Inoue Masayoshi, Starostik Petr, Zettl Andreas, Ströbel Philipp, Schwarz Stephan, Scaravilli Francesco, Henry Kristin, Willcox Nick, Müller-Hermelink Hans-Konrad, Marx Alexander
Institute of Pathology, University of Würzburg, D-97080 Würzburg, Germany.
Cancer Res. 2003 Jul 1;63(13):3708-15.
Thymomas are thymic epithelial tumors. Because most of them are rich in nonneoplastic T-cells, recurrent genetic aberrations have been reported only in the rare, lymphocyte-poor WHO types A, B3, and C. We have now investigated virtually the whole spectrum of thymomas, including the commoner types AB and B2, microdissecting or culturing neoplastic cells from these lymphocyte-rich thymomas and applying 41 microsatellite markers covering 17 loci on 10 chromosomes. In 28 cases, comparative genomic hybridization data were available. Apart from type A, there was striking heterogeneity between thymomas. Allelic imbalances were seen in 87.3% of the 55 cases, and MSI in 9.9%. Losses of heterozygosity (LOHs) were much the commonest aberration. Overall, they were most prevalent at four regions on chromosome 6. Aberrations elsewhere, affecting mainly 8p11.21 and 7p15.3, suggested a cortical footprint because they recurred only in the thymopoietically active type AB and B thymomas. LOHs were also seen at the adenomatous polyposis coli (APC) locus (5q21-22) in subsets of these thymomas, whereas combined LOHs at the APC, retinoblastoma (13q14.3), and p53 (17p13.1) loci were confined to a subset of B3 thymomas that had possibly evolved from APC-hemizygous B2 thymomas by tumor progression; indeed, thymomas combing B2 plus B3 features are common. Notably, some AB and B thymomas shared LOHs despite their nonoverlapping morphology and different clinical behavior. Finally, allelic imbalances at 8p11.21 and 16q22.1 (CDH1) were significantly more frequent in stage IV metastatic thymomas. We conclude that the WHO-defined histological thymoma types generally segregate with characteristic genetic features, type A thymomas being the most homogeneous. Many findings support the view that B2 and B3 thymomas form a continuum, with evidence of tumor progression. However, other findings imply that types A and AB are biologically distinct from the others, any potential invasiveness being severely restricted by a medullary commitment in the precursor cell undergoing neoplastic transformation.
胸腺瘤是胸腺上皮肿瘤。由于大多数胸腺瘤富含非肿瘤性T细胞，仅在罕见的、淋巴细胞稀少的世界卫生组织（WHO）A、B3和C型中报道了复发性基因畸变。我们现在研究了几乎所有类型的胸腺瘤，包括较常见的AB型和B2型，从这些富含淋巴细胞的胸腺瘤中显微切割或培养肿瘤细胞，并应用41个微卫星标记，覆盖10条染色体上的17个位点。在28例病例中，可获得比较基因组杂交数据。除了A型胸腺瘤外，胸腺瘤之间存在显著的异质性。在55例病例中，87.3%出现等位基因失衡，9.9%出现微卫星高度不稳定（MSI）。杂合性缺失（LOH）是最常见的畸变。总体而言，它们在6号染色体的四个区域最为普遍。其他部位的畸变主要影响8p11.21和7p15.3，提示有皮质印记，因为它们仅在具有胸腺生成活性的AB型和B型胸腺瘤中复发。在这些胸腺瘤的亚组中，腺瘤性息肉病基因（APC）位点（5q21 - 22）也出现了LOH，而APC、视网膜母细胞瘤（13q14.3）和p53（17p13.1）位点的联合LOH仅限于一部分B3型胸腺瘤，这些胸腺瘤可能是由APC半合子的B2型胸腺瘤通过肿瘤进展演变而来；实际上，兼具B2和B3特征的胸腺瘤很常见。值得注意的是，一些AB型和B型胸腺瘤尽管形态不重叠且临床行为不同，但仍有共同的LOH。最后，8p11.21和16q22.1（CDH1）的等位基因失衡在IV期转移性胸腺瘤中明显更频繁。我们得出结论，WHO定义的组织学胸腺瘤类型通常与特征性的基因特征相关，A型胸腺瘤最为同质。许多发现支持B2型和B3型胸腺瘤形成一个连续体且有肿瘤进展证据的观点。然而，其他发现表明A型和AB型在生物学上与其他类型不同，任何潜在的侵袭性都受到肿瘤转化前体细胞中髓质定向的严重限制。
