We are excited to receive a Knight Cancer Institute Quantitative Oncology Program Pilot Award, funded by the NCI P30 Cancer Center Support Grant, for our project, Germline and Microenvironmental Determinants of Testicular Cancer Progression.

Our first cancer-focused grant, this is an exciting opportunity to bring our expertise in male infertility and testis biology to understanding testicular cancer.

Scientific Abstract

Testicular germ cell tumors (TGCT) are the most common solid malignancy in young men. Although survival exceeds 95%, treatment-related morbidity is substantial. TGCT arises from germ cell neoplasia in situ (GCNIS), a pre-invasive lesion detectable years before invasion. However, approximately 30% of men with GCNIS never progress, and no molecular markers currently distinguish the pre-invasive from the invasive state, nor identify which lesions will become dangerous. Circulating miRNA signatures (miR-371-373 cluster) detect established disease but do not resolve progression risk in pre-invasive GCNIS.

We hypothesize that rare germline variants interact with specific microenvironmental contexts within the testis to promote progression to invasive TGCT.

Using blood-derived DNA and matched FFPE tissue from 4 biopsy-confirmed GCNIS cases and 4 invasive TGCT cases (phenotypic extremes design; population-scale validation planned in R01), we will: (1) perform PacBio HiFi long-read whole-genome sequencing to comprehensively resolve single-nucleotide and structural variation across repetitive and regulatory regions; and (2) generate high-resolution spatial transcriptomic maps using Visium HD to define cellular states and tissue architecture spanning pre-invasive and invasive disease.

We will extract quantitative genomic and spatial features and integrate these data to identify candidate molecular signatures of the GCNIS-to-invasion transition, providing new molecular markers to stratify TGCT risk. This pilot establishes feasibility for multimodal germline-spatial modeling in TGCT and generates the effect sizes and candidate loci required to power an R01 focused on predicting malignant transformation in men at high risk.