title: Clinical outcome and expression of mutant P53, P16, and Smad4 in lung adenocarcinoma: a prospective study.
abstract: BACKGROUND
  Whole-exome sequencing has shown that lung adenocarcinoma (LAC) can be driven by mutant genes, including TP53, P16, and Smad4. The aim of this study was to clarify protein alterations of P53, P16, and Smad4 and to explore their correlations between the protein alterations and clinical outcome.
  
  
  METHODS
  We investigated associations among P53 mutant (P53(Mut)) expression, and P16 and Smad4 loss-of-expression, with clinical outcome in 120 LAC patients who underwent curative resection, using immunohistochemical (IHC) methods.
  
  
  RESULTS
  Of the 120 patients, 76 (63.3%) expressed P53(Mut) protein, whereas 54 (45.0%) loss of P16 expressed and 75 (62.5%) loss of Smad4 expressed. P53(Mut) expression was associated with tumor size (P = 0.041) and pathological stage (P = 0.025). Loss of P16 expression was associated with lymph node metastasis (P = 0.001) and pathological stage (P < 0.001). Loss of Smad4 expression was associated with tumor size (P = 0.033), lymph node metastasis (P = 0.014), pathological stage (P = 0.017), and tumor differentiation (P = 0.022). Kaplan-Meier survival analysis showed that tumor size (P = 0.031), lymph node metastasis (P < 0.001), pathological stage (P < 0.001), P53(Mut) protein expression (P = 0.038), and loss of p16 or Smad4 expression (P < 0.001) were significantly associated with shorter overall survival(OS), whereas multivariate analysis indicated that lymph node metastasis (P = 0.014) and loss of p16 or Smad4 expression (P < 0.001) were independent prognostic factors. Analysis of protein combinations showed patients with more alterations had poorer survival (P < 0.001). Spearman correlation analysis showed that loss of Smad4 expression inversely correlated with expression of P53(Mut) (r = (-)0.196, P = 0.032) and positively with lost P16 expression (r =0.182, P = 0.047).
  
  
  CONCLUSIONS
  The findings indicate that IHC status of P53(Mut), P16, and Smad4 may predict patient outcomes in LAC.
authors.affiliation: Department of Thoracic Surgery, Nanjing Medical University-Affiliated Cancer Hospital, Nanjing, 210009, China. 117822663@qq.com.|Nanjing Jiangbei Peoples' Hospital, Nanjing, 210048, China. 117822663@qq.com.
authors.forename: Chunan
authors.initials: C
authors.lastname: Bian
authors.affiliation: Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, 210009, China. leeezy999@163.com.
authors.forename: Zhongyou
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Thoracic Surgery, Nanjing Medical University-Affiliated Cancer Hospital, Nanjing, 210009, China. 68136939@qq.com.
authors.forename: Youtao
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, 210009, China. 1117821502@qq.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery, Nanjing Medical University-Affiliated Cancer Hospital, Nanjing, 210009, China. xulin83cn@hotmail.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: The Public Health College of Nanjing Medical University, Nanjing, 210029, China. hbshen@hotmail.com.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shen
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality / Q000556:secondary* / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D051901:Smad4 Protein / Q000378:metabolism*; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53