Cholesterol Metabolism and Prostate Cancer Lethality.
Cholesterol metabolism has been implicated in prostate cancer pathogenesis. Here, we assessed the association of intratumoral mRNA expression of cholesterol synthesis enzymes, transporters, and regulators in tumor specimen at diagnosis and lethal prostate cancer, defined as mortality or metastases from prostate cancer in contrast to nonlethal disease without evidence of metastases after at least 8 years of follow-up. We analyzed the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (n = 249) and the Physicians' Health Study (n = 153) as well as expectantly managed patients in the Swedish Watchful Waiting Study (n = 338). The expression of squalene monooxygenase (SQLE) was associated with lethal cancer in all three cohorts. Men with high SQLE expression (>1 standard deviation above the mean) were 8.3 times (95% confidence interval, 3.5 to 19.7) more likely to have lethal cancer despite therapy compared with men with the mean level of SQLE expression. Absolute SQLE expression was associated with lethal cancer independently from Gleason grade and stage, as was a SQLE expression ratio in tumor versus surrounding benign prostate tissue. Higher SQLE expression was tightly associated with increased histologic markers of angiogenesis. Collectively, this study establishes the prognostic value of intratumoral cholesterol synthesis as measured via SQLE, its second rate-limiting enzyme. SQLE expression at cancer diagnosis is prognostic for lethal prostate cancer both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease. Cancer Res; 76(16); 4785-90. ©2016 AACR.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. stopsack@post.harvard.edu.
Konrad H
KH
Stopsack
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Epidemiology, College of Medicine and College of Public Health and Health Professions, University of Florida, Gainesville, Florida.
Travis A
TA
Gerke
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Statistics, Ohio State University, Columbus, Ohio.
Jennifer A
JA
Sinnott
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Kathryn L
KL
Penney
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Svitlana
S
Tyekucheva
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Howard D
HD
Sesso
Department of Urology, School of Health and Medical Sciences, University of Örebro, Örebro, Sweden.
Swen-Olof
SO
Andersson
Department of Urology, School of Health and Medical Sciences, University of Örebro, Örebro, Sweden.
Ove
O
Andrén
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
James R
JR
Cerhan
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
Edward L
EL
Giovannucci
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Lorelei A
LA
Mucci
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts.
Jennifer R
JR
Rider
D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D050603:Squalene Monooxygenase / Q000032:analysis* / Q000378:metabolism; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor; D002784:Cholesterol; D050603:Squalene Monooxygenase