Accumulation of copy number alterations and clinical progression across advanced prostate cancer.
Accumulation of copy number alterations and clinical progression across advanced prostate cancer.
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DOI：
10.1186/s13073-022-01080-4
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发表时间：
2022-09-05
期刊：
影响因子：
12.3
通讯作者：
中科院分区：
文献类型：
--
作者：
基因组拷贝数的改变通常发生在前列腺癌中，是基因组不稳定的一种衡量标准。晚期前列腺癌的拷贝数变化的临床意义尚不清楚，它定义了从高危局部到转移的广泛疾病范围。在前瞻性随机踩踏试验的对照组中，我们对300名在长期雄激素剥夺治疗(ADT)开始前表现为晚期前列腺癌的患者的688个肿瘤区域进行了拷贝数分析。患者被分成以下转移状态：高危非转移伴或不伴局部淋巴结受累，或转移性低/高体积。我们对患者进行了中位数7年的随访。单变量和多变量Cox生存模型被用来估计作为连续变量的拷贝数改变的负担与死亡或疾病进展的风险之间的关系。拷贝数改变的负担与诊断时放射学上明显的远处转移呈正相关(P=0.00006)，在单变量和多变量分析中显示出与临床结果的非线性关系，特征是每增加一个单位，进展(P=0.003)和死亡(P=0.045)的相对风险急剧增加，随着拷贝数负担的增加，相对风险稳定在较温和的增加。在每种转移状态下，拷贝数负担和结果之间的这种关联是相似的。在最低拷贝数负担四分位数(q=4.1×10−6)时，拷贝数丢失的频率显著高于获得。在拷贝数改变较高的病例中，染色体5q21-22的片段丢失和8q21-24的片段增加，包括chd1和cmyc的频率更高(对于任何一个区域：Kolmogorov-Smirnov距离，0.5；调整后的P<；0.0001)。拷贝数的改变显示同一前列腺中不同肿瘤区域的差异。这种差异与远处转移的风险增加有关(Kruskal-Wallis检验，P=0.037)。晚期前列腺癌的拷贝数改变与确诊时转移风险增加有关。积累有限数量的拷贝数改变与疾病进展和死亡的大部分风险增加有关。在高拷贝数改变负担癌症中，特定片段参与的可能性增加，这可能表明拷贝数改变累积的顺序。ClinicalTrials.gov NCT00268476,2005年12月22日注册。EudraCT编号2004-000193-31，注册日期为2004年10月4日。网上版载有补充材料，可在10.1186/s13073-022-01080-4查阅。
Genomic copy number alterations commonly occur in prostate cancer and are one measure of genomic instability. The clinical implication of copy number change in advanced prostate cancer, which defines a wide spectrum of disease from high-risk localised to metastatic, is unknown. We performed copy number profiling on 688 tumour regions from 300 patients, who presented with advanced prostate cancer prior to the start of long-term androgen deprivation therapy (ADT), in the control arm of the prospective randomised STAMPEDE trial. Patients were categorised into metastatic states as follows; high-risk non-metastatic with or without local lymph node involvement, or metastatic low/high volume. We followed up patients for a median of 7 years. Univariable and multivariable Cox survival models were fitted to estimate the association between the burden of copy number alteration as a continuous variable and the hazard of death or disease progression. The burden of copy number alterations positively associated with radiologically evident distant metastases at diagnosis (P=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P=0.003) and death (P=0.045) for each unit increase, stabilising into more modest increases with higher copy number burdens. This association between copy number burden and outcome was similar in each metastatic state. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1 × 10−6). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC occurred more frequently in cases with higher copy number alteration (for either region: Kolmogorov–Smirnov distance, 0.5; adjusted P<0.0001). Copy number alterations showed variability across tumour regions in the same prostate. This variance associated with increased risk of distant metastases (Kruskal-Wallis test P=0.037). Copy number alteration in advanced prostate cancer associates with increased risk of metastases at diagnosis. Accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death. The increased likelihood of involvement of specific segments in high copy number alteration burden cancers may suggest an order underlying the accumulation of copy number changes. ClinicalTrials.gov NCT00268476, registered on December 22, 2005. EudraCT 2004-000193-31, registered on October 4, 2004. The online version contains supplementary material available at 10.1186/s13073-022-01080-4.
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DOI：
10.1056/nejmoa1503747
发表时间：
2015-08-20
期刊：
The New England journal of medicine
影响因子：
--
作者：
Sweeney CJ;Chen YH;Carducci M;Liu G;Jarrard DF;Eisenberger M;Wong YN;Hahn N;Kohli M;Cooney MM;Dreicer R;Vogelzang NJ;Picus J;Shevrin D;Hussain M;Garcia JA;DiPaola RS
通讯作者：
DiPaola RS
影响因子：
7.7
作者：
Hieronymus H;Murali R;Tin A;Yadav K;Abida W;Moller H;Berney D;Scher H;Carver B;Scardino P;Schultz N;Taylor B;Vickers A;Cuzick J;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
50.3
作者：
Taylor BS;Schultz N;Hieronymus H;Gopalan A;Xiao Y;Carver BS;Arora VK;Kaushik P;Cerami E;Reva B;Antipin Y;Mitsiades N;Landers T;Dolgalev I;Major JE;Wilson M;Socci ND;Lash AE;Heguy A;Eastham JA;Scher HI;Reuter VE;Scardino PT;Sander C;Sawyers CL;Gerald WL
通讯作者：
Gerald WL
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：
4.6
作者：
Abida W;Armenia J;Gopalan A;Brennan R;Walsh M;Barron D;Danila D;Rathkopf D;Morris M;Slovin S;McLaughlin B;Curtis K;Hyman DM;Durack JC;Solomon SB;Arcila ME;Zehir A;Syed A;Gao J;Chakravarty D;Vargas HA;Robson ME;Joseph V;Offit K;Donoghue MTA;Abeshouse AA;Kundra R;Heins ZJ;Penson AV;Harris C;Taylor BS;Ladanyi M;Mandelker D;Zhang L;Reuter VE;Kantoff PW;Solit DB;Berger MF;Sawyers CL;Schultz N;Scher HI
通讯作者：
Scher HI