Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
Am J Hum Genet. 2012 Feb 10;90(2):340-6. doi: 10.1016/j.ajhg.2011.12.008. Epub 2012 Jan 19.
Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective.
原发性皮肤角化病食管癌（TOC）是一种常染色体显性遗传综合征，其特征为手掌足底角化过度、口腔前期病变以及终生罹患食管癌的风险较高。我们先前已将 TOC 基因座定位到染色体 17q25 内的一个小基因组间隔区域。使用靶向捕获阵列和下一代测序，我们现已鉴定出 RHBDF2 中的错义突变（c.557T>C [p.Ile186Thr] 和 c.566C>T [p.Pro189Leu]），该突变为 RHBDF2（也称为 iRhom2）的无活性的类糜蛋白酶，是 TOC 的根本原因。我们发现，与正常皮肤相比，在原发性皮肤角化病中 RHBDF2 的分布发生了改变，并且永生化的原发性皮肤角化病角质形成细胞的总表皮生长因子受体（EGFR）水平降低，与正常细胞相比，其增殖和迁移潜力增加，即使正常细胞受到外源性表皮生长因子的刺激也是如此。因此，EGFR 信号似乎在原发性皮肤角化病细胞中失调。此外，我们还显示 RHBDF2 在原发性皮肤角化病和散发的食管鳞状细胞肿瘤中的定位也发生了改变。阐明 RHBDF2 在食管癌中生长因子信号转导中的作用，将有助于确定针对该途径以及其他鳞状细胞癌的化疗是否有效。
