# Mechanisms of gene amplification in human cancers

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $363,375

## Abstract

PROJECT SUMMARY
The goal of our proposed study is to determine the mechanisms underlying structural chromosome
abnormalities and genomic amplification in human tumors. Genomic (gene) amplification is one of the key
drivers of tumor development and progression. There are several, recurrently amplified oncogene loci in the
genome. Enormous efforts have been directed to antagonizing the outcomes of oncogene amplification, such
as overexpressed proteins and downstream signaling pathways. So far, little attention has been paid to the
translational potential of the underlying amplification mechanisms. Our long-term goal is to translate the
knowledge from genomic amplification mechanisms for controlling aggressive tumors.
A genomic segment harboring an oncogene can accumulate either within chromosomes or
extrachromosomally in the form of circular minichromosomes. Therefore, identifying a single molecular process
for controlling genomic amplification appears challenging. We have shown that a defect in DNA replication is a
crucial initiating event for genomic amplification. To faithfully duplicate the large human genome, replication
machinery (forks) must travel a long distance and overcome a number of natural obstacles, such as DNA
secondary structures and collisions with transcription machinery. Tumor cells and pre-cancerous lesions often
fail to protect replication forks at these obstacles, and as a result, forks stall and collapse (replication stress).
Collapsed forks become broken forks with recombinogenic DNA ends, which can lead to chromosomal
abnormalities and genomic amplification.
Although we now recognize the crucial role of replication stress, molecular mechanisms from stalled/collapsed
forks to recurrent genomic amplification remain elusive. Such information is essential to identify new targets to
control genomic amplification. For recurrent genomic amplification to occur, there must be a natural obstacle
near an oncogene that repeatedly impedes replication fork movements. We hypothesize that locus-specific,
natural genomic stress impedes replication fork movements and escorts collapsed forks into recurrent genomic
amplification. We have identified candidate obstacles in two recurrently-amplified genomic loci, 8q24 with MYC
oncogene (AIM1) and 17q12-21 with ERBB2 oncogene (AIM2), and will investigate molecular mechanisms
step-by-step from stalled/collapsed forks to genomic amplification. Our results will reveal a specific interaction
between amplification mechanisms and local genomic context, which may provide us a novel mechanistic
insight with therapeutic potential.

## Key facts

- **NIH application ID:** 9984293
- **Project number:** 5R01CA149385-08
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Hisashi Tanaka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $363,375
- **Award type:** 5
- **Project period:** 2010-07-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984293

## Citation

> US National Institutes of Health, RePORTER application 9984293, Mechanisms of gene amplification in human cancers (5R01CA149385-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9984293. Licensed CC0.

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