# Age associated genomic instability and brain tumor risk

> **NIH NIH U01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $125,250

## Abstract

Abstract
 Genome instability, i.e., the acquisition of gene mutations and both structural and numerical
chromosomal aberrations, is a hallmark of cancer. Genome instability, however, also significantly contributes to
tissue degeneration and organ dysfunction in aging. How age-related changes in genome maintenance
contributes to cancer risk remains unknown. The main goal of this application is to determine the molecular
genetic basis of this association.
 Studying normative aging in the mouse Dr. Montagna (extramural PI) established a significant
accumulation of aneuploidy in non-neuronal cells (NeuN-) isolated from the cerebral cortex, but not the
cerebellum, of old mice. In this application we propose to build on this seminal observation and join forces with
Dr. Ried (intramural co-I), an expert in cancer genetics, to determine how changes in genome stability at old age
contribute to increase cancer susceptibility. To do so we propose to employ an arsenal of complementary,
cutting-edge experimental approaches used in our labs. Multicolor interphase FISH (miFISH) to measure
aneuploidy and copy number changes, and single-cell whole genome analyses to simultaneously detect all forms
of large scale genomic instability. Both assays are amenable to deal with the substantial, cell-to-cell stochastic
variation known to be associated with aging. Here we will test the novel hypothesis that astrocytes of the cerebral
cortex, but not the cerebellum, accumulate genomic instability during aging and this ultimately increase their risk
for transformation. The risk to develop brain tumors increase with age and most adult brain tumors develop in
the cerebral cortex, unlike in children where tumors originate in the cerebellum.
 Our hypothesis will be tested along two specific aims. In Aim 1 we will determine the genetic landscape
of astrocytes isolated from the cortex and the cerebellum during normative aging to establish mutation patterns
in aging brain cells. In Aim 1 we will establish the genetic landscape of non-tumor astrocytes isolated from GBM
patients relative to patient matched tumor cells.
 All experiments will utilize cortical and cerebral brain biopsies obtained from post mortem donors from
the NIH NeuroBioBank.
 A major strength of this application is the research team. Dr. Montagna and Dr. Ried have known each
other since 1998, and they have 18 joint publications. Dr. Montagna will contribute her expertise in chromosome
instability and aging, and Dr. Ried will provide knowledge on cancer genomics.

## Key facts

- **NIH application ID:** 9942400
- **Project number:** 5U01CA238726-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Cristina Montagna
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $125,250
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942400

## Citation

> US National Institutes of Health, RePORTER application 9942400, Age associated genomic instability and brain tumor risk (5U01CA238726-02). Retrieved via AI Analytics 2026-06-07 from https://api.ai-analytics.org/grant/nih/9942400. Licensed CC0.

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