Molecular heterogeneity and early metastatic clone selection in testicular germ cell cancer development

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

p53 and MDM2 expression in primary and metastatic testicular germ cell tumors: Association with clinical outcome

“…However, we found a trend for "MDM2-high" cases to associate with poor prognosis disease (P = .043, Table S4), similar to Eid et al 36 Table S5 which summarizes results of past studies 16,20,32,[34][35][36]40,[43][44][45][46][47][48][49][50][51][52], and classification and staging were reviewed (likely contributing to controversy generated by previous works, with distinct methodologies); the novelty of our study is that we acted to improve objectivity in quantification, by using a digital imaging semi-automated scoring system, shedding light on previous data on this topic. Given the impact of MDM2 upregulation in cisplatin-resistant disease, we postulate that p53-MDM2 interaction inhibitors and MDM2 antagonists might be useful for treatment of selected TGCTs.…”

Napabucasin overcomes cisplatin resistance in ovarian germ cell tumor-derived cell line by inhibiting cancer stemness

“…The MOGCTs are mainly nondiploid (tetraploid, polyploid, or aneuploid), with gain of parts or the short arm of chromosome 12 similarly to TGCTs [15]. Using high thoughput data-analyses Dorssers et al [16] confirmed that nonseminomatous TGCTs are initiated by whole-genome duplication, followed by chromosome copy number changes, and accumulation of low numbers of somatic mutations, even in therapy-resistant cases. In addition, DNA methylation changes can occur during acquisition of drug resistance [17,18].…”

Cisplatin Resistance in Testicular Germ Cell Tumors: Current Challenges from Various Perspectives

“…Both these new targets are of interest and reinforce the connection of cisplatin resistance with epigenetics (see above), as the former represents a chromatin remodeler (of the SWI/SNF family), and the latter constitutes a histone methyltransferase. Another work, including both primary and matched metastatic cisplatin refractory samples, was able to pinpoint mutations in genes, clonal in nature, that are potential effectors of cisplatin resistance; not surprisingly, again, these included mutations/amplifications in genes related to apoptosis ( RHBDD1 ); DNA repair ( XRCC2 ); p53 regulation ( MDM2 , also showed in another study using matched primary-metastatic samples [ 141 ]); and oncogenic signaling ( KIT , NRAS , and PIK3CA ) [ 142 ]. Authors highlight that mutations like the one on XRCC2 (or in other HR DNA repair genes) are already present in the chemo-naïve primary TGCT, which is then selected by cisplatin treatment and becomes dominant in the refractory disease.…”