title: Phylogenetic analysis of multiple FISH markers in oral tongue squamous cell carcinoma suggests that a diverse distribution of copy number changes is associated with poor prognosis.
abstract: Oral tongue squamous cell carcinoma (OTSCC) is associated with poor prognosis. To improve prognostication, we analyzed four gene probes (TERC, CCND1, EGFR and TP53) and the centromere probe CEP4 as a marker of chromosomal instability, using fluorescence in situ hybridization (FISH) in single cells from the tumors of sixty-five OTSCC patients (Stage I, n = 15; Stage II, n = 30; Stage III, n = 7; Stage IV, n = 13). Unsupervised hierarchical clustering of the FISH data distinguished three clusters related to smoking status. Copy number increases of all five markers were found to be correlated to non-smoking habits, while smokers in this cohort had low-level copy number gains. Using the phylogenetic modeling software FISHtrees, we constructed models of tumor progression for each patient based on the four gene probes. Then, we derived test statistics on the models that are significant predictors of disease-free and overall survival, independent of tumor stage and smoking status in multivariate analysis. The patients whose tumors were modeled as progressing by a more diverse distribution of copy number changes across the four genes have poorer prognosis. This is consistent with the view that multiple genetic pathways need to become deregulated in order for cancer to progress.
authors.affiliation: Genetics Branch, Center For Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.|Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Darawalee
authors.initials: D
authors.lastname: Wangsa
authors.affiliation: Joint Carnegie Mellon/University of Pittsburgh Ph.D. Program In Computational Biology, Carnegie Mellon University, Pittsburgh, PA.|Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA.
authors.forename: Salim Akhter
authors.initials: SA
authors.lastname: Chowdhury
authors.affiliation: Department of Otorhinolaryngology, Sophiahemmet Hospital, Stockholm, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Ryott
authors.affiliation: Computational Biology Branch, National Center For Biotechnology Information, National Institutes of Health, Bethesda, MD.
authors.forename: E Michael
authors.initials: EM
authors.lastname: Gertz
authors.affiliation: Department of Laboratory Medicine, Pathology, Örebro University Hospital, Örebro, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Elmberger
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Gert
authors.initials: G
authors.lastname: Auer
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.|Department of Oncology And Department Of Clinical And Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Åvall Lundqvist
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Küffer
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
authors.affiliation: Computational Biology Branch, National Center For Biotechnology Information, National Institutes of Health, Bethesda, MD.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.affiliation: Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA.|Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA.
authors.forename: Russell
authors.initials: R
authors.lastname: Schwartz
authors.affiliation: Department of Oto-Rhino-Laryngology, Head And Neck Surgery, Karolinska University Hospital and Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Munck-Wikland
authors.affiliation: Genetics Branch, Center For Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.affiliation: Genetics Branch, Center For Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Heselmeyer-Haddad
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000821:virology; D056915:DNA Copy Number Variations; D005260:Female; D052162:Human papillomavirus 16; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D030361:Papillomavirus Infections; D010802:Phylogeny; D011379:Prognosis; D012307:Risk Factors; D016019:Survival Analysis; D014062:Tongue Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000821:virology; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor
keywords: FISH; HPV; genetic markers; oral tongue cancer; phylogenetic modeling