Wetli Sylvia C, Leuschner Ivo, Harms Dieter, Rufle Alex, Foerster Anja, Bihl Michel, Graf Norbert, Furtwaengler Roikos, Paulussen Michael, Briner Jakob, Aslanidis Charalampos, Schmitz Gerd, Tornillo Luigi, Mihatsch Michael J, Zlobec Inti, Bruder Elisabeth
Institute for Pathology, Basel University Hospital, Schoenbeinstrasse 40, CH-4031 Basel, Switzerland.
Virchows Arch. 2008 Jun;452(6):637-50. doi: 10.1007/s00428-008-0605-x. Epub 2008 May 14.
Nephroblastoma prognosis has dramatically improved, but an unfavourable prognostic subgroup warrants development of novel therapeutic strategies. Selective KIT, PDGFRalpha and epidermal growth factor receptor (EGFR) tyrosine kinase inhibition evolved as powerful targeted therapy for gastrointestinal stromal tumours and non-small-cell lung cancer. To investigate a potential role for tyrosine kinase inhibition, we analyzed 209 nephroblastomas for immunohistochemical KIT and EGFR expression, 63 nephroblastomas for mutations in KIT exons 9, 11, 13, EGFR exons 18, 19, 20 and 21, and all 209 nephroblastomas for PDGFRalpha exons 12, 14 and 18. Twenty-two tumours (10.5%) expressed KIT, 31 (14.8%) EGFR, and 10 (4.8%) both KIT and EGFR, respectively. KIT expression was relatively more common among high-risk tumours (6/27; 22.3%) compared to low-/intermediate-risk tumours (26/181; 14.4%). Nine patients deceased, four of which had high-risk tumours with KIT expression in two of four and EGFR expression in one of four. There were no KIT, PDGFRalpha or EGFR mutations. Our results suggest no significant contribution of KIT, EGFR or PDGFRalpha mutations to nephroblastoma pathogenesis. Despite a trend towards association of immunohistochemical KIT and EGFR expression with poor outcome in high-risk nephroblastomas, statistical analysis did not yield significant correlations in this subgroup. Therefore, it remains open if KIT, PDGFRalpha or EGFR tyrosine kinase inhibition constitute a therapeutic target in nephroblastoma in the absence of KIT, PDGFRalpha or EGFR mutations.
肾母细胞瘤的预后有了显著改善，但仍有一个预后不良的亚组需要开发新的治疗策略。选择性KIT、血小板衍生生长因子受体α（PDGFRα）和表皮生长因子受体（EGFR）酪氨酸激酶抑制已发展成为胃肠道间质瘤和非小细胞肺癌的有效靶向治疗方法。为了研究酪氨酸激酶抑制的潜在作用，我们分析了209例肾母细胞瘤的KIT和EGFR免疫组化表达，63例肾母细胞瘤的KIT外显子9、11、13、EGFR外显子18、19、20和21的突变情况，以及所有209例肾母细胞瘤的PDGFRα外显子12、14和18的情况。分别有22例肿瘤（10.5%）表达KIT，31例（14.8%）表达EGFR，10例（4.8%）同时表达KIT和EGFR。与低/中危肿瘤（26/181；14.4%）相比，KIT表达在高危肿瘤中相对更常见（6/27；22.3%）。9例患者死亡，其中4例为高危肿瘤，4例中有2例表达KIT，4例中有1例表达EGFR。未发现KIT、PDGFRα或EGFR突变。我们的结果表明，KIT、EGFR或PDGFRα突变对肾母细胞瘤发病机制没有显著贡献。尽管在高危肾母细胞瘤中，免疫组化KIT和EGFR表达与不良预后有一定关联趋势，但该亚组的统计分析未得出显著相关性。因此，在不存在KIT、PDGFRα或EGFR突变的情况下，KIT、PDGFRα或EGFR酪氨酸激酶抑制是否构成肾母细胞瘤的治疗靶点仍不明确。
