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Disparity in the detection of chromosome 15 centromere in patients of African ancestry with a plasma cell neoplasm

Koleilat, Alaa ; Tang, Hongwei ; Sharma, Neeraj ; Yan, Huihuang ; Tian, Shulan ; Smadbeck, James ; Shivaram, Suganti ; Meyer, Reid ; Pearce, Kathryn and Baird, Michael , et al. (2023) In Genetics in Medicine Open 1(1).
Abstract

Purpose: Fluorescence in situ hybridization (FISH) is the current gold standard assay that provides information related to risk stratification and therapeutic selection for individuals with plasma cell neoplasms. The differential hybridization of FISH probe sets in association with individuals’ genetic ancestry has not been previously reported. Methods: This retrospective study included 1224 bone marrow samples from individuals who had an abnormal plasma cell proliferative disorder FISH result and a concurrent conventional G-banded chromosome study. DNA from bone marrow samples obtained from the G-banded chromosome study was genotyped, and a biogeographical ancestry prediction was carried out. Results: Using a cohort of individuals with... (More)

Purpose: Fluorescence in situ hybridization (FISH) is the current gold standard assay that provides information related to risk stratification and therapeutic selection for individuals with plasma cell neoplasms. The differential hybridization of FISH probe sets in association with individuals’ genetic ancestry has not been previously reported. Methods: This retrospective study included 1224 bone marrow samples from individuals who had an abnormal plasma cell proliferative disorder FISH result and a concurrent conventional G-banded chromosome study. DNA from bone marrow samples obtained from the G-banded chromosome study was genotyped, and a biogeographical ancestry prediction was carried out. Results: Using a cohort of individuals with a plasma cell neoplasm, we identified reduced hybridization of a chromosome 15 centromere FISH probe (D15Z4). Metaphase FISH studies of cells with 2 copies of chromosome 15 demonstrated a failure of the D15Z4 FISH probe to hybridize to one chromosome 15 centromere, revealing a false-positive monosomy 15 FISH result in some individuals. Surprisingly, individuals with a monosomy 15 FISH result had a median African ancestry of 77.2% (95% CI 74.1%-80.3%), compared with a median African ancestry of 2.2% (95% CI 2.0%-2.5%) in the non–monosomy 15 cohort (P value = 9.4 × 10−10). Thus, individuals with African ancestry had an 8.02-fold (95% CI 3.73-17.25) increased probability of having a false-positive monosomy 15 result (P value = 9.92 × 10−8). Conclusion: This study emphasizes a concern regarding the reliability of diagnostic genomic tools and their application in interpreting genetic testing results in diverse patient populations. We discuss alternative methodologies to better represent different ancestry groups in clinical diagnostic testing.

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type
Contribution to journal
publication status
published
subject
keywords
African ancestry, D15Z4, Fluorescence in situ hybridization, Monosomy 15, Plasma cell neoplasm
in
Genetics in Medicine Open
volume
1
issue
1
article number
100816
publisher
Elsevier
external identifiers
  • scopus:85208483901
DOI
10.1016/j.gimo.2023.100816
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2023 The Authors
id
e8858034-107b-4b9c-b079-45f42955edba
date added to LUP
2024-12-09 14:56:50
date last changed
2025-04-04 15:00:20
@article{e8858034-107b-4b9c-b079-45f42955edba,
  abstract     = {{<p>Purpose: Fluorescence in situ hybridization (FISH) is the current gold standard assay that provides information related to risk stratification and therapeutic selection for individuals with plasma cell neoplasms. The differential hybridization of FISH probe sets in association with individuals’ genetic ancestry has not been previously reported. Methods: This retrospective study included 1224 bone marrow samples from individuals who had an abnormal plasma cell proliferative disorder FISH result and a concurrent conventional G-banded chromosome study. DNA from bone marrow samples obtained from the G-banded chromosome study was genotyped, and a biogeographical ancestry prediction was carried out. Results: Using a cohort of individuals with a plasma cell neoplasm, we identified reduced hybridization of a chromosome 15 centromere FISH probe (D15Z4). Metaphase FISH studies of cells with 2 copies of chromosome 15 demonstrated a failure of the D15Z4 FISH probe to hybridize to one chromosome 15 centromere, revealing a false-positive monosomy 15 FISH result in some individuals. Surprisingly, individuals with a monosomy 15 FISH result had a median African ancestry of 77.2% (95% CI 74.1%-80.3%), compared with a median African ancestry of 2.2% (95% CI 2.0%-2.5%) in the non–monosomy 15 cohort (P value = 9.4 × 10<sup>−10</sup>). Thus, individuals with African ancestry had an 8.02-fold (95% CI 3.73-17.25) increased probability of having a false-positive monosomy 15 result (P value = 9.92 × 10<sup>−8</sup>). Conclusion: This study emphasizes a concern regarding the reliability of diagnostic genomic tools and their application in interpreting genetic testing results in diverse patient populations. We discuss alternative methodologies to better represent different ancestry groups in clinical diagnostic testing.</p>}},
  author       = {{Koleilat, Alaa and Tang, Hongwei and Sharma, Neeraj and Yan, Huihuang and Tian, Shulan and Smadbeck, James and Shivaram, Suganti and Meyer, Reid and Pearce, Kathryn and Baird, Michael and Zepeda-Mendoza, Cinthya J. and Xu, Xinjie and Greipp, Patricia T. and Peterson, Jess F. and Ketterling, Rhett P. and Bergsagel, P. Leif and Vachon, Celine and Rajkumar, S. Vincent and Kumar, Shaji and Asmann, Yan W. and Elhaik, Eran and Baughn, Linda B.}},
  keywords     = {{African ancestry; D15Z4; Fluorescence in situ hybridization; Monosomy 15; Plasma cell neoplasm}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Elsevier}},
  series       = {{Genetics in Medicine Open}},
  title        = {{Disparity in the detection of chromosome 15 centromere in patients of African ancestry with a plasma cell neoplasm}},
  url          = {{http://dx.doi.org/10.1016/j.gimo.2023.100816}},
  doi          = {{10.1016/j.gimo.2023.100816}},
  volume       = {{1}},
  year         = {{2023}},
}