前列腺组织的基因表达谱分析表明，染色质调控是肥胖与致命性前列腺癌之间的潜在联系。
Gene expression profiling of prostate tissue identifies chromatin regulation as a potential link between obesity and lethal prostate cancer.
作者信息
Ebot Ericka M, Gerke Travis, Labbé David P, Sinnott Jennifer A, Zadra Giorgia, Rider Jennifer R, Tyekucheva Svitlana, Wilson Kathryn M, Kelly Rachel S, Shui Irene M, Loda Massimo, Kantoff Philip W, Finn Stephen, Vander Heiden Matthew G, Brown Myles, Giovannucci Edward L, Mucci Lorelei A
机构信息
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, Florida.
出版信息
Cancer. 2017 Nov 1;123(21):4130-4138. doi: 10.1002/cncr.30831. Epub 2017 Jul 12.
BACKGROUND
Obese men are at higher risk of advanced prostate cancer and cancer-specific mortality; however, the biology underlying this association remains unclear. This study examined gene expression profiles of prostate tissue to identify biological processes differentially expressed by obesity status and lethal prostate cancer.
METHODS
Gene expression profiling was performed on tumor (n = 402) and adjacent normal (n = 200) prostate tissue from participants in 2 prospective cohorts who had been diagnosed with prostate cancer from 1982 to 2005. Body mass index (BMI) was calculated from the questionnaire immediately preceding cancer diagnosis. Men were followed for metastases or prostate cancer-specific death (lethal disease) through 2011. Gene Ontology biological processes differentially expressed by BMI were identified using gene set enrichment analysis. Pathway scores were computed by averaging the signal intensities of member genes. Odds ratios (ORs) for lethal prostate cancer were estimated with logistic regression.
RESULTS
Among 402 men, 48% were healthy weight, 31% were overweight, and 21% were very overweight/obese. Fifteen gene sets were enriched in tumor tissue, but not normal tissue, of very overweight/obese men versus healthy-weight men; 5 of these were related to chromatin modification and remodeling (false-discovery rate < 0.25). Patients with high tumor expression of chromatin-related genes had worse clinical characteristics (Gleason grade > 7, 41% vs 17%; P = 2 × 10 ) and an increased risk of lethal disease that was independent of grade and stage (OR, 5.26; 95% confidence interval, 2.37-12.25).
CONCLUSIONS
This study improves our understanding of the biology of aggressive prostate cancer and identifies a potential mechanistic link between obesity and prostate cancer death that warrants further study. Cancer 2017;123:4130-4138. © 2017 American Cancer Society.
背景
肥胖男性患晚期前列腺癌及癌症特异性死亡的风险更高；然而，这种关联背后的生物学机制仍不清楚。本研究检测了前列腺组织的基因表达谱，以确定因肥胖状态和致命性前列腺癌而差异表达的生物学过程。
方法
对1982年至2005年被诊断为前列腺癌的2个前瞻性队列参与者的肿瘤（n = 402）和相邻正常前列腺组织（n = 200）进行基因表达谱分析。根据癌症诊断前立即填写的问卷计算体重指数（BMI）。对男性随访至2011年，观察有无转移或前列腺癌特异性死亡（致命性疾病）。使用基因集富集分析确定由BMI差异表达的基因本体生物学过程。通过对成员基因的信号强度求平均值来计算通路分数。用逻辑回归估计致命性前列腺癌的比值比（OR）。
结果
在402名男性中，48%体重正常，31%超重，21%非常超重/肥胖。与体重正常的男性相比，15个基因集在非常超重/肥胖男性的肿瘤组织而非正常组织中富集；其中5个与染色质修饰和重塑相关（错误发现率<0.25）。染色质相关基因肿瘤表达高的患者具有更差的临床特征（ Gleason分级>7，41%对17%；P = 2×10），且致命性疾病风险增加，该风险独立于分级和分期（OR，5.26；95%置信区间，2.37 - 12.25）。
结论
本研究增进了我们对侵袭性前列腺癌生物学的理解，并确定了肥胖与前列腺癌死亡之间潜在的机制联系，值得进一步研究。《癌症》2017年；123：4130 - 4138。© 2017美国癌症协会。
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