title: Clinicopathological relevance of HER2/neu and a related gene-protein cubic regression correlation in colorectal adenocarcinomas in Taiwan.
abstract: While HER2/neu receptor tyrosine kinase is involved in various malignancies, studies on colorectal adenocarcinoma (CRC) remain controversial. To try to clarify the role played by HER2/neu in CRC, sixty-seven CRC patients in Taiwan were analyzed. For this analysis, we used normalized dual-color fluorescence in situ hybridization (FISH) and Photoshop-aided immunohistochemistry (IHC) between cancers and their autologous non-neoplastic epithelia. The results revealed that HER2/neu status was unrelated to age, sex, location and positive-nodal percentage. Intramucosal carcinomas had earlier HER2/neu protein upregulation than regional stromal invasion within Dukes' A, and had a gene level that had not risen yet. Both gene gains and protein increases were significant in later stages in regards to volumetric progression and nodal-metastatic Dukes' stage. Overall, there were 1.53-fold (gene) and 1.81-fold (protein) increases from non-neoplastic enterocytes to CRCs. The upregulating directions of gene (88%) and protein (88%) presented symmetric agreement. Most CRCs exhibited low to intermediate levels of HER2/neu overexpression with double-minute gene amplicons and cytosolic HER2/neu proteins. Normalized FISH and IHC showed high cubic-regression correlation, especially in Dukes' C. According to the correlation curve, the points with IHC index >2.41 and FISH ratio >1.22 defined the area where gene-amplification-dependent HER2/neu overexpression was present. Eleven (16%) patients had values above the cut-off point (IHC = 2.41 and FISH = 1.22), including 7 (10%) cases in cytosolic and 4 (6%) cases in membranous HER2/neu overexpressions. The results suggest that HER2/neu plays a crucial role in CRC tumorigenicity with gene-amplification-independent transcriptional activations early in the carcinogenesis, and gene-amplification-dependent overexpression later in the advanced stages. This indicates that HER2/neu can be a good biological marker for selecting patients that may improve under therapies that employ adequate HER2/neu-targeting strategies.
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, National Defense University, Neihu PO Box 90048-501, Taipei, Taiwan 114, ROC.
authors.forename: Jhy-Wei
authors.initials: JW
authors.lastname: Li
authors.forename: Tzu-Chao
authors.initials: TC
authors.lastname: Chuang
authors.forename: An-Hang
authors.initials: AH
authors.lastname: Yang
authors.forename: Chien-Kang
authors.initials: CK
authors.lastname: Hsu
authors.forename: Ming-Ching
authors.initials: MC
authors.lastname: Kao
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D018734:Genes, erbB-2; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics*; D012044:Regression Analysis; D013624:Taiwan; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases