title: Lung Adenocarcinoma With MUC4 Expression Is Associated With Smoking Status, HER2 Protein Expression, and Poor Prognosis: Clinicopathologic Analysis of 338 Cases.
abstract: MUC4 is a transmembrane glycoprotein that plays a role in the cell growth signaling pathway and has been studied in various organ malignancies. This study aimed to analyze MUC4 expression in resected lung adenocarcinomas (ADCs) to define the clinicopathologic characteristics of MUC4-positive cancers.
  
  
  
  Immunohistochemical MUC4 analysis was performed using tissue microarray slides containing 338 lung ADCs. Associations between MUC4 expression and the following clinicopathologic parameters were evaluated: sex; age; smoking status; tumor stage; tumor grade; lymphovascular invasion; pleural invasion; TTF-1 and HNF4α expression; EGFR, KRAS, BRAF, and HER2 mutation status; and ALK and ROS1 fusion status.
  
  
  
  Ninety-four tumors (27.8%) were MUC4 positive. Most patients with MUC4-positive tumors were male (P < .001) and smokers (P = .006). Moreover, MUC4 expression was significantly associated with solid ADCs (P < .001) and vascular invasion (P = .001). MUC4 expression inversely correlated with TTF-1 expression (P = .020) and EGFR mutations (P = .004). Interestingly, MUC4 expression correlated with HER2 protein expression (P = .042), although MUC4 expression did not correlate with HER2 DNA amplification or HER2 gene mutations. Patients with MUC4-positive tumors had significantly worse prognoses compared to patients with MUC4-negative tumors (P = .025).
  
  
  
  The present study showed that MUC4-positive lung ADCs correlated with male smokers, solid ADCs, negative TTF-1 expression, the EGFR wild-type gene, HER2 protein expression, and poorer prognoses. These results suggest that MUC4-positive lung ADC may be a distinct subtype found in patients with smoking-related poor outcomes, mediated by HER2 signaling pathway.
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Mariyo
authors.initials: M
authors.lastname: Rokutan-Kurata
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan. Electronic address: akyoshi@kuhp.kyoto-u.ac.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshizawa
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan; Department of Diagnostic Pathology, Kumamoto University Hospital, Kumamoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Sumiyoshi
authors.affiliation: Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sonobe
authors.affiliation: Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Toshi
authors.initials: T
authors.lastname: Menju
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Momose
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Koyama
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Shigeto
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan; Department of Diagnostic Pathology, Wakayama Medical University Hospital, Wakayama, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Surgery (2), Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.affiliation: Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Haga
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000073865:Cigarette Smoking; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D008297:Male; D055264:Mucin-4 / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction; D000074482:Thyroid Nuclear Factor 1 / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D066246:ErbB Receptors; D055264:Mucin-4; D018719:Erb-b2 Receptor Tyrosine Kinases; D000074482:Thyroid Nuclear Factor 1; C524658:MUC4 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: HER2; Lung adenocarcinoma; MUC4; Prognosis; Smoking status