Lorelei A. Mucci

TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort.

The identification of the TMPRSS2:ERG fusion in prostate cancer suggests that distinct molecular subtypes may define risk for disease progression. In surgical series, TMPRSS2:ERG fusion was identified in 50% of the tumors. Here, we report on a population-based cohort of men with localized prostate cancers followed by expectant (watchful waiting) therapy with 15% (17/111) TMPRSS2:ERG fusion. We identified a statistically significant association between TMPRSS2:ERG fusion and prostate cancer specific death (cumulative incidence ratio=2.7, P<0.01, 95% confidence interval=1.3–5.8). Quantitative reverse-transcription–polymerase chain reaction demonstrated high estrogen-regulated gene (ERG) expression to be associated with TMPRSS2:ERG fusion (P<0.005). These data suggest that TMPRSS2:ERG fusion prostate cancers may have a more aggressive phenotype, possibly mediated through increased ERG expression.

SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression

Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression. Here, we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFβ/BMP–SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment confirmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans.

Health status and health care use of Massachusetts women reporting partner abuse

BACKGROUND Studies indicate that women abused by their intimate partners are at increased risk for a number of health problems and have increased rates of health care utilization. However, these findings are based mainly on studies using clinic or health plan populations. In this study, we examined the association between intimate partner abuse (IPA) and health concerns and health care utilization in a population-based sample of adult women. METHODS We analyzed data on 2043 women aged 18 to 59 who participated in the 1998 Massachusetts Behavioral Risk Factor Surveillance System (BRFSS), a population-based health survey that included questions on IPA. IPA was defined as experiencing physical violence by, fear of, or control by an intimate partner. Consequences of IPA and self-rated health status and health care utilization of women experiencing IPA were examined. RESULTS A total of 6.3% of Massachusetts women aged 18 to 59 reported IPA during the past year. Women experiencing IPA were more likely than other women to report depression, anxiety, sleep problems, suicidal ideation, disabilities, smoking, unwanted pregnancy, HIV testing, and condom use. Women experiencing IPA were less likely to have health insurance, but received routine health care at similar rates as other women. CONCLUSIONS These results indicate that women in the general population experiencing IPA are at increased risk for several serious emotional and physical health concerns. Most of these women are in routine contact with health care providers. These findings also suggest that the BRFSS may provide a valuable mechanism for tracking state-based IPA prevalence rates over time.

Telomere length predicts survival independent of genetic influences

Telomeres prevent the loss of coding genetic material during chromosomal replication. Previous research suggests that shorter telomere length may be associated with lower survival. Because genetic factors are important for individual differences in both telomere length and mortality, this association could reflect genetic or environmental pleiotropy rather than a direct biological effect of telomeres. We demonstrate through within‐pair analyses of Swedish twins that telomere length at advanced age is a biomarker that predicts survival beyond the impact of early familial environment and genetic factors in common with telomere length and mortality. Twins with the shortest telomeres had a three times greater risk of death during the follow‐up period than their co‐twins with the longest telomere measurements [hazard ratio (RR) = 2.8, 95% confidence interval 1.1–7.3, P = 0.03].

Dietary acrylamide and cancer of the large bowel, kidney, and bladder: Absence of an association in a population-based study in Sweden

Recently, disturbingly high levels of acrylamide were unexpectedly detected in widely consumed food items, notably French fries, potato crisps, and bread. Much international public concern arose since acrylamide has been classified as a probable carcinogen, although based chiefly on laboratory evidence; informative human data are largely lacking. We reanalysed a population-based Swedish case–control study encompassing cases with cancer of the large bowel (N=591), bladder (N=263) and kidney (N=133), and 538 healthy controls, assessing dietary acrylamide by linking extensive food frequency data with acrylamide levels in certain food items recorded by the Swedish National Food Administration. Unconditional logistic regression was used to estimate odds ratios, adjusting for potential confounders. We found consistently a lack of an excess risk, or any convincing trend, of cancer of the bowel, bladder, or kidney in high consumers of 14 different food items with a high (range 300–1200 μg kg−1) or moderate (range 30–299 μg kg−1) acrylamide content. Likewise, when we analysed quartiles of known dietary acrylamide intake, no association was found with cancer of the bladder or kidney. Unexpectedly, an inverse trend was found for large bowel cancer (P for trend 0.01) with a 40% reduced risk in the highest compared to lowest quartile. We found reassuring evidence that dietary exposure to acrylamide in amounts typically ingested by Swedish adults in certain foods has no measurable impact on risk of three major types of cancer. It should be noted, however, that relation of risk to the acrylamide content of all foods could not be studied.

Fish consumption and prostate cancer risk: a review and meta-analysis

BACKGROUND Prostate cancer incidence varies 60-fold globally, which suggests the roles of lifestyle and dietary factors in its cause. To our knowledge, a comprehensive assessment of the association between fish consumption and prostate cancer incidence and mortality has not been reported. OBJECTIVE We conducted a meta-analysis of fish intake and prostate cancer by focusing on the incidence of prostate cancer and prostate cancer-specific mortality and included subgroup analyses based on race, fish type, method of fish preparation, and high-grade and high-stage cancer. DESIGN We searched MEDLINE and EMBASE databases (May 2009) for case-control and cohort studies that assessed fish intake and prostate cancer risk. Two authors independently assessed eligibility and extracted data. RESULTS There was no association between fish consumption and a significant reduction in prostate cancer incidence [12 case-control studies (n = 5777 cases and 9805 control subjects), odds ratio (OR): 0.85; 95% CI: 0.72, 1.00; and 12 cohort studies (n = 445,820), relative risk (RR): 1.01; 95% CI: 0.90, 1.14]. It was not possible to perform a meta-analysis for high-grade disease (one case-control study, OR: 1.44; 95% CI: 0.58, 3.03), locally advanced disease (one cohort study, RR: 0.80; 95% CI: 0.61, 1.13), or metastatic disease (one cohort study, RR: 0.56; 95% CI: 0.37, 0.86). There was an association between fish consumption and a significant 63% reduction in prostate cancer-specific mortality [4 cohort studies (n = 49,661), RR: 0.37; 95% CI: 0.18, 0.74]. CONCLUSION Our analyses provide no strong evidence of a protective association of fish consumption with prostate cancer incidence but showed a significant 63% reduction in prostate cancer-specific mortality.

Decreased alpha-methylacyl CoA racemase expression in localized prostate cancer is associated with an increased rate of biochemical recurrence and cancer-specific death

α-Methylacyl CoA racemase (AMACR) is overexpressed in prostate cancer relative to benign prostatic tissue. AMACR expression is highest in localized prostate cancer and decreases in metastatic prostate cancer. Herein, we explored the use of AMACR as a biomarker for aggressive prostate cancer. AMACR protein expression was determined by immunohistochemistry using an image analysis system on two localized prostate cancer cohorts consisting of 204 men treated by radical prostatectomy and 188 men followed expectantly. The end points for the cohorts were time to prostate-specific antigen (PSA) failure (i.e., elevation >0.2 ng/mL) and time to prostate cancer death in the watchful waiting cohort. Using a regression tree method, optimal AMACR protein expression cutpoints were determined to best differentiate prostate cancer outcome in each of the cohorts separately. Cox proportional hazard models were then employed to examine the effect of the AMACR cutpoint on prostate cancer outcome, and adjusted for clinical variables. Lower AMACR tissue expression was associated with worse prostate cancer outcome, independent of clinical variables (hazard ratio, 3.7 for PSA failure; P = 0.018; hazard ratio, 4.1 for prostate cancer death, P = 0.0006). Among those with both low AMACR expression and high Gleason score, the risk of prostate cancer death was 18-fold higher (P = 0.006). The AMACR cutpoint developed using prostate cancer–specific death as the end point predicted PSA failures independent of Gleason score, PSA, and margin status. This is the first study to show that AMACR expression is significantly associated with prostate cancer progression and suggests that not all surrogate end points may be optimal to define biomarkers of aggressive prostate cancer.

Immediate Risk of Suicide and Cardiovascular Death After a Prostate Cancer Diagnosis: Cohort Study in the United States

BACKGROUND Receiving a cancer diagnosis is a stressful event that may increase risks of suicide and cardiovascular death, especially soon after diagnosis. METHODS We conducted a cohort study of 342,497 patients diagnosed with prostate cancer from January 1, 1979, through December 31, 2004, in the Surveillance, Epidemiology, and End Results Program. Follow-up started from the date of prostate cancer diagnosis to the end of first 12 calendar months after diagnosis. The relative risks of suicide and cardiovascular death were calculated as standardized mortality ratios (SMRs) comparing corresponding incidences among prostate cancer patients with those of the general US male population, with adjustment for age, calendar period, and state of residence. We compared risks in the first year and months after a prostate cancer diagnosis. The analyses were further stratified by calendar period at diagnosis, tumor characteristics, and other variables. RESULTS During follow-up, 148 men died of suicide (mortality rate = 0.5 per 1000 person-years) and 6845 died of cardiovascular diseases (mortality rate = 21.8 per 1000 person-years). Patients with prostate cancer were at increased risk of suicide during the first year (SMR = 1.4, 95% confidence interval [CI] = 1.2 to 1.6), especially during the first 3 months (SMR = 1.9, 95% CI = 1.4 to 2.6), after diagnosis. The elevated risk was apparent in pre-prostate-specific antigen (PSA) (1979-1986) and peri-PSA (1987-1992) eras but not since PSA testing has been widespread (1993-2004). The risk of cardiovascular death was slightly elevated during the first year (SMR = 1.09, 95% CI = 1.06 to 1.12), with the highest risk in the first month (SMR = 2.05, 95% CI = 1.89 to 2.22), after diagnosis. The first-month risk was statistically significantly elevated during the entire study period, and the risk was higher for patients with metastatic tumors (SMR = 3.22, 95% CI = 2.68 to 3.84) than for those with local or regional tumors (SMR = 1.57, 95% CI = 1.42 to 1.74). CONCLUSION A diagnosis of prostate cancer may increase the immediate risks of suicide and cardiovascular death.

Mediterranean dietary pattern and mortality among young women: a cohort study in Sweden

Studies of diet and health focus increasingly on dietary patterns. Although the traditional Mediterranean diet is perceived as being healthy, there is little information on its possible benefit to young people. We studied whether closer adherence to the traditional Mediterranean dietary pattern was associated with overall and cancer mortality in a cohort of 42,237 young women, aged 30-49 years at enrollment, who were recruited in 1991-2 from the general population in the Uppsala Health Care Region, Sweden, and followed up, almost completely, for about 12 years. Adherence to the Mediterranean diet was assessed by a 10-point score incorporating the characteristics of this diet. Among women less than 40 years old at enrollment--whose causes of death are mainly cancer with probable genetic influences, injuries or suicide--there was no association of the Mediterranean diet score with total or cancer mortality. Among women 40-49 years old at enrollment, a 2-point increase in the score was associated with considerable reductions in overall mortality (13%; 95% CI 1%, 23%; P approximately 0.05) and cancer mortality (16%; 95% CI -1%, 29%; P approximately 0.06). Few cardiovascular deaths occurred in this cohort of young women. The findings of the present study in a northern European population of young women indicate that closer adherence to a Mediterranean dietary pattern reduces mortality even among young persons.

Are dietary influences on the risk of prostate cancer mediated through the insulin‐like growth factor system?

Objectives To investigate whether dietary factors that appear to affect the risk of prostate cancer may be similarly associated with serum levels of insulin‐like growth factor 1 (IGF‐1).