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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 LU ; Borg, David LU ; Fay, Joanna ; O’grady, Anthony ; Hill, Arnold D.K. ; Jirström, Karin LU orcid and Hopkins, Ann M. (2021) In Cancers 13(6).
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... (More)

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 sig-nificant correlations between JAM-A/HER2 expression. Given the growing importance of immuno-histochemistry 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.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cancer, Gastro-esophageal cancer, HER2, Immunohistochemistry, Intra-tumoral heterogeneity, JAM-A, Tissue microarray, Tumor
in
Cancers
volume
13
issue
6
article number
1286
pages
12 pages
publisher
MDPI AG
external identifiers
  • scopus:85102340850
  • pmid:33805812
ISSN
2072-6694
DOI
10.3390/cancers13061286
language
English
LU publication?
yes
id
fe1c78fc-d355-4f8c-9b15-91fb9c2c5b26
date added to LUP
2021-03-24 12:52:32
date last changed
2024-06-15 08:32:36
@article{fe1c78fc-d355-4f8c-9b15-91fb9c2c5b26,
  abstract     = {{<p>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 sig-nificant correlations between JAM-A/HER2 expression. Given the growing importance of immuno-histochemistry 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.</p>}},
  author       = {{Richards, Cathy E. and Sheehan, Katherine M. and Kay, Elaine W. and Hedner, Charlotta and Borg, David and Fay, Joanna and O’grady, Anthony and Hill, Arnold D.K. and Jirström, Karin and Hopkins, Ann M.}},
  issn         = {{2072-6694}},
  keywords     = {{Cancer; Gastro-esophageal cancer; HER2; Immunohistochemistry; Intra-tumoral heterogeneity; JAM-A; Tissue microarray; Tumor}},
  language     = {{eng}},
  number       = {{6}},
  publisher    = {{MDPI AG}},
  series       = {{Cancers}},
  title        = {{Development of a novel weighted ranking method for immunohistochemical quantification of a heterogeneously expressed protein in gastro-esophageal cancers}},
  url          = {{http://dx.doi.org/10.3390/cancers13061286}},
  doi          = {{10.3390/cancers13061286}},
  volume       = {{13}},
  year         = {{2021}},
}