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Development of a Novel Weighted Ranking Method for Immunohistochemical Quantification of a Heterogeneously Expressed Protein in Gastro-Esophageal Cancers.
Richards, Cathy E Sheehan, Katherine M Kay, Elaine W Hedner, Charlotta Borg, David Fay, Joanna O'Grady, Anthony Hill, Arnold D K Jirström, Karin Hopkins, Ann M
Richards, Cathy E
Sheehan, Katherine M
Kay, Elaine W
Hedner, Charlotta
Borg, David
Fay, Joanna
O'Grady, Anthony
Hill, Arnold D K
Jirström, Karin
Hopkins, Ann M
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Other Contributors
Departments
Date
2021-03-13
Date Submitted
Keywords
HER2
JAM-A
CANCER
gastro-esophageal cancer
immunohistochemistry
intra-tumoral heterogeneity
tissue microarray
tumor
JAM-A
CANCER
gastro-esophageal cancer
immunohistochemistry
intra-tumoral heterogeneity
tissue microarray
tumor
Other Subjects
Subject Mesh
Planned Date
Start Date
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Principal Investigators
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cancers-13-01286-v4.pdf
Adobe PDF, 20.48 MB
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Abstract
High expression of Junctional Adhesion Molecule-A (JAM-A) has been linked with poor prognosis in several cancers, including breast cancers overexpressing the human epidermal growth factor receptor-2 (HER2). Furthermore, JAM-A expression has been linked with regulating that of HER2, and associated with the development of resistance to HER2-targeted therapies in breast cancer patients. The purpose of this study was to establish a potential relationship between JAM-A and HER2 in HER2-overexpressing gastro-esophageal (GE) cancers. Interrogation of gene expression datasets revealed that high JAM-A mRNA expression was associated with poorer survival in HER2-positive gastric cancer patients. However, high intra-tumoral heterogeneity of JAM-A protein expression was noted upon immunohistochemical scoring of a GE cancer tissue microarray (TMA), precluding a simple confirmation of any relationship between JAM-A and HER2 at protein level. However, in a test-set of 25 full-face GE cancer tissue sections, a novel weighted ranking system proved effective in capturing JAM-A intra-tumoral heterogeneity and confirming statistically significant correlations between JAM-A/HER2 expression. Given the growing importance of immunohistochemistry in stratifying cancer patients for the receipt of new targeted therapies, this may sound a cautionary note against over-relying on cancer TMAs in biomarker discovery studies of heterogeneously expressed proteins. It also highlights a timely need to develop validated mechanisms of capturing intra-tumoral heterogeneity to aid in future biomarker/therapeutic target development for the benefit of cancer patients.
Language
en
Citation
ISSN
2072-6694
eISSN
ISBN
DOI
10.3390/cancers13061286
PMID
33805812