Elizabeth A. Platz

Proportion of colon cancer risk that might be preventable in a cohort of middle-aged US men

AbstractObjective: Diet and lifestyle likely play major roles in colon cancer incidence; however, the proportion of colon cancer risk that might be preventable is unknown. Thus, we estimated the proportion of colon cancer risk among men in the prospective Health Professionals Follow-up Study that might be attributable to a constellation of modifiable risk factors, and thus might be preventable. Methods: We included 47,927 men aged 40–75 years in 1986, among whom we confirmed 411 colon cancer cases from 1986 to 1996. Risk factors considered were obesity, physical inactivity, alcohol consumption, early adulthood cigarette smoking, red meat consumption, and low intake of folic acid from supplements. We calculated a risk score that was the sum across the six risk factors of the values of 1 (better exposure) to 5 (worse exposure) corresponding to the exposure category. We entered the risk score into a logistic regression model and estimated the population attributable risk percent (PAR%) using the method of Bruzzi et al.Results: After adjusting for age and family history of colorectal cancer and comparing the risk score for the combined six modifiable colon cancer risk factors at or above the approximate 20th, 10th, or 5th percentiles vs. below, the PAR% increased from 39% (95% confidence interval (CI) = 23–58%), to 48% (95% CI = 25–71%), to 55% (95% CI = 27–80%), respectively. Using a second method in which we used cut-points consistent with general-good health behaviors for each risk factor, comparing men with at least one risk factor to men without any risk factors (3.1% of the men), the PAR% was 71% (95% CI = 33–92%). Conclusion: The findings from this analysis suggest that, if all the members of this cohort of middle-aged US men had a modifiable exposure distribution comparable to the men with low risk scores, a large proportion of colon cancer risk might be avoidable. Additional study is required to determine whether making changes in these six risk factors now would reduce the risk of colorectal neoplasia, or whether the proportion of colon neoplasia that might be avoidable would be similar in populations with different characteristics.

Telomere Length Assessment in Human Archival Tissues : Combined Telomere Fluorescence in Situ Hybridization and Immunostaining

A method was developed to assess human telomere lengths at the individual cell level in tissue sections from standard formalin-fixed paraffin-embedded tissues. We coupled this method with immunofluorescence to allow the simultaneous identification of specific cell types. Validation of this in situ quantification method showed excellent agreement with the commonly used telomere repeat fragment-Southern blot method. The assay requires very few cells ( approximately 10 to 15). Thus, small tissue samples, including clinical biopsies, can be easily accommodated. In addition, the cells under study need not be actively cycling and there is no requirement for tissue disaggregation or cell culture. This method provides a more accurate assessment of telomere lengths than Southern blotting because confounding contributions from undesired cell types within tissue samples are avoided. Using this technique, we were able to perform the first comparison of relative telomere lengths in matched tumor versus normal epithelial cells within archival human prostate tissues.

The CAG Repeat Within the Androgen Receptor Gene and Benign Prostatic Hyperplasia

OBJECTIVES Shorter CAG repeat lengths in exon 1 of the androgen receptor (AR) gene are associated with a stronger transcriptional activity of the AR and with a higher risk of prostate cancer. Because benign prostatic hyperplasia (BPH) is an androgen-dependent condition, we examined the hypothesis that men with shorter AR gene CAG repeat lengths have an increased risk of developing BPH. METHODS Using data from the Health Professionals Follow-up Study (HPFS), we evaluated the relationship between AR gene CAG repeat length and prevalent BPH, as defined by BPH surgery, by enlarged prostate gland detected by digital rectal examination, and by urinary symptoms as determined by the American Urological Association Symptom Index. RESULTS The odds ratio for BPH surgery or enlarged prostate gland was 1.92 (95% confidence interval [CI] 1.22 to 3.03; P [trend] = 0.0002), comparing AR gene CAG repeat length of 1 9 or less to 25 or more. Results were similar for the end points of BPH surgery (P [trend] = 0.002) and for enlarged prostate gland (P [trend] = 0.001). For a six-repeat decrease in CAG repeat length, the odds ratio for having moderate or severe urinary obstructive symptoms from an enlarged prostate gland was 3.62 (95% CI 1.51 to 8.67; P = 0.004). CONCLUSIONS Variability in the AR gene CAG repeat influences the development of symptomatic BPH, particularly in predicting obstructive urinary symptoms. Our findings support further study to establish the appropriate clinical relevance.

Selenium and Prostate Cancer: Analysis of Individual Participant Data From Fifteen Prospective Studies

Background: Some observational studies suggest that a higher selenium status is associated with a lower risk of prostate cancer but have been generally too small to provide precise estimates of associations, particularly by disease stage and grade. Methods: Collaborating investigators from 15 prospective studies provided individual-participant records (from predominantly men of white European ancestry) on blood or toenail selenium concentrations and prostate cancer risk. Odds ratios of prostate cancer by selenium concentration were estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided. Results: Blood selenium was not associated with the risk of total prostate cancer (multivariable-adjusted odds ratio [OR] per 80 percentile increase = 1.01, 95% confidence interval [CI] = 0.83 to 1.23, based on 4527 case patients and 6021 control subjects). However, there was heterogeneity by disease aggressiveness (ie, advanced stage and/or prostate cancer death, Pheterogeneity = .01), with high blood selenium associated with a lower risk of aggressive disease (OR = 0.43, 95% CI = 0.21 to 0.87) but not with nonaggressive disease. Nail selenium was inversely associated with total prostate cancer (OR = 0.29, 95% CI = 0.22 to 0.40, Ptrend < .001, based on 1970 case patients and 2086 control subjects), including both nonaggressive (OR = 0.33, 95% CI = 0.22 to 0.50) and aggressive disease (OR = 0.18, 95% CI = 0.11 to 0.31, Pheterogeneity = .08). Conclusions: Nail, but not blood, selenium concentration is inversely associated with risk of total prostate cancer, possibly because nails are a more reliable marker of long-term selenium exposure. Both blood and nail selenium concentrations are associated with a reduced risk of aggressive disease, which warrants further investigation.

Shift from pStat6 to pStat3 predominance is associated with inflammatory bowel disease-associated dysplasia†

Background: Activated Stat3 is an important mediator of oncogenesis in the colon. To test the hypothesis that select Stat activation and/or the pattern of Stat activation serves as a marker for early neoplastic transformation, we examined the distribution of activated Stat1(pStat1), Stat6(pStat6), and Stat3(pStat3) in colitis along the continuum of inactive disease to colitis‐associated cancer. Methods: Tissue microarrays were constructed using colonoscopy biopsy and surgical specimens from 67 patients with ulcerative colitis or Crohns colitis and 11 controls. In all, 111 sets of samples were analyzed representing normal tissue, active disease, low‐grade dysplasia, high‐grade dysplasia, and colitis‐associated cancer. Immunohistochemistry to detect pStat1, pStat6, and pStat3 in colonic epithelial and mucosal immune cells was then correlated with clinical and pathological data (tumor location, histologic type, grade, and lymph node involvement). Results: In 50% of colitis‐associated cancer samples, pStat3 was detected prominently in epithelial cells, where it was routinely associated with intense pStat3 staining in surrounding immune cells. Stat3 activation was greater in low‐grade tumors than in high‐grade ones (P < 0.05). pStat6 expression was more common in normal tissues than in colitis‐associated cancer (P < 0.05). pStat1 was detected in a small subset of immune cells in patients with chronic inactive and active colitis, low‐ and high‐grade dysplasia, but not in colitis‐associated cancer. Conclusions: pStat3 may be a marker for neoplastic transformation in patients with colitis. A shift from predominant immune cell Stat6 activation to Stat3 activation accompanies the onset of dysplasia with concomitant increased epithelial cell Stat3 activation in a subset of patients. (Inflamm Bowel Dis 2011;)

Epidemiology of and Risk Factors for Prostate Cancer

Prostate cancer (CaP) is the second leading cause of cancer death in US males, and it accounts for almost 30% of all cancers diagnosed in men. During the 1990s, the CaP incidence rate rapidly increased, which has been mainly attributed to heightened screening using prostate-specific antigen (PSA). Established risk factors for CaP are primarily nonmodifiable; these include older age; race, with greatest risk being among African Americans followed by Caucasians; and a family history of CaP. Possible modifiable risk factors are now beginning to emerge, including those that increase risk, such as intake of saturated fat and calcium, and those that decrease risk, such as selenium, vitamin E, and tomato products, which contain the carotenoid lycopene. Androgens, vitamin D, and insulin-like growth factor-1 (IGF-1) have been explored recently for their relationship with CaP risk; these hormonal systems may be influenced by external factors, such as diet, as well as genetics.