Dataset Information

Clonal diversification and histogenesis of malignant germ cell tumours.

ABSTRACT: Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells. They are uniquely able to recapitulate embryonic and extraembryonic tissues, which carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here, we study the relationship of histogenesis and clonal diversification in GCTs by analysing the genomes and transcriptomes of 547 microdissected histological units. We find no correlation between genomic and histological heterogeneity. However, we identify unifying features including the retention of fetal developmental transcripts across tissues, expression changes on chromosome 12p, and a conserved somatic evolutionary sequence of whole genome duplication followed by clonal diversification. While this pattern is preserved across all GCTs, the developmental timing of the duplication varies between prepubertal and postpubertal cases. In addition, tumours of younger children exhibit distinct substitution signatures which may lend themselves as potential biomarkers for risk stratification. Our findings portray the extensive diversification of GCT tissues and genetic subclones as randomly distributed, while identifying overarching transcriptional and genomic features.

SUBMITTER: Oliver TRW

PROVIDER: S-EPMC9372159 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Clonal diversification and histogenesis of malignant germ cell tumours.

Oliver Thomas R W TRW Chappell Lia L Sanghvi Rashesh R Deighton Lauren L Ansari-Pour Naser N Dentro Stefan C SC Young Matthew D MD Coorens Tim H H THH Jung Hyunchul H Butler Tim T Neville Matthew D C MDC Leongamornlert Daniel D Sanders Mathijs A MA Hooks Yvette Y Cagan Alex A Mitchell Thomas J TJ Cortes-Ciriano Isidro I Warren Anne Y AY Wedge David C DC Heer Rakesh R Coleman Nicholas N Murray Matthew J MJ Campbell Peter J PJ Rahbari Raheleh R Behjati Sam S

Nature communications 20220811 1

Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells. They are uniquely able to recapitulate embryonic and extraembryonic tissues, which carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here, we study the relationship of histogenesis and clonal diversification in GCTs by analysing the genomes and transcriptomes of 547 microdissected histol ...[more]

PMID: 35953478

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Project description:This systematic review and meta-analysis was performed to explore overall survival (OS) and event free survival (EFS) rates internationally over the past two decades and to define specific subgroups with inferior outcomes which may demand different treatment strategies. The search focused on malignant extracranial germ cell tumours (GCTs) in the paediatric population. The initial database search identified 12,556 articles; 32 articles were finally included in this review, comprising a total of 5095 patients. The studies were heterogeneous, varying from single institution reports to large prospective trials. Older studies, describing eras where non-platinum-based chemotherapy regimens were used, showed clearly worse outcomes. Survival for stage I-II gonadal disease is excellent. On the other hand, patients with an initial alpha-fetoprotein (AFP) > 10,000 ng/mL or kU/L, age > 11 years and stage IV disease confer a survival disadvantage. For testicular disease in particular, lymphovascular invasion and certain histopathological subtypes, such as embryonal carcinoma (EC) and mixed malignant GCTs, survival is poorer. Survival data for sacrococcygeal and mediastinal GCTs show a heterogeneous distribution across studies in this review, independent of year of publication. Patients > 12 years presenting with a mediastinal GCT pose a subpopulation which fares worse than GCTs in other locations or age groups. This is independent of AFP levels, stage of disease or treatment protocol, and these patients may demand a different treatment strategy. This review describes the heterogeneous nature of GCTs in different anatomical locations, impacting on stage at presentation, treatment modalities used and survival data. Despite this heterogeneity, in line with the current developmental biology-based classification system, subpopulations can be defined which have an inferior EFS and OS and where future research and more individualised treatment would help to improve survival.

Dataset Information

Clonal diversification and histogenesis of malignant germ cell tumours.

Publications

Clonal diversification and histogenesis of malignant germ cell tumours.

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