Department of Pathology, Wytemaweg 80, 3015 CN, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
University Medical Center Utrecht, Universiteitsweg 100, STR 1.305, Utrecht, 3584 CG, The Netherlands.
Br J Cancer. 2019 Feb;120(4):444-452. doi: 10.1038/s41416-019-0381-1. Epub 2019 Feb 11.
Testicular germ cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an embryonic germ cell. This study determines intratumour heterogeneity to unravel tumour progression from initiation until metastasis.
In total, 42 purified samples of four treatment-resistant nonseminomatous (NS) TGCC were investigated, including the precursor germ cell neoplasia in situ (GCNIS) and metastatic specimens, using whole-genome and targeted sequencing. Their evolution was reconstructed.
Intratumour molecular heterogeneity did not correspond to the supposed primary tumour histological evolution. Metastases after systemic treatment could be derived from cancer stem cells not identified in the primary cancer. GCNIS mostly lacked the molecular marks of the primary NS and comprised dominant clones that failed to progress. A BRCA-like mutational signature was observed without evidence for direct involvement of BRCA1 and BRCA2 genes.
Our data strongly support the hypothesis that NS is initiated by whole-genome duplication, followed by chromosome copy number alterations in the cancer stem cell population, and accumulation of low numbers of somatic mutations, even in therapy-resistant cases. These observations of heterogeneity at all stages of tumourigenesis should be considered when treating patients with GCNIS-only disease, or with clinically overt NS.
睾丸生殖细胞癌（TGCC）是年轻白种男性中最常见的恶性肿瘤，起源于胚胎生殖细胞。本研究旨在确定肿瘤内异质性，以揭示从起始到转移的肿瘤进展过程。
共研究了 42 例经治疗后仍未缓解的非精原细胞瘤（NS） TGCC 的纯样本，包括生殖细胞肿瘤原位（GCNIS）和转移性标本，采用全基因组和靶向测序。对其进化进行了重建。
肿瘤内分子异质性与假定的原发性肿瘤组织学演变不相符。全身性治疗后的转移瘤可能来源于原发性癌症中未识别的癌症干细胞。GCNIS 主要缺乏原发性 NS 的分子标志，并且包含未能进展的优势克隆。观察到 BRCA 样突变特征，但没有证据表明 BRCA1 和 BRCA2 基因直接参与。
我们的数据强烈支持这样一种假设，即 NS 是由全基因组复制引发的，随后是癌症干细胞群体中的染色体拷贝数改变，并积累了少量的体细胞突变，即使在治疗耐药的情况下也是如此。在治疗仅有 GCNIS 疾病或临床显性 NS 的患者时，应考虑到肿瘤发生的所有阶段的这种异质性观察。
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