Molecular Heterogeneity and Early Metastatic Clone Selection in Testicular Germ Cell Cancer Development

Abstract

Novelty and Impact: The nonseminoma subtype of testicular germ cell cancer is characterized by totipotency of the cancer stem cell which may differentiate into all embryonal tissue lineages.We investigated a large series of purified tumor cell samples of four nonseminoma cases using different omics methods. We demonstrate that intratumoral heterogeneity exists among the cancer stem cells and the histological components. Furthermore, metastases appeared to be derived from cancer stem cells not identified in the primary tumor.Keywords (3-5): Tumor Initiation; Genome Duplication; Copy Number Alteration; Cancer Progression, Cancer Stem Cell Abbreviations used: CG: Complete Genomics Inc.; ChC: choriocarcinoma; CNA: copy number alterations; dAP: direct alkaline phosphatase; EB: embryonal bodies; EC: embryonal carcinoma; FISH: fluorescent in situ hybridization; GCNIS: germ cell neoplasia in situ; IHC: immunohistochemistry; LAF: lesser allele frequency; LOH: loss of heterozygosity; NAP: nonmalignant adjacent parenchyma; NS: nonseminoma ; PGC: primordial germ cells; SE: seminoma; SNP: single nucleotide polymorphism; SNV: somatic DNA variants; TE: teratoma; TGCC: testicular germ cell cancer; TGCT: testicular germ cell tumor; WGS: whole genome sequencing; YST: yolk sac tumor.All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/385807 doi: bioRxiv preprint first posted online Aug. 8, 2018; 3 Abstract Testicular germ cell cancer (TGCC) is initiated during early life from a totipotent embryonic germ cell, and the most frequent malignant cancer in young Caucasian males. The goal of this study is to determine the intratumor heterogeneity, and to unravel tumor progression from initiation till therapy-resistant metastasis. In this study, we have investigated 42 purified samples of four cases of nonseminoma with intrinsic resistance to chemotherapy including different histological elements, metastatic specimens and the precursor cancer stem cells (germ cell neoplasia in situ, GCNIS) using whole genome-, and targeted sequencing. Sequence data were used to reconstruct the evolution of these cancers. Intratumor molecular heterogeneity was observed and did not correspond to the supposed histological evolution of the primary tumor. Metastases after systemic treatment were derived from cancer stem cells frequently not identified in the primary cancer. The GCNIS mostly lacked the molecular marks of the primary TGCC and comprised dominant clones that had failed to progress into a manifest malignancy. A BRCA-like mutational signature was found without evidence for direct involvement of BRCA1 and BRCA2

Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic

“…Polyploidization, in addition to a hypomethylated genome, contribute to chromosomal instability in these neoplasms, which further drives tumor progression [80]; however, mutations and amplifications of oncogenes are rather rare in TGCTs, with KIT mutation being the most common, especially in SEs and in bilateral cases [81,82,83]. In fact, recent work by Dorssers et al [84] has showed, by use of whole genome and targeted-sequencing, that NSTs are initiated by genome duplication, followed by chromosome copy number alterations in cancer stem cells, with very low accumulation of somatic mutations, even in cases resistant to therapy. Metastatic tumors show, in fact, very little overlap with the originating primary tumor and precursor lesions, meaning that treatment of recurrences deserve therapies targeted at their specific molecular landscape.…”