title: Prognostic significance of cytoplasmic S100A2 overexpression in oral cancer patients.
abstract: BACKGROUND
  Oral squamous cell carcinoma (OSCC) patients are at high risk of loco-regional recurrence and 5-year survival rates are about 50%. Identification of patients at high risk of recurrence will enable rigorous personalized post-treatment management. Most novel biomarkers have failed translation for clinical use because of their limited successful validation in external patient cohorts. The aim of this study was to determine the prognostic significance of alterations in sub-cellular expression of S100A2, a pro-tumorigenic calcium binding protein, identified as a candidate biomarker in our proteomic analysis in OSCC and validation of its clinical utility in an external cohort.
  
  
  METHODS
  In a retrospective study, immunohistochemical analysis of S100A2 was carried out in 235 Indian OSCC (Test set) and 129 normal oral tissues, correlated with clinicopathological parameters and disease outcome over 122 months for OSCC patients following the REMARK criteria. The findings were validated in an external cohort (Validation set 115 Canadian OSCC and 51 normal tissues) and data analyzed using the R package.
  
  
  RESULTS
  Significant increase in cytoplasmic and decrease in nuclear S100A2 expression was observed in OSCC in comparison with normal tissues. Cox multivariable regression analysis internally and externally validated cytoplasmic S100A2 association with tumor recurrence. Kaplan Meier analysis of patients stratified to high and low risk groups showed significantly different recurrence free survival (Test set- log rank test, p = 0.005, median survival 16 and 69 months respectively and Validation set - p < 0.00001, median survival 9.4 and 59.9 months respectively); 86% and 81% of patients who had recurrence were correctly stratified into the high risk group. Seventy percent and 81% patients stratified into low risk group did not show cancer recurrence within 1 year in Test and Validation sets.
  
  
  CONCLUSIONS
  Our study provided clinical evidence for the potential of cytoplasmic S100A2 overexpression as a predictor of recurrence risk in OSCC patients. A unique translational aspect of our study is validation of S100A2 as prognostic marker in two independent cohorts (Canadian and Indian) suggesting this protein is likely to find widespread utility in clinical practice for identifying oral cancer patients at high risk of disease recurrence.
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India. manishkaiims@gmail.com.
authors.forename: Manish
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Alex and Simona Shnaider Laboratory of Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada. gsrivastava123@gmail.com.
authors.forename: Gunjan
authors.initials: G
authors.lastname: Srivastava
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India. jatinkaur@gmail.com.
authors.forename: Jatinder
authors.initials: J
authors.lastname: Kaur
authors.affiliation: Alex and Simona Shnaider Laboratory of Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada. jasmeet.assi@gmail.com.
authors.forename: Jasmeet
authors.initials: J
authors.lastname: Assi
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada. akramalyass@gmail.com.
authors.forename: Akram
authors.initials: A
authors.lastname: Alyass
authors.affiliation: Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, Joseph & Wolf Lebovic Health Complex, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada. ileong@mtsinai.on.ca.|Department of Oral Pathology and Oral Medicine, Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, Ontario, M5G 1G6, Canada. ileong@mtsinai.on.ca.
authors.forename: Iona
authors.initials: I
authors.lastname: Leong
authors.affiliation: Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, Joseph & Wolf Lebovic Health Complex, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada. CMacMillan@mtsinai.on.ca.
authors.forename: Christina
authors.initials: C
authors.lastname: MacMillan
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada. iwitterick@mtsinai.on.ca.|Department of Otolaryngology - Head and Neck Surgery, University of Toronto, 190 Elizabeth Street, Toronto, Ontario, M5G 2N2, Canada. iwitterick@mtsinai.on.ca.
authors.forename: Ian
authors.initials: I
authors.lastname: Witterick
authors.affiliation: Department of Surgery, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India. nootanshukla@hotmail.com.
authors.forename: Nootan Kumar
authors.initials: NK
authors.lastname: Shukla
authors.affiliation: Department of Otorhinolaryngology, All India Institute of Medical Sciences, New Delhi, India. drathakar@gmail.com.
authors.forename: Alok
authors.initials: A
authors.lastname: Thakar
authors.affiliation: Centre for Dental Education and Research, All India Institute of Medical Sciences, New Delhi, India. duggal@medinst.ernet.in.
authors.forename: Ritu
authors.initials: R
authors.lastname: Duggal
authors.affiliation: Centre for Dental Education and Research, All India Institute of Medical Sciences, New Delhi, India. ajoyroy@hotmail.com.
authors.forename: Ajoy
authors.initials: A
authors.lastname: Roychoudhury
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India. sharmamehar@yahoo.co.in.
authors.forename: Mehar Chand
authors.initials: MC
authors.lastname: Sharma
authors.affiliation: Alex and Simona Shnaider Laboratory of Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada. pwalfish@mtsinai.on.ca.|Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, Joseph & Wolf Lebovic Health Complex, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada. pwalfish@mtsinai.on.ca.|Department of Otolaryngology - Head and Neck Surgery, Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada. pwalfish@mtsinai.on.ca.|Department of Otolaryngology - Head and Neck Surgery, University of Toronto, 190 Elizabeth Street, Toronto, Ontario, M5G 2N2, Canada. pwalfish@mtsinai.on.ca.|Department of Medicine, Endocrine Division, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, M5G 1X5, Canada. pwalfish@mtsinai.on.ca.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Walfish
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India. s_s_chauhan@hotmail.com.
authors.forename: Shyam Singh
authors.initials: SS
authors.lastname: Chauhan
authors.affiliation: Alex and Simona Shnaider Laboratory of Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada. rralhan@mtsinai.on.ca.|Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, Joseph & Wolf Lebovic Health Complex, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada. rralhan@mtsinai.on.ca.|Department of Otolaryngology - Head and Neck Surgery, Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada. rralhan@mtsinai.on.ca.|Department of Otolaryngology - Head and Neck Surgery, University of Toronto, 190 Elizabeth Street, Toronto, Ontario, M5G 2N2, Canada. rralhan@mtsinai.on.ca.
authors.forename: Ranju
authors.initials: R
authors.lastname: Ralhan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002630:Chemotactic Factors / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D009418:S100 Proteins / Q000378:metabolism*; D013997:Time Factors; D055815:Young Adult
chemical_list: D002630:Chemotactic Factors; D009418:S100 Proteins; C098997:S100A2 protein, human