Validation of HER2 Status in Whole Genome Sequencing Data of Breast Cancers with the Ploidy-Corrected Copy Number Approach.
Journal
Molecular diagnosis & therapy
ISSN: 1179-2000
Titre abrégé: Mol Diagn Ther
Pays: New Zealand
ID NLM: 101264260
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
accepted:
02
12
2021
pubmed:
22
12
2021
medline:
23
4
2022
entrez:
21
12
2021
Statut:
ppublish
Résumé
Human epidermal growth factor receptor 2 (HER2) protein overexpression is one of the most significant biomarkers for breast cancer diagnostics, treatment prediction, and prognostics. The high accessibility of HER2 inhibitors in routine clinical practice directly translates into the diagnostic need for precise and robust marker identification. Even though multigene next-generation sequencing methodologies have slowly taken over the field of single-biomarker molecular tests, the copy number alterations such as amplification of the HER2-coding ERBB2 gene are hard to validate on next-generation sequencing platforms as they are characterized by chromosomal structural heterogeneity, polysomy, and genomic context of ploidy. In our study, we tested the approach of using whole genome sequencing instead of next-generation sequencing panels to determine HER2 status in the clinical set-up. We used a large dataset of 876 patients with breast cancer whole genomes with curated clinical data and an additional set of 551 patients' external genomic data. We used the decision-tree-based algorithm for optimization of the diagnostic tool for HER2 status assessment by whole genome sequencing. The most efficient approach to assess HER2 status in whole genome sequencing data was the ploidy-corrected copy number, utilizing ERBB2 copy number and mean tumor ploidy. The classifier achieved sensitivity of 91.18% and specificity of 98.69% on the internal validation dataset and 89.86% and 96.06% on the external data, which is similar to other next-generation sequencing methods, currently tested in the clinic. We provide evidence that the HER2 status may be reliably determined by whole genome sequencing and is applicable across different laboratory protocols and pipelines. We suggest using the ploidy-corrected copy number for diagnostic purposes.
Sections du résumé
BACKGROUND AND OBJECTIVE
Human epidermal growth factor receptor 2 (HER2) protein overexpression is one of the most significant biomarkers for breast cancer diagnostics, treatment prediction, and prognostics. The high accessibility of HER2 inhibitors in routine clinical practice directly translates into the diagnostic need for precise and robust marker identification. Even though multigene next-generation sequencing methodologies have slowly taken over the field of single-biomarker molecular tests, the copy number alterations such as amplification of the HER2-coding ERBB2 gene are hard to validate on next-generation sequencing platforms as they are characterized by chromosomal structural heterogeneity, polysomy, and genomic context of ploidy. In our study, we tested the approach of using whole genome sequencing instead of next-generation sequencing panels to determine HER2 status in the clinical set-up.
METHODS
We used a large dataset of 876 patients with breast cancer whole genomes with curated clinical data and an additional set of 551 patients' external genomic data. We used the decision-tree-based algorithm for optimization of the diagnostic tool for HER2 status assessment by whole genome sequencing.
RESULTS
The most efficient approach to assess HER2 status in whole genome sequencing data was the ploidy-corrected copy number, utilizing ERBB2 copy number and mean tumor ploidy. The classifier achieved sensitivity of 91.18% and specificity of 98.69% on the internal validation dataset and 89.86% and 96.06% on the external data, which is similar to other next-generation sequencing methods, currently tested in the clinic.
CONCLUSIONS
We provide evidence that the HER2 status may be reliably determined by whole genome sequencing and is applicable across different laboratory protocols and pipelines. We suggest using the ploidy-corrected copy number for diagnostic purposes.
Identifiants
pubmed: 34932189
doi: 10.1007/s40291-021-00571-1
pii: 10.1007/s40291-021-00571-1
pmc: PMC8766398
doi:
Substances chimiques
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
105-116Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
Références
Sci Rep. 2021 Jul 22;11(1):14932
pubmed: 34294755
BMC Cancer. 2015 Feb 06;15:35
pubmed: 25655188
Sci Rep. 2019 Dec 13;9(1):19123
pubmed: 31836783
Cancer. 2020 Oct 1;126(19):4278-4288
pubmed: 32721042
Curr Protoc Bioinformatics. 2016 Dec 8;56:15.9.1-15.9.17
pubmed: 27930809
Histopathology. 2021 Mar;78(4):498-507
pubmed: 32841416
J Mol Diagn. 2017 Mar;19(2):244-254
pubmed: 28027945
Nature. 2019 Nov;575(7781):210-216
pubmed: 31645765
Bioinformatics. 2010 Nov 1;26(21):2778-9
pubmed: 20847218
Pathol Oncol Res. 2020 Oct;26(4):2577-2585
pubmed: 32621174
Genes Chromosomes Cancer. 2017 Apr;56(4):255-265
pubmed: 27792260
Sci Rep. 2020 Apr 29;10(1):7275
pubmed: 32350370
Science. 1985 Sep 6;229(4717):974-6
pubmed: 2992089
Cytometry. 1987 Mar;8(2):225-34
pubmed: 3582068
J Clin Oncol. 1999 Jul;17(7):1974-82
pubmed: 10561247
Eur J Breast Health. 2021 Mar 31;17(2):128-136
pubmed: 33870112
J Clin Microbiol. 2020 Mar 25;58(4):
pubmed: 32024725
Nat Biotechnol. 2013 Mar;31(3):213-9
pubmed: 23396013
J Clin Pathol. 2021 Nov;74(11):718-723
pubmed: 33122190
Genome Biol. 2016 Jun 06;17(1):122
pubmed: 27268795
EMBO J. 2013 Mar 6;32(5):617-28
pubmed: 23395906
J Clin Oncol. 2008 Oct 20;26(30):4869-74
pubmed: 18794552
Nature. 2016 May 02;534(7605):47-54
pubmed: 27135926
J Clin Oncol. 2018 Jul 10;36(20):2105-2122
pubmed: 29846122
Sci Rep. 2019 Jun 3;9(1):8231
pubmed: 31160649
Nat Commun. 2015 Dec 09;6:10001
pubmed: 26647970
Nature. 2020 Feb;578(7793):82-93
pubmed: 32025007
BMC Med Genomics. 2019 Dec 19;12(1):195
pubmed: 31856832
Insights Imaging. 2020 Feb 10;11(1):22
pubmed: 32040647
Genome Res. 2018 Aug;28(8):1126-1135
pubmed: 29954844
Nat Rev Clin Oncol. 2019 Nov;16(11):703-715
pubmed: 31399699
Sci Rep. 2019 Aug 12;9(1):11679
pubmed: 31406196
J Mol Diagn. 2021 Jul;23(7):816-833
pubmed: 33964451
PLoS Comput Biol. 2012;8(7):e1002549
pubmed: 22807659