Molecular genetic alterations in egfr CA-SSR-1 microsatellite and egfr copy number changes are associated with aggressiveness in thymoma

Salvatore Conti, Enzo Gallo, Stefano Sioletic, Francesco Facciolo, Giovannella Palmieri, Libero Lauriola, Amelia Evoli, Robert Martucci, Anna Di Benedetto, Flavia Novelli, Diana Giannarelli, Gloria Deriu, Pierluigi Granone, Margaret Ottaviano, Paola Muti, Edoardo Pescarmona, Mirella Marino

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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.

Original languageEnglish
Pages (from-to)386-395
Number of pages10
JournalJournal of Thoracic Disease
Volume8
Issue number3
DOIs
Publication statusPublished - Mar 1 2016

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Thymoma
Microsatellite Repeats
Molecular Biology
Allelic Imbalance
Fluorescence In Situ Hybridization
Alleles
Gene Dosage
Loss of Heterozygosity
Genotype
Chromosomes, Human, Pair 7
Neoplasms

Keywords

  • Allelic imbalance (AI)
  • Egfr microsatellite CA-SSR-1
  • Egfr-fluorescent in situ hybridization (egfr-FISH)
  • Loss of heterozygosity
  • Thymic epithelial tumors (TET)
  • Thymoma

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Molecular genetic alterations in egfr CA-SSR-1 microsatellite and egfr copy number changes are associated with aggressiveness in thymoma. / Conti, Salvatore; Gallo, Enzo; Sioletic, Stefano; Facciolo, Francesco; Palmieri, Giovannella; Lauriola, Libero; Evoli, Amelia; Martucci, Robert; Di Benedetto, Anna; Novelli, Flavia; Giannarelli, Diana; Deriu, Gloria; Granone, Pierluigi; Ottaviano, Margaret; Muti, Paola; Pescarmona, Edoardo; Marino, Mirella.

In: Journal of Thoracic Disease, Vol. 8, No. 3, 01.03.2016, p. 386-395.

Research output: Contribution to journalArticle

Conti, S, Gallo, E, Sioletic, S, Facciolo, F, Palmieri, G, Lauriola, L, Evoli, A, Martucci, R, Di Benedetto, A, Novelli, F, Giannarelli, D, Deriu, G, Granone, P, Ottaviano, M, Muti, P, Pescarmona, E & Marino, M 2016, 'Molecular genetic alterations in egfr CA-SSR-1 microsatellite and egfr copy number changes are associated with aggressiveness in thymoma', Journal of Thoracic Disease, vol. 8, no. 3, pp. 386-395. https://doi.org/10.21037/jtd.2016.02.40
Conti, Salvatore ; Gallo, Enzo ; Sioletic, Stefano ; Facciolo, Francesco ; Palmieri, Giovannella ; Lauriola, Libero ; Evoli, Amelia ; Martucci, Robert ; Di Benedetto, Anna ; Novelli, Flavia ; Giannarelli, Diana ; Deriu, Gloria ; Granone, Pierluigi ; Ottaviano, Margaret ; Muti, Paola ; Pescarmona, Edoardo ; Marino, Mirella. / Molecular genetic alterations in egfr CA-SSR-1 microsatellite and egfr copy number changes are associated with aggressiveness in thymoma. In: Journal of Thoracic Disease. 2016 ; Vol. 8, No. 3. pp. 386-395.
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T1 - Molecular genetic alterations in egfr CA-SSR-1 microsatellite and egfr copy number changes are associated with aggressiveness in thymoma

AU - Conti, Salvatore

AU - Gallo, Enzo

AU - Sioletic, Stefano

AU - Facciolo, Francesco

AU - Palmieri, Giovannella

AU - Lauriola, Libero

AU - Evoli, Amelia

AU - Martucci, Robert

AU - Di Benedetto, Anna

AU - Novelli, Flavia

AU - Giannarelli, Diana

AU - Deriu, Gloria

AU - Granone, Pierluigi

AU - Ottaviano, Margaret

AU - Muti, Paola

AU - Pescarmona, Edoardo

AU - Marino, Mirella

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

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KW - Egfr-fluorescent in situ hybridization (egfr-FISH)

KW - Loss of heterozygosity

KW - Thymic epithelial tumors (TET)

KW - Thymoma

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