# Polyploidy, aneuploidy, and genome stability

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2021 · $400,313

## Abstract

PROJECT SUMMARY/ABSTRACT
The primary goal of this proposal is to elucidate the mechanism of a newly discovered mutational process
called chromothripsis. Chromothripsis generates rapid karyotype evolution in cancer, congenital disease, and
other contexts. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating
pattern of DNA copy number levels, all surprisingly restricted to one or a few chromosomes. We have made
significant recent progress in defining a mechanism for chromothripsis. We showed that intact chromosomes
missegregated into aberrant cancer-associated nuclear structures called micronuclei (MN) develop extensive
DNA damage. This led us to propose that the physical isolation of chromosomes into MN could cause
chromothripsis. Recently, we developed a method (Look-Seq) to combine live cell imaging and single cell
genome sequencing, enabling us to recreate chromothripsis in the laboratory and directly demonstrate that it
can originate from disrupted MN. We established that chromothripsis could arise by fragmentation and
reassembly of MN chromosomes. These fragments can also circularize, potentially providing a mechanism for
forming double minute chromosomes, major vehicles for oncogene amplification in cancer. The Look-Seq
approach now positions the laboratory to attack the key mechanistic questions in the field: the timing and order
of chromosome fragmentation and reassembly, the mechanism of MN chromosome fragmentation; and how it
is reassembled. We also propose a series of experiments to define the contribution of DNA replication errors in
generating localized chromosome rearrangements. Finally, we propose experiments to elucidate the
mechanistic basis for two major sources of oncogene amplification in cancer.

## Key facts

- **NIH application ID:** 10048686
- **Project number:** 5R01CA213404-23
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** DAVID S PELLMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $400,313
- **Award type:** 5
- **Project period:** 1997-05-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10048686

## Citation

> US National Institutes of Health, RePORTER application 10048686, Polyploidy, aneuploidy, and genome stability (5R01CA213404-23). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10048686. Licensed CC0.

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