The relationship between biochemical failure and TP53 genetic polymorphism in patients with prostate cancer

5133 Background: TP53 is a tumour suppressor gene, located at chromosome 17p13, referred as altered in 50–55% of cancer cases. The p53 protein, encoded by the TP53 gene, is known as the cellular gatekeeper for growth and division, as it plays an essential role in safeguarding the integrity of the genome. This protein is involved in processes as cell cycle arrest, gene transcription, DNA repair and apoptosis and may influence cancer progression. Few studies have been published regarding TP53 codon 72 genetic polymorphism and prostate cancer behaviour. Methods: We analysed the frequency of TP53 codon 72 genetic polymorphism in DNA isolated from blood samples of 265 individuals with prostate cancer using the Real-time PCR methodology. Biochemical failure was defined as two successive post- treatment rises in serum PSA, greater than 50 %. Results: From the 265 prostate cancer cases, we observed that 54.7% were found to be homozygous for the Arg allele (AA), 38.1% were heterozygous (AP) and 7.2% homozygous for the Pro allele (PP). We find that individuals carriers of PP genotype have three fold increased risk of biochemical relapse (OR=3.43, 95% CI 1.31–9.01; p= 0.008). Furthermore, we observed that this genotype was not associated to the gleason score (OR=1.66, 95%CI 0.53–5.13; p=0.372) or the presence of advanced disease (OR=1.69, 95%CI 0.62–4.6; p=0.296). Conclusions: We demonstrate that TP53 codon 72 genetic polymorphism may influence the clinical progression of patients with prostate cancer. Furthermore, our results are consistent with literature regarding other neoplasia suggesting that the Pro allele was associated to a poorer prognosis and survival. No significant financial relationships to disclose.

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Genetic Variants of DICE1/INTS6 in German Prostate Cancer Families with Linkage to 13q14

Urologia Internationalis ◽

10.1159/000366229 ◽

2015 ◽

Vol 95 (4) ◽

pp. 386-389 ◽

Cited By ~ 2

Author(s):

Malte Böhm ◽

Christiane Maier ◽

Rainer Küfer ◽

Albrecht Röpke ◽

Walther Vogel ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Cancer Progression ◽

Genetic Basis ◽

Cancer Susceptibility ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Caucasian Men ◽

Chromosome 13Q14 ◽

Exon 10

Introduction: Prostate cancer is the most frequent malignancy found to occur in Caucasian men, but its genetic basis remains elusive. A prostate cancer-susceptibility locus has been identified on chromosome 13q14. The tumour suppressor gene deleted in cancer cells 1 (DICE1/INTS6) is located within this interval on 13q14.3. Materials and Methods: We performed mutation analysis of the DICE1/INTS6 gene in thirteen German prostate cancer families. Results and Conclusion: None of the patients harboured DICE1 mutations, and similar frequencies of the previously identified 13 bp deletion polymorphism in the DICE1 promoter were observed in the familial prostate cancer patients as compared with sporadic prostate cancer patients and controls. However, in one family with three affected brothers, the variations c.1215A>C (p.T405T) in exon 10 and c.2568A>G (p.S856S) in exon 17 were detected in a heterozygous pattern. In sporadic prostate cancer patients, variant c.2568A>G (p.S856S) was detected in 10/325 (3.08%) compared with 5/207 (2.42%) control samples (p > 0.05). We conclude that DICE1 appears to be involved in prostate cancer progression rather than in the initiation of prostate cancer.

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The Discrepancy Between Genetic Polymorphism of p53 Codon 72 and the Expression of p53 Protein in Helicobacter pylori-Associated Gastric Cancer in Korea

Digestive Diseases and Sciences ◽

10.1007/s10620-008-0688-x ◽

2009 ◽

Vol 55 (1) ◽

pp. 101-110 ◽

Cited By ~ 8

Author(s):

Nayoung Kim ◽

Sung-Il Cho ◽

Hye Seung Lee ◽

Ji Hyun Park ◽

Jee Hyun Kim ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Genetic Polymorphism ◽

P53 Protein ◽

P53 Codon 72 ◽

Codon 72

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Mutations within the tumour suppressor gene p53 are not confined to a late event in prostate cancer progression

Urologic Oncology Seminars and Original Investigations ◽

10.1016/s1078-1439(00)00119-8 ◽

2001 ◽

Vol 6 (3) ◽

pp. 103-110 ◽

Cited By ~ 21

Author(s):

Sean R Downing ◽

Paul Jackson ◽

Pamela J Russell

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Tumour Suppressor ◽

Prostate Cancer Progression ◽

Late Event

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The Combined Percentage of Gleason Patterns 4 and 5 Is the Best Predictor of Cancer Progression After Radical Prostatectomy

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.018 ◽

2005 ◽

Vol 23 (13) ◽

pp. 2911-2917 ◽

Cited By ~ 75

Author(s):

Liang Cheng ◽

Michael O. Koch ◽

Beth E. Juliar ◽

Joanne K. Daggy ◽

Richard S. Foster ◽

...

Keyword(s):

Prostate Cancer ◽

Radical Prostatectomy ◽

Cancer Patients ◽

Gleason Score ◽

Cancer Progression ◽

Tumor Volume ◽

High Grade ◽

Cox Regression Analysis ◽

Total Tumor Volume ◽

Increased Risk

Purpose Clinical outcome is variable in prostate cancer patients treated with radical prostatectomy. The Gleason histologic grade of prostatic adenocarcinoma is one of the strongest predictors of biologic aggressiveness of prostate cancer. We evaluated the significance of the relative proportion of high-grade cancer (Gleason patterns 4 and/or 5) in predicting cancer progression in prostate cancer patients treated with radical prostatectomy. Patients and Methods Radical prostatectomy specimens from 364 consecutive prostate cancer patients were totally embedded and whole mounted. Various clinical and pathologic characteristics were analyzed. All pathologic data, including Gleason grading variables, were collected prospectively. Results A multiple-factor analysis was performed that included the combined percentage of Gleason patterns 4 and 5, Gleason score, tumor stage, surgical margin status, preoperative prostate-specific antigen (PSA), extraprostatic extension, and total tumor volume. Using Cox regression analysis with bootstrap resampling for predictor selection, we identified the combined percentage of Gleason patterns 4 and 5 (P < .0001) and total tumor volume (P = .009) as significant predictors of PSA recurrence. Conclusion The combined percentage of Gleason patterns 4 and 5 is one of the most powerful predictors of patient outcome, and appears superior to conventional Gleason score in identifying patients at increased risk of disease progression. On the basis of our results, we recommend that the combined percentage of Gleason patterns 4 and 5 be evaluated in radical prostatectomy specimens. The amount of high-grade cancer in a prostatectomy specimen should be taken into account in therapeutic decision making and assessment of patient prognosis.

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Linking obesogenic dysregulation to prostate cancer progression

Endocrine Connections ◽

10.1530/ec-15-0080 ◽

2015 ◽

Vol 4 (4) ◽

pp. R68-R80 ◽

Cited By ~ 16

Author(s):

Renea A Taylor ◽

Jennifer Lo ◽

Natasha Ascui ◽

Matthew J Watt

Keyword(s):

Prostate Cancer ◽

Adipose Tissue ◽

Cancer Progression ◽

Prostate Gland ◽

The Body ◽

Endocrine Function ◽

Low Grade ◽

Prostate Cancer Progression ◽

Cancer Aggressiveness ◽

Increased Risk

The global epidemic of obesity is closely linked to the development of serious co-morbidities, including many forms of cancer. Epidemiological evidence consistently shows that obesity is associated with a similar or mildly increased incidence of prostate cancer but, more prominently, an increased risk for aggressive prostate cancer and prostate cancer-specific mortality. Studies in mice demonstrate that obesity induced by high-fat feeding increases prostate cancer progression; however, the mechanisms underpinning this relationship remain incompletely understood. Adipose tissue expansion in obesity leads to local tissue dysfunction and is associated with low-grade inflammation, alterations in endocrine function and changes in lipolysis that result in increased delivery of fatty acids to tissues of the body. The human prostate gland is covered anteriorly by the prominent peri-prostatic adipose tissue and laterally by smaller adipose tissue depots that lie directly adjacent to the prostatic surface. We discuss how the close association between dysfunctional adipose tissue and prostate epithelial cells might result in bi-directional communication to cause increased prostate cancer aggressiveness and progression. However, the literature indicates that several ‘mainstream’ hypotheses regarding obesity-related drivers of prostate cancer progression are not yet supported by a solid evidence base and, in particular, are not supported by experiments using human tissue. Understanding the links between obesity and prostate cancer will have major implications for the health policy for men with prostate cancer and the development of new therapeutic or preventative strategies.

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Effect of serum testosterone on treatment outcomes in patients with intermediate- to high-grade prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.180 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 180-180

Author(s):

Matthew W. Jackson ◽

Emma Ramahi ◽

Gregory P. Swanson ◽

Joseph W. Basler

Keyword(s):

Prostate Cancer ◽

Treatment Outcomes ◽

Serum Testosterone ◽

Biochemical Failure ◽

Study Cohort ◽

Potential Marker ◽

Primary Endpoints ◽

Increased Risk ◽

Significant Difference ◽

Adenocarcinoma Of The Prostate

180 Background: Low serum testosterone (TS) has been suggested to be a potential marker for more aggressive prostate cancer. However, there are conflicting data regarding whether or not patients with low TS have a higher rate of biochemical recurrence following radical prostatectomy (RP). We evaluated the relationship between postoperative TS and treatment outcomes in patients with Gleason 7–10 adenocarcinoma of the prostate. Methods: Our retrospective study cohort included 462 men diagnosed with Gleason 7–10 prostate cancer who underwent RP between 1998 and 2008 at a single institution. Patients were stratified into five groups on the basis of their postoperative TS percentile within the study cohort (<10th percentile, 10–25, 25–75, 75–90, or >90th percentile). Primary endpoints for comparison were biochemical failure free survival (BFFS) and overall survival (OS). PSA >0.2 ng/dl was used to define biochemical failure. Results: In the study cohort, mean TS was 345.2 ng/dl ± 125.2 and range 107–872 ng/dl. 44 of the 462 men had TS ≤203 ng/dl. This group had a 5-year BFFS of 43% which was significantly worse than all other TS strata (p=0.0017). Range of 5-year BFFS in all other percentile groups was 61.4 – 68.6%. There was no significant difference noted between patients with TS ≥508 ng/dl (>90th percentile) and all other TS strata (p=0.694). Furthermore, no difference in OS was noted among any of the groups (p=0.842). Groups did not differ significantly with respect to age, BMI, presence of diabetes, or known cardiovascular disease. Conclusions: Patients with exceedingly low TS are at significantly increased risk for biochemical failure following RP. Further prospective study is warranted to elucidate interventions that might improve biochemical outcomes in these patients. [Table: see text]

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Positive surgical margins and biochemical recurrence in obese patients with intermediate- and high-grade prostate cancer with radical prostatectomy.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.50 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 50-50

Author(s):

Emma Holliday Ramahi ◽

Katherine Cox Ansley ◽

Matthew W. Jackson ◽

Joseph W. Basler ◽

Fei Du ◽

...

Keyword(s):

Prostate Cancer ◽

Radical Prostatectomy ◽

Technical Difficulty ◽

Biochemical Failure ◽

Study Cohort ◽

High Grade ◽

Positive Margins ◽

Primary Endpoints ◽

Increased Risk ◽

Pre Treatment

50 Background: The relationship between obesity and prostate cancer outcomes is unclear. We performed a retrospective cohort study to determine the effect of body mass index (BMI) on a cohort of patients with intermediate to high grade prostate cancer treated with radical prostatectomy (RP). Methods: Our retrospective study cohort included 582 men diagnosed with Gleason 7-10 prostate cancer between 1998 and 2008 and treated with RP at a single institution. Patients were stratified into four groups on the basis of their BMI at the time of prostate cancer diagnosis (<25, 25-30, 30-35 or >35). The primary endpoints for comparison were biochemical failure free survival (BFFS) and the incidence of positive margins. PSA >0.2 ng/dl was used to define biochemical failure. Results: After adjusting for age, Gleason score, pre-treatment PSA and the presence of diabetes, we found patients with increasing BMI had an increased frequency of biochemical failure after RP. Compared to patients with a normal BMI (<25), patients with BMI 25-30, 30-35, and >35 had 1.82 (1.12, 2.97; p = 0.02), 2.14 (1.33, 3.45; p = 0.002) and 2.29 (1.1, 4.78; p = 0.03) times higher rates of biochemical failure, respectively. We additionally found increased positive margins after RP in patients with a BMI 30-35 and >35 (41.4% and 45.5%, respectively) when compared to patients with a BMI of <25 and 25-30 (33.3% and 28.9%, respectively); p = 0.02. Conclusions: Patients with increasing BMI seem to be at significantly increased risk for biochemical failure following RP potentially due to the increased technical difficulty of the surgery and increased incidence of positive margins. [Table: see text]

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Increased cholesterol synthesis via squalene monooxygenase to predict lethal prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.77 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 77-77 ◽

Cited By ~ 1

Author(s):

Konrad Hermann Stopsack ◽

Travis Gerke ◽

James Robert Cerhan ◽

Lorelei A. Mucci ◽

Jennifer R. Rider

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Cholesterol Synthesis ◽

Watchful Waiting ◽

Prostate Tissue ◽

Health Study ◽

Squalene Monooxygenase ◽

Increased Risk ◽

The Mean ◽

Benign Prostate

77 Background: Prostate cancer cells rely on cholesterol for proliferation and androgen production. We recently demonstrated that increased expression of the second key enzyme of cholesterol synthesis, squalene monooxygenase (SQLE), is associated with higher prostate cancer-specific mortality (PCSM). We here validate findings in two additional prospective studies and investigate putative mechanisms. Methods: We analyzed the prospective prostatectomy cohorts within the Health Professionals Follow-up Study (HPFS) and the Physicians’ Health Study (PHS) as well as initially expectantly managed patients in the Swedish Watchful Waiting Study (SWWS). 258 lethal cancer cases and 469 patients who survived > 8 years without metastases were included. SQLE mRNA was measured in tumor specimens at diagnosis of all patients and in benign prostate tissue of 197 patients. Markers of tumor angiogenesis were assessed via immunohistochemistry in 169 HPFS patients. We estimated multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. Results: Higher SQLE expression was confirmed to be predictive of higher PCSM in the validation prostatectomy cohort PHS. Combining the two prostatectomy cohorts, men with high SQLE expression ( > 1 standard deviation above the mean) were 6.7 times (95% CI, 2.9 to 15.8; p < 0.001) more likely to die from their cancer compared to men with the mean level of SQLE expression. A 10% higher ratio of SQLE mRNA expression in tumor vs. benign prostate tissue of the same patient was predictive of 42% higher PCSM (95% CI, 15% to 74%). Higher SQLE expression was strongly associated with increased angiogenesis markers (all p ≤ 0.001). This increased risk associated with high SQLE expression was not modified by statin use (p ≥ 0.52). In initially untreated patients in SWWS, a more modest association of tumor SQLE expression with PCSM was observed (p = 0.047). Conclusions: SQLE, the second rate-limiting enzyme of cholesterol synthesis, is associated with prostate cancer progression. Its expression at cancer diagnosis is predictive of lethal disease both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease.

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Milk and other dairy foods in relation to prostate cancer progression: Data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CAPSURE).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.5_suppl.168 ◽

2017 ◽

Vol 35 (5_suppl) ◽

pp. 168-168

Author(s):

David Tat ◽

Erin Van Blarigan ◽

Stacey A. Kenfield ◽

Jenny Broering ◽

Janet E. Cowan ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

P Value ◽

High Fat ◽

Low Fat ◽

Dairy Foods ◽

Whole Milk ◽

Increased Risk

168 Background: Recent research suggests a positive relationship between intake of high-fat dairy, particularly whole milk, and prostate cancer (PC) mortality. However, data are limited in men after PC diagnosis. Methods: We conducted a prospective cohort study among 1336 men with non-metastatic PC in CaPSURE. The men answered a food frequency questionnaire (FFQ) in 2004-2005 (median time from diagnosis to the FFQ: 2 y) and were followed for PC progression until April 2016. PC progression was defined as: prostate cancer death, bone metastasis from PC, biochemical recurrence, or secondary treatment. Multivariate Cox Proportional Hazards regression was used to calculate hazards ratios (HR) and 95% confidence intervals (CI) for associations between total, whole fat, and low-fat milk; total, high-fat, and low-fat dairy; and specific dairy items and PC progression. We adjusted for time from diagnosis to FFQ, calories, age at diagnosis, CAPRA score, smoking, BMI, walking pace, and primary PC treatment. Results: 314 events were observed (mean follow-up: 7.2 y). Whole milk was associated with an increased risk of PC progression when adjusting for age, calories, and time since diagnosis (HR ≥1 vs. <1 serving/wk: 1.37; 95% CI: 1.03, 1.84; p-value: 0.03). This association was slightly attenuated, and not statistically significant, when adjusting for clinical and other lifestyle factors (HR: 1.27; 95% CI: 0.91, 1.77; p-value: 0.15). High-fat dairy intake also appeared associated with an increased risk of PC progression, but the association was not statistically significant (adjusted HR ≥4 vs. <1 servings/day: 1.40; 95% CI: 0.92, 2.13; p-trend: 0.18). Post-diagnostic intakes of low-fat milk and other dairy foods were not associated with PC progression. Conclusions: Post-diagnostic intake of milk and other dairy foods was not associated with PC progression. Research in populations with greater intake of whole milk is warranted to further investigate whether post-diagnostic whole milk intake increases risk of PC progression. Funding: This work was funded by the DOD Prostate Cancer Research Program (W81XWH-13-2-0074) and the NIH (K07CA197077).

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