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个衡量标准。晚期前列腺癌的拷贝数变化的临床意义尚不清楚，它定义了从高风险局部到转移性的广泛疾病。

在前瞻性随机STAMPEDE试验的对照组中，我们对300名在长期雄激素剥夺治疗(ADT)开始前出现晚期前列腺癌的患者的688个肿瘤区域进行了拷贝数谱分析。将患者分为转移状态如下:高危非转移性伴或不伴局部淋巴结转移，或低/高容量转移。我们随访患者的平均时间为7年。拟合单变量和多变量Cox生存模型，以估计作为连续变量的拷贝数改变负担与死亡或疾病进展危险之间的关联。

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与临床结果呈非线性关系，特征是每增加一个单位，进展的相对风险(P=0.003)和死亡的相对风险(P=0.045)急剧增加，随着拷贝数负担的增加稳定在更温和的增长中。拷贝数负担与转归之间的关系在每个转移状态下都是相似的。拷贝数负担最低的四分位数(q=4.1 10-6)，拷贝数损失发生的频率显著高于增加的频率。在拷贝数变化较大的情况下，5q21-22染色体片段的丢失和8q21-24染色体片段的获得(包括CHD1和cMYC)更为频繁(两个区域的Kolmogorov-Smirnov距离均为0.5;调整术;0.0001)。拷贝数的改变显示了同一前列腺肿瘤区域的差异性。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诊断时转移风险增加有关。有限数量的拷贝数改变的积累与大多数疾病进展和死亡风险的增加有关。在高拷贝数变化负担癌症中，特定片段参与的可能性增加，可能提示了拷贝数变化积累的顺序。

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

原文链接

pubmed.ncbi.nlm.nih.gov/36059000/

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