# The origins of chromosome rearrangement in the cancer genome

> **NIH NIH R00** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $171,851

## Abstract

Project Summary
Research
Advances in DNA sequencing have revealed that cancer genomes harbor chromosome rearrangements of
unexpected frequency and staggering complexity. Despite the recognition that these variations can enable
cancer development by inducing pro-growth genetic change and facilitating clonal evolution, the instigating
factors and mechanisms behind rearrangement are often unknown. This proposal aims to identify the
underlying causes of cancer-associated chromosome rearrangements by focusing on errors during mitosis,
especially in the context of dicentric chromosome formation. Telomere fusions, which occur during human
tumorigenesis when critically short telomeres become dysfunctional, generate dicentric chromosomes. This
stage of telomere fusion, genomic instability, and frequent cell death is known as telomere crisis (TC). Dr. John
Maciejowski's previous work has shown that the dicentric chromosomes formed during TC are resolved after
attack by the cytoplasmic nuclease, TREX1, yielding chromothripsis (chromosome shattering) and kataegis
(clustered hypermutation). Here, Dr. Maciejowski will use his established, genetically tractable model of TC to
determine if enzymatic attack is directly responsible for observed genomic variants (Aim 1). This approach will
utilize whole genome sequencing to assess rearrangement and mutation phenotypes associated with loss of a
specific gene. In addition, he will develop novel assays to detect prior TC in cancer genomes (Aim 2) with the
overall goal of defining the role of TC in cancer etiology (Aim 3). Finally, he will use his previously developed
karyotype-based rearrangement screening and whole genome sequencing pipeline to identify additional
causes of genome rearrangement by defining the genomic changes associated with dysfunction of the spindle
assembly checkpoint, a cell cycle checkpoint that ensures high fidelity chromosome segregation during mitosis
and is often dysregulated in cancer (Aim 4). Collectively, this proposal combines the versatility of mammalian
tissue culture genetics and the power of whole genome sequencing with the aim to provide deep insights into a
key aspect of tumorigenesis: the genome rearrangements that spur cancer progression and tumor evolution.
Candidate
Dr. Maciejowski's long-term goal is to understand the impact of errors in chromosome segregation on
chromosome rearrangement, aneuploidy, and cancer development. He plans to use whole genome
sequencing to assess genomic instability after the introduction of chemical or genetic perturbations in
chromosome segregation or DNA repair pathways. His background in Mathematics and extensive training in
chromosomal biology, the mechanisms of mitotic chromosome segregation, and human tissue culture systems
provide him a solid foundation to achieve this goal. During the K99/Mentored Phase, Dr. Maciejowski will be
trained in bioinformatic methods with applications in whole genome sequencing analysis. This will be critical for
h...

## Key facts

- **NIH application ID:** 9828552
- **Project number:** 5R00CA212290-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** JOHN MACIEJOWSKI
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $171,851
- **Award type:** 5
- **Project period:** 2017-12-06 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828552

## Citation

> US National Institutes of Health, RePORTER application 9828552, The origins of chromosome rearrangement in the cancer genome (5R00CA212290-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9828552. Licensed CC0.

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