A Thiopurine-like Mutagenic Process Defines TGCT Subtypes.

Area of Science:

• Genomics
• Oncology
• Developmental Biology

Background:

• Testicular germ cell tumors (TGCTs) are the most common male cancer in young adults.
• Understanding molecular differences between TGCT subtypes is crucial for targeted therapies.
• TGCTs possess unique developmental origins and high chemosensitivity.

Purpose of the Study:

• To conduct a comprehensive genomic analysis of treatment-naive primary TGCTs.
• To identify novel driver genes and defining molecular characteristics of TGCT subtypes.
• To investigate the role of whole genome doubling (WGD) and specific mutational signatures in TGCT pathogenesis.

Main Methods:

• Deep whole-genome sequencing of 252 primary TGCTs.
• Integration of matched transcriptomic and epigenomic data.
• Comparative analysis of genomic features between TGCT subtypes (seminomas vs. non-seminomas).

Main Results:

• Identification of new driver genes and pervasive chromosome X amplification with subtype-specific inactivation.
• Characterization of ubiquitous, early whole genome doubling (WGD) associated with age at onset.
• Discovery of a novel mutational signature (SBS87) prevalent in TGCTs, particularly non-seminomas, linked to extended tumor latency and telomere elongation.

Conclusions:

• TGCTs are molecularly distinct, shaped by early genomic instability.
• Subtype-specific genomic features, including X chromosome alterations and WGD patterns, differentiate seminomas and non-seminomas.
• The novel SBS87 mutational signature in TGCTs suggests potential environmental or endogenous etiologies mimicking DNA damage.