Integrated Molecular and Histopathological Studies of Testicular Germ Cell Tumor Biology

Abstract

In the United States, approximately 9,000 people are diagnosed with germ cell tumors in 2022. Testicular GCTs (TGCTs) are the most common malignancy among men between ages 14 and 40, and the incidence has been increasing since the mid-20th century. GCTs are highly sensitive to a regimen of systemic platinum-based chemotherapy; however, better risk stratification and more refined management guidelines are required to minimize unnecessary interventions and their associated adverse effects. Furthermore, platinum-refractory and resistant disease remains a significant issue in 5-10% of patients, for which treatment options are limited, and survival rate is poor. Given its diagnosis at earlier ages, lethal TGCTs comprise the most life years lost for non-pediatric malignancies.

Macroscopic and histopathologic evaluation of primary biopsies remains the foundation for clinical management of patients with TGCTs. TGCTs are classified according to their histological composition as interpreted by hematoxylin and eosin (H&E)-staining. Accurate histological classification of patient biopsies is paramount, as these subtypes differ in clinical and biologic behavior and, therefore, affect treatment and prognosis. However, this task may be complicated by the presence of multiple subtypes within a single tumor, and challenges for manual pathology interpretation of whole slide images to determine these features. Characterization and the clinical significance of TGCT heterogeneity remains poorly understood. Even further, attempts to identify histological features of TGCTs for early clinical distinction of high risk and chemo-resistant tumors have yielded sparse insights and remain heavily debated.

Further, compared to other solid tumors in adults, TGCTs have very limited model systems and few somatic mutations, with a relatively low mutation rate ranging from 0.5 to 1 mutation per megabase. Also, recurrent mutations in known driver genes are infrequent and discordant between studies. Despite low point mutational loads, TGCTs are defined by chromosomal instability and extensive copy number changes, including highly recurrent chromosomal arm-level amplifications and reciprocal deletions that is particularly enriched in TGCTs compared to other malignancies; however, the transcriptional and epigenetic programs that not only underlie TGCT pathogenesis, but also distinguish TGCT subtypes remain unknown.

In this dissertation, I use computational and deep learning approaches in interpreting H&E-stained whole slide images, single-cell RNA-sequencing, and orthogonal epigenetic profiling data to both investigate transcriptional and epigenetic modes of TGCT subtype pathogenesis and evolution as well as also guide the discovery of histopathologic biomarkers and clinically actionable targets to inform treatment, better risk stratification, and more refined management guidelines.