# Whole Genome Sequencing for Genomic Evaluation and Risk Stratification of Patients with Myelodysplastic Syndromes

> **NIH NIH UH2** · WASHINGTON UNIVERSITY · 2022 · $261,450

## Abstract

The goal of this proposal is to improve genetic profiling and risk stratification for patients with
myelodysplastic syndromes (MDS) using clinical whole-genome sequencing. MDS is a heterogenous
group of clonal bone marrow disorders that are often fatal due to marrow failure or progression to acute myeloid
leukemia (AML). Accurate prediction progression risk is therefore critical for the management of MDS patients
in order to prolong survival and minimize the potential for morbidity and mortality associated with more
aggressive treatments. Cytogenetic analysis of bone marrow cells from MDS patients via metaphase karyotyping
is an essential component of MDS risk assessment algorithms, and is used to detect chromosomal deletions,
duplications, and aneuploidies that are associated with differential clinical outcomes. Although karyotyping has
been used effectively for decades, it has several disadvantages. These include low genomic resolution and high
failure rates that can result in incomplete genetic risk profiles for some patients. We recently developed and
validated ChromoSeq, a robust CAP/CLIA-compliant whole-genome sequencing (WGS) assay for genetic
profiling of patients with myeloid malignancies. We showed that this method was 100% sensitivity for clinically
relevant cytogenetic abnormalities in AML and identified additional cytogenetic events in up to 25% of patients
that were not detected by standard cytogenetics. These findings included new risk-defining chromosomal
abnormalities in almost 15% of patients, which resulted in better prediction of clinical outcomes. Although MDS
and AML are closely related diseases that share many features, the genomic characteristics and cellular
composition of MDS is distinct. In addition, the use of ChromoSeq results to form existing MDS risk groups has
not been clinically validated. We hypothesize that optimization of the ChromoSeq whole-genome
sequencing assay for MDS samples will improve the accuracy of genetic profiling and risk stratification
of MDS patients. Here we propose to use a combination of retrospective and prospective clinical MDS samples
to validate ChromoSeq for genetic profiling and risk assessment in MDS patients. We will first use retrospective
MDS samples to optimize and validate our existing CAP/CLIA-compliant ChromoSeq WGS assay to improve the
detection of low frequency mutations, copy number alterations (CNAs) and copy neutral loss of heterozygosity
(CNLOH), which are common in MDS (Aim 1; UH2 component). We will then use a prospective MDS cohort to
establish the clinical validity of ChromoSeq assay for genomic profiling and risk assessment of MDS patients.
This project will expand the use of the CAP/CLIA-compliant ChromoSeq assay to MDS samples so that it may
be used for future interventional clinical trials and routine clinical testing of patients with this malignancy.

## Key facts

- **NIH application ID:** 10506155
- **Project number:** 1UH2CA272904-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** ERIC J DUNCAVAGE
- **Activity code:** UH2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $261,450
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10506155

## Citation

> US National Institutes of Health, RePORTER application 10506155, Whole Genome Sequencing for Genomic Evaluation and Risk Stratification of Patients with Myelodysplastic Syndromes (1UH2CA272904-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10506155. Licensed CC0.

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