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

Lambert C J Dorssers,J Wolter Oosterhuis,Marleen M Nieboer,Hans Stoop,Jeroen De Ridder,Harmen J G Van De Werken,Leendert H J Looijenga,Job Van Riet,Ronald Van Marion,Ad J M Gillis

doi:10.1038/s41416-019-0381-1

Abstract

BackgroundTesticular 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.MethodsIn 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.ResultsIntratumour 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.ConclusionsOur 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.

Highlights

Testicular germ cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an embryonic germ cell
About 50% of the TGCC patients present with a NS that can be composed of different histological elements, embryonal carcinoma (EC), teratoma (TE), yolk sac tumour (YST), and choriocarcinoma, either pure or mixed
Pathogenic somatic mutations in BRCA1 or BRCA2 were not observed in the four included TGCC, case T1382 carried a predicted, nonpathogenic BRCA1 missense variant (Supplementary Table S6), nor in the cases of the Taylor-Weiner study.[14]

Summary

Introduction

Testicular germ cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an embryonic germ cell. 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. Malignant germ cell tumours of the adult testis, referred to as type II TGCTs of testicular germ cell cancer (TGCC), are the most frequent cancer in young Caucasian males.[1] TGCC are thought to be initiated during early embryogenesis affecting an embryonic germ cell, and become clinically manifest during young adulthood with an annual frequency of approximately 5–12 per 100,000 men in the western world and may require “aggressive” medical treatment These cancers are clinically and histologically classified into two variants, being seminoma (SE) and nonseminoma (NS). The EC is the pluripotent stem cell component of NS, which can mimic normal early embryogenesis including the formation of so-called embryonal bodies (EBs), and thereby give rise to all differentiated components.[3,4,5]

Methods

Results

Conclusion