title: In epithelial cancers, aberrantCOL17A1promoter methylation predicts its misexpression and increased invasion.
abstract: Metastasis is a leading cause of death among cancer patients. In the tumor microenvironment, altered levels of extracellular matrix proteins, such as collagens, can facilitate the first steps of cancer cell metastasis, including invasion into surrounding tissue and intravasation into the blood stream. However, the degree of misexpression of collagen genes in tumors remains understudied, even though this knowledge could greatly facilitate the development of cancer treatment options aimed at preventing metastasis.
  
  
  
  We systematically evaluate the expression of all 44 collagen genes in breast cancer and assess whether their misexpression provides clinical prognostic significance. We use immunohistochemistry on 150 ductal breast cancers and 361 cervical cancers and study DNA methylation in various epithelial cancers.
  
  
  
  In breast cancer, various tests show thatCOL4A1andCOL4A2overexpression andCOL17A1(BP180,BPAG2) underexpression provide independent prognostic strength (HR = 1.25, 95% CI = 1.17-1.34,p= 3.03 × 10-10; HR = 1.18, 95% CI = 1.11-1.25,p= 8.11 × 10-10; HR = 0.86, 95% CI = 0.81-0.92,p= 4.57 × 10-6; respectively). Immunohistochemistry on ductal breast cancers confirmed that theCOL17A1protein product, collagen XVII, is underexpressed. This strongly correlates with advanced stage, increased invasion, and postmenopausal status. In contrast, immunohistochemistry on cervical tumors showed that collagen XVII is overexpressed in cervical cancer and this is associated with increased local dissemination. Interestingly, consistent with the opposed direction of misexpression in these cancers, theCOL17A1promoter is hypermethylated in breast cancer and hypomethylated in cervical cancer. We also find that theCOL17A1promoter is hypomethylated in head and neck squamous cell carcinoma, lung squamous cell carcinoma, and lung adenocarcinoma, in all of which collagen XVII overexpression has previously been shown.
  
  
  
  Paradoxically, collagen XVII is underexpressed in breast cancer and overexpressed in cervical and other epithelial cancers. However, theCOL17A1promoter methylation status accurately predicts both the direction of misexpression and the increased invasive nature for five out of five epithelial cancers. This implies that aberrant epigenetic control is a key driver ofCOL17A1gene misexpression and tumor cell invasion. These findings have significant clinical implications, suggesting that theCOL17A1promoter methylation status can be used to predict patient outcome. Moreover, epigenetic targeting ofCOL17A1could represent a novel strategy to prevent metastasis in patients.
authors.affiliation: University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Brisbane, QLD 4102 Australia.
authors.forename: Pulari U
authors.initials: PU
authors.lastname: Thangavelu
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University and MTA-SE Cancer Progression Research Group, Budapest, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Krenács
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, QLD 4102 Australia.
authors.forename: Eloise
authors.initials: E
authors.lastname: Dray
authors.affiliation: University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Brisbane, QLD 4102 Australia.
authors.forename: Pascal H G
authors.initials: PH
authors.lastname: Duijf
mesh_terms: D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D024041:Non-Fibrillar Collagens / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII
keywords: Breast cancer; Cervical cancer; Collagen XVII; Epigenetics; Invasion; Prognosis