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Population bias in somatic measurement of microsatellite instability status
- Source :
- Cancer Medicine, Cancer Medicine, Vol 9, Iss 17, Pp 6452-6460 (2020)
- Publication Year :
- 2020
-
Abstract
- Microsatellite instability (MSI) is a key secondary effect of a defective DNA mismatch repair mechanism resulting in incorrectly replicated microsatellites in many malignant tumors. Historically, MSI detection has been performed by fragment analysis (FA) on a panel of representative genomic markers. More recently, using next‐generation sequencing (NGS) to analyze thousands of microsatellites has been shown to improve the robustness and sensitivity of MSI detection. However, NGS‐based MSI tests can be prone to population biases if NGS results are aligned to a reference genome instead of patient‐matched normal tissue. We observed an increased rate of false positives in patients of African ancestry with an NGS‐based diagnostic for MSI status utilizing 7317 microsatellite loci. We then minimized this bias by training a modified calling model that utilized 2011 microsatellite loci. With these adjustments 100% (95% CI: 89.1% to 100%) of African ancestry patients in an independent validation test were called correctly using the updated model. This poses not only a significant technical improvement but also has an important clinical impact on directing immune checkpoint inhibitor therapy.<br />This work presents observations of a significant population bias in an NGS‐based MSI test and minimizes this bias using a computational‐based approach. The research poses not only a significant technical improvement to the NGS‐based MSI diagnostic, but has an important clinical impact on directing immune‐check point inhibitor therapy for late‐stage cancer patients of non‐European descent.
- Subjects :
- 0301 basic medicine
Male
population bias
Cancer Research
DNA mismatch repair
next‐generation sequencing
0302 clinical medicine
Neoplasms
False positive paradox
reference genome
Mismatch Repair Endonuclease PMS2
Original Research
education.field_of_study
High-Throughput Nucleotide Sequencing
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
DNA-Binding Proteins
MutS Homolog 2 Protein
Oncology
030220 oncology & carcinogenesis
Microsatellite
Female
immunotherapy
MutL Protein Homolog 1
Cancer Prevention
Genetic Markers
precision medicine
Population
Black People
Computational biology
Biology
lcsh:RC254-282
DNA sequencing
03 medical and health sciences
Sex Factors
Bias
medicine
Confidence Intervals
Humans
Radiology, Nuclear Medicine and imaging
False Positive Reactions
education
Robustness (evolution)
Microsatellite instability
Reproducibility of Results
medicine.disease
030104 developmental biology
checkpoint inhibitor
microsatellite instability
Reference genome
Subjects
Details
- ISSN :
- 20457634
- Volume :
- 9
- Issue :
- 17
- Database :
- OpenAIRE
- Journal :
- Cancer medicine
- Accession number :
- edsair.doi.dedup.....7205db37f3d0013bbcf07e6b875d02de