# Mechanisms and Fetal Origins Underlying Gonadal Germ Cell Tumor-AWARDED

> **NIH NIH K08** · CHILDREN'S RESEARCH INSTITUTE · 2022 · $216,761

## Abstract

PROJECT SUMMARY
Testicular germ cell tumor (TGCT) is the most common cancer in men 15-45 years old, and among adult
cancers results in the greatest years of life lost. Among children with gonadal/genital atypia (the applicant’s
specialty), the lifetime risk of gonadal germ cell tumor is up to 50%. However, which genes predispose to these
tumors, and thus would be targets for precision-medicine-based prevention and treatment approaches, remain
mostly unknown. The applicant recently identified both the first Mendelian gene predisposing to TGCT, and
new genome-wide association hits for TGCT. In the research project proposed here we will determine the
mechanisms through which these genomic variations impair cell-autonomous germ cell specification and/or
epigenetic reprogramming (Aim 1) and gonadal niche formation (Aim 2). I hypothesize that alleles which
predispose to TGCT impair specific stages of germ cell development. These aims will be accomplished using
innovative modeling of human germ cells with induced pluripotent stem cells (iPSCs), and a genetic biobank of
~100,000 children with phenotypic data by which to identify those with gonadal/genital atypia and risk for
TGCT. This data will advance our understanding of TGCT predisposition and initiation, and will expand our
knowledge of typical gonadal development. The results from this study will provide rationale for future precision
cancer prevention and treatment strategies. This proposal describes a five-year plan for the applicant to
develop an independent research career as an academic oncogeneticist focused on germ cell tumor
predisposition and prevention. The applicant, Dr. Pyle, is an attending pediatric geneticist at Children’s Hospital
of Philadelphia (CHOP) with PhD training in basic molecular biology and precision medicine. Her research
focuses on identifying germline genetic features that predispose to TGCT, and understanding their
mechanisms of action. The goals for this award are to further develop the skills required for a successful career
as an independent investigator, including expertise in bioinformatic analysis and handling of large genetic and
phenotypic data sets, modeling of human tissue with iPSCs, and cancer biology. The mentors for this award,
Drs. Hakon Hakonarson and Katherine L. Nathanson, are internationally recognized leaders in pediatric
genetic discovery and genetic predisposition to cancer, respectively. Dr. Pyle will be supported by a
mentorship committee comprising leaders in oncology, statistical genetics, and gonadal development. Dr. Pyle
will also benefit from the unparalleled resources and mentorship available at CHOP and the University of
Pennsylvania.

## Key facts

- **NIH application ID:** 10622303
- **Project number:** 7K08CA248704-03
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Louise Clare Pyle
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $216,761
- **Award type:** 7
- **Project period:** 2022-05-14 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10622303

## Citation

> US National Institutes of Health, RePORTER application 10622303, Mechanisms and Fetal Origins Underlying Gonadal Germ Cell Tumor-AWARDED (7K08CA248704-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10622303. Licensed CC0.

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