# Frequency and consequences of chromosome missegregation in breast cancer

> **NIH NIH F31** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $33,847

## Abstract

PROJECT SUMMARY
Research. Chromosomal instability (CIN) – observed as the first cancer hallmark over 100 years ago – is
characterized by the persistent loss and gain of whole chromosomes through abnormal cell division. This process
results in aneuploidy, the state of having an incorrect number of chromosomes, which is present in over 70% of
solid tumors, some of which display recurring patterns of aneuploidy. Persistent ‘missegregation’ of
chromosomes is associated with worse patient prognosis and advanced clinical features. This is attributed to the
increased adaptability of a tumor having increased genomic diversity via a broad landscape of different aneuploid
clones. At higher rates of missegregation it appears to cause cell death and tumor inhibition. The occurrence of
CIN is also theorized to sensitize tumors to CIN-inducing chemotherapies like taxanes. Despite CIN’s long
history, its clinical use as a prognostic marker and biomarker for taxane efficacy is inaccessible as current
methods of quantifying rates of chromosome missegregation are either infeasible in tissue, insufficiently
informative and/or labor intensive. A critical goal for this proposal to combine stochastic computational
modeling of cell division with single cell sequencing of tumors in order to allow for the quantification of
intratumoral rates of chromosome missegregation. Additionally, cellular processes after chromosome
missegregation that underlie karyotypic selection have not been explored. We hypothesize that post-
missegregation transcriptional processes either preclude or permit the propagation of clones with
specific aneuploid chromosome combinations. We will stochastically generate many combinations of
chromosome copy number alterations in transformed and non-transformed cell lines and analyze the acute
transcriptional alterations and clonal composition at single cell resolution. Overall, the long-term goal for this
proposal is to resolve the complex relationship between chromosome missegregation and breast cancer
progression with respect to its incidence in human breast tumors and downstream transcriptional
consequences that underlie tumor evolution. This work is innovative in its approach and will significantly
improve our understanding of tumor evolution and how to evaluate CIN in patients.
Training. Through completion of the proposed research, I will develop my skills in the design and implementation
of high impact and rigorous scientific studies. Through coursework and interactions with lab members and
collaborators, I will develop multi-disciplinary expertise in cell biological and genomics/transcriptomics
experimental and analytical methods. I will hone professional skills in scientific communication, public
engagement, and networking through the many opportunities afforded to me to interact with and present my
research to collaborators, field-experts, legislators, and community members. The unique, multi-disciplinary
training proposed here will position me...

## Key facts

- **NIH application ID:** 10362558
- **Project number:** 5F31CA254247-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Andrew Lynch
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $33,847
- **Award type:** 5
- **Project period:** 2021-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10362558

## Citation

> US National Institutes of Health, RePORTER application 10362558, Frequency and consequences of chromosome missegregation in breast cancer (5F31CA254247-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10362558. Licensed CC0.

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