Genomic evolution and chemoresistance in germ-cell tumours

Abstract

Germ-cell tumours (GCTs) are derived from germ cells and occur most frequently in the testes1,2. GCTs are histologically heterogeneous and distinctly curable with chemotherapy3. Gains of chromosome arm 12p and aneuploidy are nearly universal in GCTs4–6, but specific somatic genomic features driving tumour initiation, chemosensitivity and progression are incompletely characterized. Here, using clinical whole-exome and transcriptome sequencing of precursor, primary (testicular and mediastinal) and chemoresistant metastatic human GCTs, we show that the primary somatic feature of GCTs is highly recurrent chromosome arm level amplifications and reciprocal deletions (reciprocal loss of heterozygosity), variations that are significantly enriched in GCTs compared to 19 other cancer types. These tumours also acquire KRAS mutations during the development from precursor to primary disease, and primary testicular GCTs (TGCTs) are uniformly wild type for TP53. In addition, by functional measurement of apoptotic signalling (BH3 profiling) of fresh tumour and adjacent tissue7, we find that primary TGCTs have high mitochondrial priming that facilitates chemotherapy-induced apoptosis. Finally, by phylogenetic analysis of serial TGCTs that emerge with chemotherapy resistance, we show how TGCTs gain additional reciprocal loss of heterozygosity and that this is associated with loss of pluripotency markers (NANOG and POU5F1)8,9 in chemoresistant teratomas or transformed carcinomas. Our results demonstrate the distinct genomic features underlying the origins of this disease and associated with the chemosensitivity phenotype, as well as the rare progression to chemoresistance. These results identify the convergence of cancer genomics, mitochondrial priming and GCT evolution, and may provide insights into chemosensitivity and resistance in other cancers.

Mediastinal germ cell tumors: new therapeutic insights

“…Moreover, KRAS mutations seem to concur to germ cell tumour carcinogenesis during the carcinogenetic development from precursor to primary disease (12 NANOG and POU5F in chemoresistant teratomas or transformed carcinomas (13). Altogether, those results strongly support that biological aggressiveness in germ cell tumours associates with the progressive gain of a distinct multifactorial genomic profile leading to the progression to chemoresistance (12).…”

“…R e c e n t l y, i n v e s t i g a t i o n o f w h o l e -e x o m e a n d transcriptome sequencing of both human primary and metastatic gonadal and MGCTs revealed that the primary somatic feature of germ cell tumours are recurrent chromosome arm level amplifications and reciprocal deletions, and those variations are increased in germ cell tumours compared to many other cancer types (12). Moreover, KRAS mutations seem to concur to germ cell tumour carcinogenesis during the carcinogenetic development from precursor to primary disease (12 NANOG and POU5F in chemoresistant teratomas or transformed carcinomas (13).…”

Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline

“…Although whole-exome sequencing (WES) was recently used to describe the mutational landscape of classical seminoma and non-seminoma, the most common forms of TGCTs [46,47,48,49], to our knowledge the present study represents the first WGS analysis of any type of TGCT. By providing a genome-wide overview of the mutational landscape acquired by tumor samples, WGS offers insights into the processes responsible for tumor pathology.…”

Recent developments in the management of germ cell tumors

“…Whole exome sequencing of testicular GCTs has revealed a relatively low frequency of somatic point mutations (average mutation rate of 0.5–0.9 per Mb) which supports the embryological origin of this malignancy [42–44]. Conversely, chromosome arm-level copy number gains, particularly the presence of an isochromosome of the short arm of chromosome 12 (i12p), are significantly more frequent events [42, 44]. Most GCTs are hyperploid based on cytogenetic studies [45].…”

“…Such comprehensive profiling has been undertaken by The Cancer Genome Atlas project (https://cancergenome.nih.gov/) and the results are publicly available for investigators to use in generating or validating hypotheses based on the observed genomic and biological patterns. Whole exome sequencing of testicular GCTs has revealed a relatively low frequency of somatic point mutations (average mutation rate of 0.5–0.9 per Mb) which supports the embryological origin of this malignancy [42–44]. Conversely, chromosome arm-level copy number gains, particularly the presence of an isochromosome of the short arm of chromosome 12 (i12p), are significantly more frequent events [42, 44].…”