Germ cell tumor treatment resistance and liquid biopsy-based microRNA biomarkers

Abstract

Malignant germ cell tumors (GCTs) constitute about 1% of male cancers globally, prevalent primarily among males aged 15 to 44. These tumors arise in testicular or extra-testicular regions along the body's midline. Despite their rarity, they're a significant cause of mortality, particularly affecting young individuals, ranking high in potential years of life lost.

GCTs are diverse, notably distinguished between embryonic GCT elements and fully differentiated teratomas. Sensitivity to DNA damage, akin to embryonal germ and stem cells, marks GCT cells, making platinum-based therapies, like cisplatin, the primary treatment. While effective for most, treatment resistance often results in limited options and mortality in nearly 50% of cases. Additionally, cisplatin's high toxicity poses severe side effects, emphasizing the need to understand resistance for improved treatment and patient stratification.

Current clinical biomarkers for GCT detection have about 60% accuracy, underscoring the necessity for better options. The microRNA cluster 371a-3 stands out as a promising biomarker, displaying high accuracy in marking GCTs, potentially revolutionizing clinical applications.

TP53, known for safeguarding genomic integrity, is rarely mutated in GCTs due to their embryonal origin. Its role in cisplatin resistance in GCTs remains unclear, a subject this thesis addresses.

Chapters 2 and 3 delve into TP53's potential role in GCTs. The thesis investigates TP53 mutations in GCTs, showcasing their rare occurrence and association with treatment resistance. Artificial mutations rendering TP53 non-functional increased cellular resistance to cisplatin.

Chapter 4 focuses on identifying a chromosomal gain associated with cisplatin resistance in GCTs. This discovery enhances diagnostic value, aiding patient stratification and avoiding overtreatment.

Chapters 5, 6, and 7 center on microRNAs as potential biomarkers. They explore detection methods, scrutinize the microRNA cluster's function in GCTs, and demonstrate its detection in a mouse model, potentially enabling early detection in at-risk pregnancies.

Overall, the thesis contributes significant insights into GCT research. Notably, it uncovers TP53's potential role in resistance, identifies a chromosomal marker, and highlights microRNA371a-3's promise as a diagnostic biomarker. While it paves the way for further exploration, the search for a biomarker for teratoma identification remains an area of interest.