TY - JOUR
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 Stampanoni-B, 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
Y1 - 2016
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.
KW - Allelic imbalance (AI)
KW - Egfr microsatellite CA-SSR-1
KW - Egfr-fluorescent in situ hybridization (egfr-FISH)
KW - Loss of heterozygosity
KW - Pulmonary and Respiratory Medicine
KW - Thymic epithelial tumors (TET)
KW - Thymoma
KW - Allelic imbalance (AI)
KW - Egfr microsatellite CA-SSR-1
KW - Egfr-fluorescent in situ hybridization (egfr-FISH)
KW - Loss of heterozygosity
KW - Pulmonary and Respiratory Medicine
KW - Thymic epithelial tumors (TET)
KW - Thymoma
UR - http://hdl.handle.net/10807/94693
UR - http://jtd.amegroups.com/article/download/6830/6422
U2 - 10.21037/jtd.2016.02.40
DO - 10.21037/jtd.2016.02.40
M3 - Article
SN - 2072-1439
VL - 8
SP - 386
EP - 395
JO - Journal of Thoracic Disease
JF - Journal of Thoracic Disease
ER -