title: Low expression of ITIH5 in adenocarcinoma of the lung is associated with unfavorable patients' outcome.
abstract: Inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is supposed to be involved in extracellular matrix stability and thus may play a key role in the inhibition of tumor progression. The current study is the first to analyze in depth ITIH5 expression and DNA methylation, as well as its potential clinical impact in non-small-cell lung carcinoma (NSCLC). We examined ITIH5 mRNA expression in tumor and adjacent normal lung tissue specimens of NSCLC patients. In addition, methylation frequency of the ITIH5 promoter was investigated using methylation-specific PCR and pyrosequencing. Significance of our data was validated by independent data sets from The Cancer Genome Atlas and the Kaplan-Meier Plotter platform. Furthermore, ITIH5 protein expression was evaluated by immunohistochemistry utilizing a tissue microarray with 385 distinct lung tissue samples. Based on our tissue collections, ITIH5 mRNA expression was significantly decreased in NSCLC compared to normal lung tissue in line with an increased methylation frequency in lung cancer tissue. Independent TCGA data confirmed significant expression loss of ITIH5 in lung cancer concordant with ITIH5 promoter hypermethylation in NSCLC. Of interest, low ITIH5 mRNA expression was particularly found in the magnoid and squamoid ADC expression subtype, concordant with an unfavorable patients' outcome in squamoid as well as tobacco smoking ADC patients. In conclusion, ITIH5 may be a novel putative tumor suppressor gene in NSCLC with a potential molecular significance in the squamoid ADC subtype and further clinical impact for risk stratification of adenocarcinoma patients. In addition, ITIH5 may serve as a novel biomarker for prognosis of tobacco smoking ADC patients.
authors.affiliation: a Institute of Pathology; Medical Faculty of the RWTH Aachen University ; Aachen , Germany.
authors.forename: Magnus Mathias
authors.initials: MM
authors.lastname: Dötsch
authors.affiliation: a Institute of Pathology; Medical Faculty of the RWTH Aachen University ; Aachen , Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Kloten
authors.affiliation: a Institute of Pathology; Medical Faculty of the RWTH Aachen University ; Aachen , Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schlensog
authors.affiliation: a Institute of Pathology; Medical Faculty of the RWTH Aachen University ; Aachen , Germany.
authors.forename: Timon
authors.initials: T
authors.lastname: Heide
authors.affiliation: a Institute of Pathology; Medical Faculty of the RWTH Aachen University ; Aachen , Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Braunschweig
authors.affiliation: b RWTH Centralized Biomaterial Bank at the Institute of Pathology; Medical Faculty of the RWTH Aachen University ; Aachen , Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Veeck
authors.affiliation: c Institute of Pathology; University Hospital Jena ; Jena , Germany.
authors.forename: Iver
authors.initials: I
authors.lastname: Petersen
authors.affiliation: a Institute of Pathology; Medical Faculty of the RWTH Aachen University ; Aachen , Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Knüchel
authors.affiliation: a Institute of Pathology; Medical Faculty of the RWTH Aachen University ; Aachen , Germany.|b RWTH Centralized Biomaterial Bank at the Institute of Pathology; Medical Faculty of the RWTH Aachen University ; Aachen , Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Dahl
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D053491:Proteinase Inhibitory Proteins, Secretory / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D014408:Biomarkers, Tumor; C482680:ITIH5 protein, human; D053491:Proteinase Inhibitory Proteins, Secretory; D012333:RNA, Messenger
keywords: DNA-methylation, non-small-cell lung cancer (NSCLC); ITIH5; biomarker; gene signature; intrinsic expression subtype