke. These factors contributed to the declining social acceptance of smoking, especially with the advent of legal restrictions on smoking in public spaces, mass media counter- marketing campaigns, and higher taxes on cigarettes. This paper reviews some of the forces that have helped change the public image of smoking, focusing on the 50 years since the 1964 Surgeon General’s report on smoking and health.
A comparative effectiveness intervention by this team improved initial fecal occult blood testing (FOBT) rates from 3% to 53% among community clinic patients. The purpose of this study was to evaluate the effectiveness and costs associated with a literacy-informed intervention on repeat FOBT testing.
Between 2008 and 2011, a three-arm quasi-experiential comparative effectiveness evaluation was conducted in 8 community clinics in Louisiana. Clinics were randomly assigned to receive: enhanced care, a screening recommendation and FOBT kit annually; a brief educational intervention where patients additionally received a literacy appropriate pamphlet and simplified FOBT instructions; or nurse support where a nurse manager provided the education and followed up with phone support. In year 2 all materials were mailed. The study consisted of 461 patients, ages 50–85, with a negative initial FOBT.
Repeat FOBT rates were 38% enhanced care, 33% education, and 59% with nurse support (p=0.017). After adjusting for age, race, gender, and literacy, patients receiving nurse support were 1.46 times more likely to complete repeat FOBT screening than those receiving education (95% CI 1.14–1.06, p=0.002) and 1.45 times more likely than those in enhanced care but this was not significant (95% CI 0.93–2.26 p=0.10). The incremental cost per additional person screened was $2,450 for nurse over enhanced care.
A mailed pamphlet and FOBT with simplified instructions did not improve annual screening.
Telephone outreach by a nurse manager was effective in improving rates of repeat FOBT yet this may be too costly for community clinics.
Health Literacy; Colon Cancer Screening; Annual screening; Cost effectiveness; Federally Qualified Health Centers
Genome-wide association studies (GWAS) of renal cell carcinoma (RCC) in populations of European ancestry have identified four susceptibility loci. No GWAS has been conducted among African Americans (AAs), who experience a higher incidence of RCC. We conducted a GWAS in which we analyzed 1,136,723 common single-nucleotide polymorphisms (SNPs) among 255 cases and 375 controls of African ancestry, and further investigated 16 SNPs in a replication set (140 cases, 543 controls). The 12p11.23 variant rs10771279, located 77kb from the European-ancestry RCC marker rs718314, was associated with RCC risk in the GWAS (P=1.2 × 10−7) but did not replicate (P=0.99). Consistent with European-ancestry findings, the A allele of rs7105934 on 11q13.3 was associated with decreased risk [odds ratio (OR)=0.76, 95% confidence interval (CI)=0.64–0.91; P=0.0022]. The frequency of this allele was higher than that observed in the European-ancestry GWAS (0.56 and 0.07 respectively among controls). The rs7105934 association was stronger for clear cell RCC (ccRCC: OR=0.56; P=7.4 × 10−7) and absent for cases of other or unknown histology (OR=1.02; P=0.86). Analyses of rs7105934 by subtype among European-ancestry participants from these studies yielded similar findings (ORs 0.69 and 0.92 respectively). This study provides, to our knowledge, the first evidence that rs7105934 is an RCC susceptibility locus among AAs. Our finding that the association with this SNP may be specific to ccRCC is novel and requires additional investigation. Additional investigation of rs10771279 and other suggestive GWAS findings is also needed.
Serum C-reactive protein (CRP) is a marker of acute inflammatory response and has been associated with health outcomes in some studies. Inflammation and immune response may have potential prognostic implications for breast cancer survivors.
The Women’s Healthy Eating and Living (WHEL) Study includes 2919 early stage breast cancer survivors with serum collected 2 years post-diagnosis and follow-up for clinical outcomes over approximately 7 years. CRP concentrations were measured using high-sensitivity electrochemiluminescence assay. Outcomes, including all-cause mortality, breast cancer-specific mortality, and additional breast cancer events were oncologist verified from medical records and death certificates. Cox proportional hazards models were conducted with adjustment for potential confounding factors to generate hazard ratios (HR) and 95% confidence intervals (CI).
CRP concentrations in women diagnosed with breast cancer were associated with death due to any cause, death due to breast cancer, and additional breast cancer events, after adjustment for sociodemographic and cancer characteristics (lnCRP: P<0.05 for all three outcomes). The HR for women with (versus without) acute inflammation suggests a threshold effect on overall survival, rather than a dose-response relationship (≥10.0 mg/L v <1 mg/L: HR 1.96; 95% CI, 1.22–3.13). Associations were similar for breast cancer-specific mortality (HR 1.91; 95% CI, 1.13–3.23) and any additional breast cancer-related event (HR 1.69; 95% CI, 1.17–2.43).
Acute inflammation status (CRP ≥10 mg/L) may be an important independent biomarker for long-term survival in breast cancer survivors.
Interventions to decrease circulating CRP concentrations in breast cancer survivors with acute inflammation may improve prognosis.
C-reactive protein; all-cause mortality; breast cancer-specific mortality; recurrence
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by deficiency in endoglin, an angiogenic protein. The net effect of endoglin expression on cancer outcomes from animal studies has proven controversial. We evaluated whether reduced systemic endoglin levels, expected in patients diagnosed with HHT, impacted clinical outcomes for cancer.
A retrospective cohort analysis using SEER-Medicare was conducted to evaluate the effect of HHT on survival among patients diagnosed with breast, colorectal, lung, or prostate cancer between 2000 and 2007 (n=540,520). We generated Kaplan-Meir survival curves and Cox models to compare the effect of HHT on all cause survival for a composite of the four cancers, and separate models by cancer, adjusting for demographic variables, cancer type, cancer stage, and comorbidities.
All cause survival analysis for a composite of the four cancers showed an adjusted hazard ratio of 0.69 (95% confidence interval (CI) of 0.51-0.91, p=0.009) for HHT, indicating significantly improved survival outcome. When stratified by cancer type, HHT diagnosis showed a significant protective effect among breast cancer patients with an adjusted hazard ratio of 0.31 (CI: 0.13-0.75, p=0.009).
There was a significant association between HHT and improved survival outcome for a composite of patients with breast, prostate, colorectal, and lung cancer, and in analysis stratified by cancer, the association was significant for HHT patients with breast cancer.
SEER/Medicare; endoglin; HHT; stroma; breast cancer
Brain glioma is a relatively rare and fatal malignancy in adulthood with few known risk factors. Some observational studies have reported inverse associations between diabetes and subsequent glioma risk, but possible mechanisms are unclear.
We conducted a pooled analysis of original data from five nested case-control studies and two case-control studies from the U.S. and China that included 962 glioma cases and 2,195 controls. We examined self-reported diabetes history in relation to glioma risk, as well as effect modification by seven glioma risk-associated single-nucleotide polymorphisms (SNPs). We also examined the associations between 13 diabetes risk-associated SNPs, identified from genome-wide association studies, and glioma risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted logistic regression models.
We observed a 42% reduced risk of glioma for individuals with a history of diabetes (OR=0.58, 95% CI: 0.40–0.84). The association did not differ by sex, study design, or after restricting to glioblastoma, the most common histological sub-type. We did not observe any significant per-allele trends among the 13 diabetes-related SNPs examined in relation to glioma risk.
These results support an inverse association between diabetes history and glioma risk. The role of genetic susceptibility to diabetes cannot be excluded, and should be pursued in future studies together with other factors that might be responsible for the diabetes-glioma association.
These data suggest the need for studies that can evaluate, separately, the association between type 1 and type 2 diabetes and subsequent risk of adult glioma.
diabetes mellitus; brain cancer; glioma; cancer; epidemiology
The effects of hepatocellular carcinoma (HCC) on liver metabolism and circulating metabolites have been subjected to continuing investigation. This study compares the levels of selected metabolites in sera of HCC cases versus patients with liver cirrhosis and evaluates the influence of gender, race, and alcoholic cirrhosis on the performance of the metabolites as candidate biomarkers for HCC.
Targeted quantitation of 15 metabolites is performed by selected research monitoring (SRM) in sera from 89 Egyptian subjects (40 HCC cases and 49 cirrhotic controls) and 110 US subjects (56 HCC cases and 54 cirrhotic controls). Logistic regression models are used to evaluate the ability of these metabolites in distinguishing HCC cases from cirrhotic controls. The influences of gender, race, and alcoholic cirrhosis on the performance of the metabolites are analyzed by stratified logistic regression.
Two metabolites are selected based on their significance to both cohorts. While both metabolites discriminate HCC cases from cirrhotic controls in males and Caucasians, they are insignificant in females and African Americans. One metabolite is significant in patients with alcoholic cirrhosis and the other in non-alcoholic cirrhosis.
The study demonstrates the potential of two metabolites as candidate biomarkers for HCC by combining them with α-fetoprotein and gender. Stratified statistical analyses reveal that gender, race, and alcoholic cirrhosis affect the relative levels of small molecules in serum.
The findings of this study contribute to a better understanding of the influence of gender, race, and alcoholic cirrhosis in investigating small molecules as biomarkers for HCC.
Mass spectrometry; metabolomics; cancer biomarker; liver cirrhosis; health disparity
Maté tea is non-alcoholic infusion widely consumed in southern South America, and may increase risk of esophageal squamous cell carcinoma (ESCC) and other cancers due to polycyclic aromatic hydrocarbons and/or thermal injury.
We pooled two case-control studies: a 1988–2005 Uruguay study and a 1986–1992 multinational study in Argentina, Brazil, Paraguay and Uruguay, including 1,400 cases and 3,229 controls. We computed odds ratios (OR) and fitted a linear excess odds ratio (EOR) model for cumulative maté consumption in liters/day-year (LPDY).
The adjusted OR for ESCC with 95% confidence interval (CI) by ever compared with never use of maté was 1.60 (1.2,2.2). ORs increased linearly with LPDY (test of non-linearity, P=0.69). The estimate of slope (EOR/LPDY) was 0.009 (0.005,0.014) and did not vary with daily intake, indicating maté intensity did not influence the strength of association. EOR/LPDY estimates for consumption at warm, hot and very hot beverage temperatures were 0.004 (−0.002,0.013), 0.007 (0.003,0.013) and 0.016 (0.009,0.027), respectively, and differed significantly (P<0.01). EOR/LPDY estimates were increased in younger (<65) individuals and never alcohol drinkers, but these evaluations were post hoc, and were homogeneous by sex.
ORs for ESCC increased linearly with cumulative maté consumption and were unrelated to intensity, so greater daily consumption for shorter duration or lesser daily consumption for longer duration resulted in comparable ORs. The strength of association increased with higher mate temperatures.
Increased understanding of cancer risks with maté consumption enhances the understanding of the public health consequences given its purported health benefits.