Cancer Institute, University College London, London, UK.
MRC Clinical Trials Unit at University College London, London, UK.
Genome Med. 2022 Sep 5;14(1):102. doi: 10.1186/s13073-022-01080-4.
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). 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.
基因组拷贝数改变在前列腺癌中经常发生，是基因组不稳定性的一个衡量标准。在广泛的疾病谱中，从高危局限性到转移性疾病，高级别前列腺癌中拷贝数改变的临床意义尚不清楚。
我们对 300 名接受长期雄激素剥夺治疗（ADT）前患有高级别前列腺癌的患者的 688 个肿瘤区域进行了拷贝数谱分析，这些患者均来自前瞻性随机 STAMPEDE 试验的对照组。根据转移性状态，患者被分为以下几类：有或无局部淋巴结受累的高危局限性、或转移性低/高容量。我们对患者进行了中位数为 7 年的随访。使用单变量和多变量 Cox 生存模型来估计拷贝数改变负担作为连续变量与死亡或疾病进展风险之间的关联。
拷贝数改变负担与诊断时放射学上明显的远处转移呈正相关（P=0.00006），并且在单变量和多变量分析中与临床结果呈非线性关系，表现为进展（P=0.003）和死亡（P=0.045）的相对风险每增加一个单位就急剧增加，而在更高的拷贝数负担下则趋于适度增加。这种拷贝数负担与结局之间的关联在每个转移性状态中均相似。在最低拷贝数负担四分位数（q=4.1×10），拷贝数缺失的频率显著高于增益。在具有更高拷贝数改变的病例中，分别位于染色体 5q21-22 和 8q21-24 上的 CHD1 和 cMYC 的缺失和增益更为常见（对于任一区域：柯尔莫哥洛夫-斯米尔诺夫距离，0.5；调整后 P<0.0001）。拷贝数改变在同一前列腺的肿瘤区域之间存在变异性。这种变异与远处转移的风险增加有关（Kruskal-Wallis 检验 P=0.037）。
高级别前列腺癌中的拷贝数改变与诊断时转移风险增加相关。有限数量的拷贝数改变的积累与疾病进展和死亡风险的大部分增加相关。在高拷贝数改变负担的癌症中，特定片段的受累可能性增加，这可能提示了拷贝数改变积累的一个顺序。
ClinicalTrials.gov NCT00268476，于 2005 年 12 月 22 日注册。EudraCT 2004-000193-31，于 2004 年 10 月 4 日注册。
