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Optimised ARID1A immunohistochemistry is an accurate predictor of ARID1A mutational status in gynaecological cancers
- Source :
- The Journal of Pathology: Clinical Research
- Publication Year :
- 2018
- Publisher :
- John Wiley and Sons Inc., 2018.
-
Abstract
- ARID1A is a tumour suppressor gene that is frequently mutated in clear cell and endometrioid carcinomas of the ovary and endometrium and is an important clinical biomarker for novel treatment approaches for patients with ARID1A defects. However, the accuracy of ARID1A immunohistochemistry (IHC) as a surrogate for mutation status has not fully been established for patient stratification in clinical trials. Here we tested whether ARID1A IHC could reliably predict ARID1A mutations identified by next‐generation sequencing. Three commercially available antibodies – EPR13501 (Abcam), D2A8U (Cell Signaling), and HPA005456 (Sigma) – were optimised for IHC using cell line models and human tissue, and screened across a cohort of 45 gynaecological tumours. IHC was scored independently by three pathologists using an immunoreactive score. ARID1A mutation status was assessed using two independent sequencing platforms and the concordance between ARID1A mutation and protein expression was evaluated using Receiver Operating Characteristic statistics. Overall, 21 ARID1A mutations were identified in 14/43 assessable tumours (33%), the majority of which were predicted to be deleterious. Mutations were identified in 6/17 (35%) ovarian clear cell carcinomas, 5/8 (63%) ovarian endometrioid carcinomas, 2/5 (40%) endometrial carcinomas, and 1/7 (14%) carcinosarcomas. ROC analysis identified greater than 95% concordance between mutation status and IHC using a modified immunoreactive score for all three antibodies allowing a definitive cut‐point for ARID1A mutant status to be calculated. Comprehensive assessment of concordance of ARID1A IHC and mutation status identified EPR13501 as an optimal antibody, with 100% concordance between ARID1A mutation status and protein expression, across different gynaecological histological subtypes. It delivered the best inter‐rater agreement between all pathologists, as well as a clear cost‐benefit advantage. This could allow patients to be accurately stratified based on their ARID1A IHC status into early phase clinical trials. Gynaecological Cancer Fund The Royal Marsden Cancer Charity Breast Cancer Now . Grant Numbers: PRJNA432413 , PRJNA432343 Cancer Research UK The Monument Trust NHS NIHR Royal Marsden Hospital Biomedical Research Centre NCBI Sequence Read Archive
- Subjects :
- next generation sequencing
clear cell ovarian cancer
Genital Neoplasms, Female
Nuclear Proteins
Biomarker
Original Articles
ARID1A immunohistochemistry
Immunohistochemistry
DNA-Binding Proteins
Next generation sequencing
Mutation
biomarker
Humans
Clear cell ovarian cancer
Original Article
Female
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 20564538
- Volume :
- 4
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- The Journal of Pathology: Clinical Research
- Accession number :
- edsair.pmid.dedup....4ae27022087bf05461795708f41bc2d1