title: Molecular genetic alterations in egfr CA-SSR-1 microsatellite and egfr copy number changes are associated with aggressiveness in thymoma.
abstract: BACKGROUND
  The key role of egfr in thymoma pathogenesis has been questioned following the failure in identifying recurrent genetic alterations of egfr coding sequences and relevant egfr amplification rate. We investigated the role of the non-coding egfr CA simple sequence repeat 1 (CA-SSR-1) in a thymoma case series.
  
  
  METHODS
  We used sequencing and egfr-fluorescence in situ hybridization (FISH) to genotype 43 thymomas; (I) for polymorphisms and somatic loss of heterozygosity of the non-coding egfr CA-SSR-1 microsatellite and (II) for egfr gene copy number changes.
  
  
  RESULTS
  We found two prevalent CA-SSR-1 genotypes: a homozygous 16 CA repeat and a heterozygous genotype, bearing alleles with 16 and 20 CA repeats. The average combined allele length was correlated with tumor subtype: shorter sequences were significantly associated with the more aggressive WHO thymoma subtype group including B2/B3, B3 and B3/C histotypes. Four out of 29 informative cases analysed for somatic CA-SSR-1 loss of heterozygosity showed allelic imbalance (AI), 3/4 with loss of the longer allele. By egfr-FISH analysis, 9 out of 33 cases were FISH positive. Moreover, the two integrated techniques demonstrated that 3 out of 4 CA-SSR-1-AI positive cases with short allele relative prevalence showed significantly low or high chromosome 7 "polysomy"/increased gene copy number by egfr-FISH.
  
  
  CONCLUSIONS
  Our molecular and genetic and follow up data indicated that CA-SSR-1-allelic imbalance with short allele relative prevalence significantly correlated with EGFR 3+ immunohistochemical score, increased egfr Gene Copy Number, advanced stage and with relapsing/metastatic behaviour in thymomas.
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Conti
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Enzo
authors.initials: E
authors.lastname: Gallo
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Stefano
authors.initials: S
authors.lastname: Sioletic
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Francesco
authors.initials: F
authors.lastname: Facciolo
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Giovannella
authors.initials: G
authors.lastname: Palmieri
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Libero
authors.initials: L
authors.lastname: Lauriola
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Amelia
authors.initials: A
authors.lastname: Evoli
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Martucci
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Benedetto
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Flavia
authors.initials: F
authors.lastname: Novelli
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Diana
authors.initials: D
authors.lastname: Giannarelli
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Gloria
authors.initials: G
authors.lastname: Deriu
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Granone
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Margaret
authors.initials: M
authors.lastname: Ottaviano
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Paola
authors.initials: P
authors.lastname: Muti
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Pescarmona
authors.affiliation: 1 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy ; 2 Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy ; 3 Rare Tumors Reference Center, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy ; 4 Pathology, Catholic University, Rome, Italy ; 5 Department of Neurosciences, Catholic University, Rome, Italy ; 6 Division of Health Technologies-ENEA C.R. Casaccia, Rome, Italy ; 7 Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy ; 8 Thoracic Surgery, Catholic University, Rome, Italy ; 9 Department of Oncology, Faculty of Health Science, McMaster University, Hamilton, Canada.
authors.forename: Mirella
authors.initials: M
authors.lastname: Marino
keywords: Thymoma; allelic imbalance (AI); egfr microsatellite CA-SSR-1; egfr-fluorescent in situ hybridization (egfr-FISH); loss of heterozygosity; thymic epithelial tumors (TET)