Combined impact of lipidomic and genetic aberrations on clinical outcomes in metastatic castration-resistant prostate cancer.
Combined impact of lipidomic and genetic aberrations on clinical outcomes in metastatic castration-resistant prostate cancer.
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DOI：
10.1186/s12916-022-02298-0
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发表时间：
2022-03-25
期刊：
影响因子：
9.3
通讯作者：
Horvath LG
中科院分区：
文献类型：
--
作者：
Mak B;Lin HM;Kwan EM;Fettke H;Tran B;Davis ID;Mahon K;Stockler MR;Briscoe K;Marx G;Zhang A;Crumbaker M;Tan W;Huynh K;Meikle TG;Mellett NA;Hoy AJ;Du P;Yu J;Jia S;Joshua AM;Waugh DJ;Butler LM;Kohli M;Meikle PJ;Azad AA;Horvath LG
在转移性去势抵抗性前列腺癌（mCRPC）男性中，由经验证的预后不良3-脂质特征（3LS）和体细胞肿瘤遗传畸变代表的循环脂质变化均与较差的临床结局相关。一个关键问题是脂质环境和癌症基因组如何相互关联，以便在治疗上利用这一点。我们评估了mCRPC中预后不良的3-脂质特征（3LS）、体细胞遗传畸变和临床结局之间的相关性。我们对106例开始多西他赛、卡巴他赛、阿比特龙或Enzalutamide治疗的mCRPC男性（发现队列）和94例开始多西他赛治疗的mCRPC男性（验证队列）进行了血浆脂质组学分析和无细胞DNA（cfDNA）测序。采用t检验评估男性±体细胞遗传畸变之间的脂质水平差异。采用Kaplan-Meier方法和考克斯比例风险模型分析3LS和遗传畸变与总生存期（OS）的关系。3LS与发现组（风险比[HR] 2.15，95%置信区间[CI] 1.4-3.3，p < 0.001）和验证组（HR 2.32，95% CI 1.59-3.38，p < 0.001）的OS较短相关。血浆鞘脂升高与AR、TP 53、RB 1和PI 3 K畸变相关（p < 0.05）。在两个队列中，同时具有3LS和AR、TP 53、RB 1或PI 3 K畸变的男性的OS短于均不具有的男性（p ≤ 0. 001）。3LS和/或遗传畸变的存在与AR、TP 53、RB 1和PI 3 K畸变男性的较短OS独立相关（p < 0.02）。此外，侵袭性变异型前列腺癌（AVPC），定义为TP 53，RB 1和/或PTEN中的2个或更多个畸变，与鞘脂升高相关。AVPC和3LS的组合预测中位生存期约为12个月。队列的样本量相对较小，限制了临床适用性，需要进一步研究。循环鞘脂升高与mCRPC中的AR、TP 53、RB 1、PI 3 K和AVPC畸变相关，脂质和遗传异常的组合导致预后更差。这些结果表明，mCRPC中的某些基因型可能从代谢治疗中获益。在线版本包含补充材料，可通过10.1186/s12916-022-02298-0获得。
Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC. We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models. The 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59–3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies. Elevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies. The online version contains supplementary material available at 10.1186/s12916-022-02298-0.
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影响因子：
6.5
作者：
Meikle PJ;Wong G;Tan R;Giral P;Robillard P;Orsoni A;Hounslow N;Magliano DJ;Shaw JE;Curran JE;Blangero J;Kingwell BA;Chapman MJ
通讯作者：
Chapman MJ
DOI：
10.1158/1078-0432.ccr-16-2363
发表时间：
2017-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Britten CD;Garrett-Mayer E;Chin SH;Shirai K;Ogretmen B;Bentz TA;Brisendine A;Anderton K;Cusack SL;Maines LW;Zhuang Y;Smith CD;Thomas MB
通讯作者：
Thomas MB
影响因子：
50.5
作者：
Flanagan, J.;Gray, P. Kathryn;Sweeney, C. J.
通讯作者：
Sweeney, C. J.
影响因子：
8.6
作者：
Huynh, Kevin;Barlow, Christopher K.;Meikle, Peter J.
通讯作者：
Meikle, Peter J.
DOI：
10.1073/pnas.1902651116
发表时间：
2019-06-04
影响因子：
11.1
作者：
Abida, Wassim;Cyrta, Joanna;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.