Department of Medical Epidemiology and Biostatistics, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
Eur Urol. 2013 Feb;63(2):347-53. doi: 10.1016/j.eururo.2012.03.050. Epub 2012 Mar 31.
Prostate cancer (PCa) is a clinically and pathologically heterogeneous disease. The rapid development of sequencing technology has the potential to deliver new biomarkers with emphasis on aggressive disease and to revolutionise personalised cancer treatment. However, a prostate harbouring cancer commonly contains multiple separate tumour foci, with the potential to aggravate tumour sampling. The level of intraprostatic tumour heterogeneity remains to be determined.
To determine the level of intraprostatic tumour heterogeneity through genome-wide, high-resolution profiling of multiple tumour samples from the same individual.
DESIGN, SETTINGS, AND PARTICIPANTS: Multiple tumour samples were obtained from four individuals following radical prostatectomy. One individual (SWE-1) contained >70% cancer cells in all tumour samples, whereas the other three (SWE-2 to SWE-4) required the use of laser capture microdissection for tumour cell enrichment. Subsequently, DNA was extracted from all tissue samples, and exome sequencing was performed. All tumour foci of SWE-1 were also profiled using a high-resolution array for the identification of copy number alterations (CNA).
Shared somatic high-frequency single nucleotide variants (SNV) and CNAs were used to infer the level of intraprostatic tumour heterogeneity.
No high-frequency mutations, common for the three tumour samples of SWE-1, were identified. Ten randomly chosen positions were validated with Sanger sequencing in all foci, which verified the exome data. The high level of intraprostatic heterogeneity was consistent in all individuals. In total, three out of four individuals harboured tumours without an apparent common somatic denominator. Although we cannot exclude the presence of common structural rearrangements, a high-density array was used for the detection of deletions and amplifications in SWE-1, which agreed with the exome data.
We present evidence for the presence of somatically independent tumours within the same prostate. This finding will have implications for personalised cancer treatment and biomarker discovery.
前列腺癌（PCa）是一种临床表现和病理表现均具有异质性的疾病。测序技术的快速发展有可能提供新的生物标志物，侧重于侵袭性疾病，并彻底改变个性化癌症治疗。然而，通常含有癌症的前列腺内存在多个独立的肿瘤灶，这有可能加重肿瘤采样的难度。肿瘤内异质性的程度仍有待确定。
通过对同一患者的多个肿瘤样本进行全基因组、高分辨率分析，确定肿瘤内异质性的程度。
设计、设置和参与者：对 4 名接受根治性前列腺切除术的患者的多个肿瘤样本进行了采集。其中一名患者（SWE-1）所有肿瘤样本中均含有>70%的癌细胞，而另外三名患者（SWE-2 至 SWE-4）需要使用激光捕获显微切割进行肿瘤细胞富集。随后，从所有组织样本中提取 DNA，并进行外显子组测序。SWE-1 的所有肿瘤灶也使用高分辨率阵列进行了拷贝数改变（CNA）的鉴定。
使用共享体细胞高频单核苷酸变异（SNV）和 CNA 来推断肿瘤内异质性的程度。
未发现 SWE-1 的三个肿瘤样本中常见的高频突变。在所有焦点中，用 Sanger 测序随机验证了 10 个位置，验证了外显子组数据的准确性。所有个体的肿瘤内异质性水平均较高。在总共 4 名患者中，有 3 名患者的肿瘤似乎没有明显的共同体细胞标志物。尽管我们不能排除常见结构重排的存在，但使用高密度阵列检测了 SWE-1 中的缺失和扩增，与外显子组数据一致。
我们提供了证据表明在同一前列腺中存在具有体细胞独立性的肿瘤。这一发现将对个性化癌症治疗和生物标志物的发现产生影响。
