Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
Department of Pathology, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
Eur Urol. 2019 Mar;75(3):498-505. doi: 10.1016/j.eururo.2018.08.009. Epub 2018 Sep 1.
Most primary prostate cancers are multifocal with individual tumors harboring different aggressiveness; however, the genomic heterogeneity among these tumors is poorly understood.
To better understand the biological basis for clinical variability among different lesions, we sought to comprehensively characterize the heterogeneity of somatic gene mutations in multifocal prostate cancer.
DESIGN, SETTING, AND PARTICIPANTS: High-coverage whole-exome sequencing of 153 frozen tissue samples, taken from two to three distinct tumor foci and one non-cancerous area from each of 41 patients, covering a total of 89 tumor foci.
State-of-the-art bioinformatics tools for mutation calling and copy number determination from whole-exome sequencing data.
We found a very high degree of interfocal heterogeneity among tumors, that is, 76% of pairwise-compared tumor foci from the same prostatectomy specimen had no point mutations in common and DNA copy number changes were rarely shared across cancer foci. The few point mutations shared across tumor foci were seldom in cancer-critical genes.
In this first large genomic heterogeneity study of primary prostate cancer, we observe that different tumor foci within the same patient are genetically distinct, only rarely sharing any somatic gene mutations, including those in cancer driver genes. This heterogeneity affects how genomics-based management of prostate cancer can be implemented, as information from all tumor foci is necessary to draw valid conclusions about the cancer's genomic alterations.
Most primary prostate cancers consist of multiple tumors within the same organ, but little is known about their relationships. We have compared the sets of gene mutations among such tumors and found that they only exceptionally have any in common. This will influence treatment decisions in the future as each tumor's mutations will render it unique and have to be considered to gain the best treatment results.
大多数原发性前列腺癌呈多灶性，每个肿瘤具有不同的侵袭性；然而，这些肿瘤之间的基因组异质性尚不清楚。
为了更好地理解不同病变之间临床变异性的生物学基础，我们试图全面描述多灶性前列腺癌中体细胞基因突变的异质性。
设计、设置和参与者：对 41 名患者的每个患者的两个到三个不同肿瘤灶和一个非癌区域的 153 个冷冻组织样本进行高覆盖率全外显子组测序，总共覆盖了 89 个肿瘤灶。
用于从全外显子组测序数据中调用突变和确定拷贝数的最先进的生物信息学工具。
我们发现肿瘤之间存在非常高的灶间异质性，即来自同一前列腺切除术标本的 76%的成对比较肿瘤灶没有共同的点突变，并且肿瘤灶之间很少共享 DNA 拷贝数变化。肿瘤灶之间共享的少数点突变很少发生在癌症关键基因中。
在原发性前列腺癌的首次大规模基因组异质性研究中，我们观察到同一患者内的不同肿瘤灶在遗传上是不同的，很少共享任何体细胞基因突变，包括癌症驱动基因中的突变。这种异质性影响了基于基因组学的前列腺癌管理的实施方式，因为需要从所有肿瘤灶获取信息才能得出关于癌症基因组改变的有效结论。
大多数原发性前列腺癌由同一器官内的多个肿瘤组成，但对它们之间的关系知之甚少。我们比较了这些肿瘤中的基因突变集，发现它们很少有共同之处。这将影响未来的治疗决策，因为每个肿瘤的突变将使其变得独特，并且必须考虑到每个肿瘤的突变来获得最佳的治疗效果。
