Inamura Kentaro, Takeuchi Kengo, Togashi Yuki, Hatano Satoko, Ninomiya Hironori, Motoi Noriko, Mun Ming-yon, Sakao Yukinori, Okumura Sakae, Nakagawa Ken, Soda Manabu, Choi Young Lim, Mano Hiroyuki, Ishikawa Yuichi
Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
Mod Pathol. 2009 Apr;22(4):508-15. doi: 10.1038/modpathol.2009.2. Epub 2009 Feb 20.
A subset of lung cancers harbors a small inversion within chromosome 2p, giving rise to a transforming fusion gene, EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene), which encodes an activated tyrosine kinase. We have earlier examined the presence of EML4-ALK by multiplex reverse transcription-polymerase chain reaction in 363 specimens of lung cancer, identifying 11 adenocarcinoma cases featuring the fusion gene. In this study, we clinicopathologically examined the characteristics of the EML4-ALK-positive cases, including the mutation status of EGFR, KRAS, and TP53, and whether they were of thyroid transcription factor-1 (TTF-1) cell lineage or not. Of 11 patients, 4 (36%) with EML4-ALK-positive lung adenocarcinomas who were below 50 years of age were affected by these diseases, as compared with 12 of 242 patients (5.0%) with EML4-ALK-negative lung adenocarcinomas (P=0.00038). EML4-ALK-positive lung adenocarcinomas were characterized by less-differentiated grade (P=0.0082) and acinar-predominant structure (P<0.0001) in histology. Furthermore, the presence of EML4-ALK appears to be mutually exclusive for EGFR and KRAS mutations (P=0.00018), whereas coexisting with TP53 mutations at a low frequency (1/11=9.1%), and correlating with non- or light smoking (P=0.040), in line with the TTF-1 immunoreactivity. Thus, EML4-ALK-positive tumors may form a distinct entity among lung adenocarcinomas, characterized by young onset, acinar histology, no or rare mutations in EGFR, KRAS, and TP53, and a TTF-1 cell lineage, all in agreement with the prevalence in non- or light smokers.
一部分肺癌在2号染色体短臂上存在一个小的倒位，从而产生一种具有转化能力的融合基因EML4-ALK（棘皮动物微管相关蛋白样4基因和间变性淋巴瘤激酶基因），该基因编码一种活化的酪氨酸激酶。我们之前通过多重逆转录-聚合酶链反应检测了363例肺癌标本中EML4-ALK的存在情况，鉴定出11例具有该融合基因的腺癌病例。在本研究中，我们对EML4-ALK阳性病例的临床病理特征进行了检查，包括表皮生长因子受体（EGFR）、 Kirsten大鼠肉瘤病毒癌基因（KRAS）和肿瘤蛋白p53（TP53）的突变状态，以及它们是否属于甲状腺转录因子-1（TTF-1）细胞谱系。在11例患者中，4例（36%）年龄小于50岁的EML4-ALK阳性肺腺癌患者患有这些疾病，而242例EML4-ALK阴性肺腺癌患者中有12例（5.0%）患有这些疾病（P=0.00038）。EML4-ALK阳性肺腺癌的组织学特征为分化程度较低（P=0.0082）和以腺泡为主的结构（P<0.0001）。此外，EML4-ALK的存在似乎与EGFR和KRAS突变相互排斥（P=0.00018），而与TP53突变低频率共存（1/11=9.1%），并且与不吸烟或轻度吸烟相关（P=0.040），这与TTF-1免疫反应性一致。因此，EML4-ALK阳性肿瘤可能在肺腺癌中形成一个独特的实体，其特征为发病年龄较轻、腺泡组织学、EGFR、KRAS和TP53无突变或罕见突变，以及TTF-1细胞谱系，所有这些都与不吸烟或轻度吸烟者中的患病率一致。
