# Structure and function of genome plasticity in human cancer

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $519,902

## Abstract

Project Summary
Despite intense efforts, the long-term cure rates of childhood and adult solid tumors such as rhabdoid tumors
are not satisfactory. Resistance to intensive chemotherapy is nearly universal, and targets for molecular
therapies are largely undefined. For example, inactivating mutations of SMARCB1 cause rhabdoid tumors, but
their molecular pathophysiology and genetics remain poorly understood. We have now found that the majority
of childhood and distinct adult solid tumors, including rhabdoid tumors, express PGBD5, a DNA transposase-
derived human gene. We have now found that human rhabdoid and numerous solid tumors are characterized
by previously unknown somatic deletions and inversions involving PGBD5-specific signal sequences (PSS) at
their breakpoints. Remarkably, PGBD5's DNA transposase enzymatic activity is both necessary and sufficient
for cell transformation, and induces recurrent and site-specific genomic rearrangements, leading to cooperative
inactivation of tumor suppressor genes. The central hypothesis of this proposal is that defining the genetic and
epigenetic mechanisms PGBD5-induced tumorigenesis will identify fundamental causes of PGBD5-induced
solid tumors and refractory rhabdoid tumors in particular. The applicant will test this hypothesis by
investigating the molecular mechanisms of PGBD5-induced cell transformation and rhabdoid tumorigenesis
using primary human and genetically-engineered mouse tumors. Aim 1 will elucidate genetic and epigenetic
mechanisms of PGBD5-induced cell transformation, with the goal of identifying PGBD5 targets that are
necessary for malignant transformation, and molecular mechanisms that control their induction. Aim 2 will
pursue the preliminary evidence that PGBD5-induced genomic rearrangements cooperate with SMARCB1
mutations in rhabdoid tumors and determine the function of PGBD5 using developmentally faithful mouse
rhabdoid tumor models in vivo. Successful completion of this project is expected to yield essential molecular
mechanisms of PGBD5-induced tumorigenesis, thus providing key insights into a fundamental biological and
clinical problem, which should have broad and lasting significance for understanding and treating solid tumors.

## Key facts

- **NIH application ID:** 9828537
- **Project number:** 5R01CA214812-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Alex Kentsis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $519,902
- **Award type:** 5
- **Project period:** 2017-12-13 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828537

## Citation

> US National Institutes of Health, RePORTER application 9828537, Structure and function of genome plasticity in human cancer (5R01CA214812-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828537. Licensed CC0.

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