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
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.
J Thorac Dis. 2016 Mar;8(3):386-95. doi: 10.21037/jtd.2016.02.40.
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.
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.
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.
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.
在未能识别表皮生长因子受体（EGFR）编码序列的复发性基因改变及相关EGFR扩增率之后，EGFR在胸腺瘤发病机制中的关键作用受到质疑。我们在一个胸腺瘤病例系列中研究了非编码EGFR CA简单序列重复1（CA-SSR-1）的作用。
我们使用测序和EGFR荧光原位杂交（FISH）对43例胸腺瘤进行基因分型；（I）针对非编码EGFR CA-SSR-1微卫星的多态性和杂合性的体细胞缺失，以及（II）针对EGFR基因拷贝数变化。
我们发现两种常见的CA-SSR-1基因型：纯合的16个CA重复和杂合基因型，携带16个和20个CA重复的等位基因。平均合并等位基因长度与肿瘤亚型相关：较短序列与侵袭性更强的世界卫生组织（WHO）胸腺瘤亚型组显著相关，包括B2/B3、B3和B3/C组织学类型。在分析体细胞CA-SSR-1杂合性缺失的29例信息充分的病例中，有4例显示等位基因失衡（AI），其中3/4为较长等位基因缺失。通过EGFR-FISH分析，33例中有9例FISH阳性。此外，这两种综合技术表明，在4例CA-SSR-1-AI阳性且短等位基因相对患病率较高的病例中，有3例通过EGFR-FISH显示7号染色体“多体性”显著低或高/基因拷贝数增加。
我们的分子、遗传和随访数据表明，短等位基因相对患病率的CA-SSR-1等位基因失衡与胸腺瘤中EGFR 3+免疫组化评分、EGFR基因拷贝数增加、晚期以及复发/转移行为显著相关。
