Androgen Receptor Signaling in Prostate Cancer Genomic Subtypes.
Androgen Receptor Signaling in Prostate Cancer Genomic Subtypes.
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DOI：
10.3390/cancers13133272
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发表时间：
2021-06-30
期刊：
影响因子：
5.2
通讯作者：
Cramer SD
中科院分区：
文献类型：
--
作者：
Jillson LK;Yette GA;Laajala TD;Tilley WD;Costello JC;Cramer SD
大约八分之一的男性将在一生中的某个时候被诊断出患有前列腺癌（PCa）。患有局部或区域性疾病的患者的五年生存率接近100%，但当癌症扩散到远处时，这一比例下降到30%。雄激素受体（AR）信号传导在正常前列腺发育和PCa细胞存活中起关键作用。靶向AR途径的治疗是主流治疗，但耐药性是一个主要的临床问题。从文献和我们自己的PCa数据库的荟萃分析，我们的目的是审查PCa遗传变异和AR信号轴在初级阶段之间的联系。评估患者中出现的PCa遗传驱动因素的组合如何影响AR信号传导将有助于对可能对AR导向疗法有反应的患者以及需要其他治疗药物以预防疾病进展的患者进行分层。虽然许多前列腺癌（PCa）病例仍然是惰性和可治疗的，但其他病例是侵袭性的，并进展到转移阶段，其中治愈性疗法有限。雄激素受体（AR）信号传导仍然是PCa增殖和存活程序的重要途径，使得AR信号传导的中断成为可行的治疗选择。然而，大多数患者对AR靶向治疗产生耐药性，或者根本没有反应。该领域已经转向PCa基因组学，以帮助对高风险患者进行分层，并更好地了解驱动侵袭性PCa和治疗抗性的机制。虽然AR基因本身的改变发生在后期，但初级阶段的基因组变化可能影响AR轴并影响对AR导向疗法的反应。在这里，我们审查常见的基因组改变原发性前列腺癌及其对AR功能和活性的影响。通过对多个独立的原发性PCa数据库的荟萃分析，我们还确定了显著共同发生的改变的亚型，并检查了它们对AR轴的组合效应。此外，我们还讨论了对AR靶向治疗和其他治疗反应的后续影响。我们鉴定了多个原发性PCa基因组亚型，鉴于它们对AR活性的不同影响，患者肿瘤遗传学可能是AR治疗耐药性的重要分层因素。
Approximately 1 in 8 men will be diagnosed with prostate cancer (PCa) at some point in their lifetime. Five-year survival rate for patients with local or regionally spread disease is near 100%, but this drops to 30% when the cancer has spread to distant sites. Androgen receptor (AR) signaling plays a pivotal role in normal prostate development and PCa cell survival. Therapies targeting the AR pathway are mainline treatments, but resistance is a major clinical problem. From the literature and our own meta-analysis of PCa databases, we aimed to review the connections between PCa genetic alterations and the AR signaling axis at the primary stage. Assessing how combinations of PCa genetic drivers that arise in patients affect AR signaling will aid in stratifying patients who will likely respond to AR-directed therapies, and those who will require other therapeutic agents upfront in order to prevent disease progression. While many prostate cancer (PCa) cases remain indolent and treatable, others are aggressive and progress to the metastatic stage where there are limited curative therapies. Androgen receptor (AR) signaling remains an important pathway for proliferative and survival programs in PCa, making disruption of AR signaling a viable therapy option. However, most patients develop resistance to AR-targeted therapies or inherently never respond. The field has turned to PCa genomics to aid in stratifying high risk patients, and to better understand the mechanisms driving aggressive PCa and therapy resistance. While alterations to the AR gene itself occur at later stages, genomic changes at the primary stage can affect the AR axis and impact response to AR-directed therapies. Here, we review common genomic alterations in primary PCa and their influence on AR function and activity. Through a meta-analysis of multiple independent primary PCa databases, we also identified subtypes of significantly co-occurring alterations and examined their combinatorial effects on the AR axis. Further, we discussed the subsequent implications for response to AR-targeted therapies and other treatments. We identified multiple primary PCa genomic subtypes, and given their differing effects on AR activity, patient tumor genetics may be an important stratifying factor for AR therapy resistance.
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影响因子：
--
作者：
Barfeld SJ;Fazli L;Persson M;Marjavaara L;Urbanucci A;Kaukoniemi KM;Rennie PS;Ceder Y;Chabes A;Visakorpi T;Mills IG
通讯作者：
Mills IG
DOI：
10.1158/1078-0432.ccr-18-0653
发表时间：
2018-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Blee AM;He Y;Yang Y;Ye Z;Yan Y;Pan Y;Ma T;Dugdale J;Kuehn E;Kohli M;Jimenez R;Chen Y;Xu W;Wang L;Huang H
通讯作者：
Huang H
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
16.6
作者：
Bernasocchi T;El Tekle G;Bolis M;Mutti A;Vallerga A;Brandt LP;Spriano F;Svinkina T;Zoma M;Ceserani V;Rinaldi A;Janouskova H;Bossi D;Cavalli M;Mosole S;Geiger R;Dong Z;Yang CG;Albino D;Rinaldi A;Schraml P;Linder S;Carbone GM;Alimonti A;Bertoni F;Moch H;Carr SA;Zwart W;Kruithof-de Julio M;Rubin MA;Udeshi ND;Theurillat JP
通讯作者：
Theurillat JP
影响因子：
11.5
作者：
Chakraborty, Goutam;Armenia, Joshua;Kantoff, Philip W.
通讯作者：
Kantoff, Philip W.