子宫浆液性癌中EGFR和PIK3CA的分子改变
Molecular alterations of EGFR and PIK3CA in uterine serous carcinoma.
作者信息
Hayes Monica Prasad, Douglas Wayne, Ellenson Lora Hedrick
机构信息
Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, USA.
出版信息
Gynecol Oncol. 2009 Jun;113(3):370-3. doi: 10.1016/j.ygyno.2008.12.021. Epub 2009 Mar 9.
OBJECTIVES
Uterine serous carcinoma (USC) is an aggressive endometrial cancer associated with poor prognosis despite comprehensive surgical staging and adjuvant chemotherapy and radiation therapy. Biologic targets have yet to be fully explored in this disease and research on such targets could lead to clinical trials utilizing a new class of therapeutics. This study sought to evaluate primary USC tumors for molecular alterations in epidermal growth factor receptor (EGFR) and the recently characterized oncogene PIK3CA, which encodes the catalytic p110-alpha subunit of phosphatidylinositol 3-kinase (PI3K) and thus activates the AKT-mTOR oncogenic pathway.
METHODS
Paraffin-embedded archival tissue of 45 primary USC tumors was utilized in this study. Immunohistochemical analysis of EGFR was performed and cases given a score of 0 to 12 calculated as the product of staining intensity (0 to 3+) and the percentage of positively stained cells (0-4), with 1=1-25%, 2=26-50%, 3=51-75%, and 4=76-100%. For mutational analysis, neoplastic tissue was microdissected and DNA was extracted with phenol-chloroform. Exons 18 through 21 of EGFR and exons 9 and 20 of PIK3CA, the most commonly mutated exons of these genes, were amplified and directly sequenced.
RESULTS
When EGFR was evaluated, moderate or strong EGFR membranous staining was observed in 25/45 (56%) USC cases. Thus, a mutational analysis was performed on 35 cases, including all cases with moderate and strong EGFR staining. No mutations were identified in EGFR. In contrast, PIK3CA mutations were confirmed in 5/34 (15%) of USC cases. Four cases were mutated in exon 20 and one case was mutated in exon 9.
CONCLUSIONS
Since optimal treatment of uterine serous carcinoma remains unknown, novel therapeutic approaches need to be actively pursued. In the current study of primary USC tumors, oncogenic mutations of the PIK3CA gene were seen in 15% of USC cases. This represents the first report of this gene mutation in USC. In addition, EGFR stained positively in the majority of cases, suggesting a possible target protein. These findings warrant further investigation and suggest a potential role for therapeutic agents targeting the PI3K-AKT-mTOR pathway, such as rapamycin, as well as possible targets of EGFR in the treatment of uterine serous carcinoma.
目的
子宫浆液性癌（USC）是一种侵袭性子宫内膜癌，尽管进行了全面的手术分期及辅助化疗和放疗，其预后仍较差。该疾病的生物学靶点尚未得到充分研究，对此类靶点的研究可能会引发使用新型治疗药物的临床试验。本研究旨在评估原发性USC肿瘤中表皮生长因子受体（EGFR）和最近鉴定的致癌基因PIK3CA的分子改变，PIK3CA编码磷脂酰肌醇3激酶（PI3K）的催化性p110-α亚基，从而激活AKT-mTOR致癌途径。
方法
本研究使用了45例原发性USC肿瘤的石蜡包埋存档组织。对EGFR进行免疫组织化学分析，病例得分为0至12分，计算方法为染色强度（0至3+）与阳性染色细胞百分比（0 - 4）的乘积，其中1 = 1 - 25%，2 = 26 - 50%，3 = 51 - 75%，4 = 76 - 100%。对于突变分析，对肿瘤组织进行显微切割，并用苯酚 - 氯仿提取DNA。扩增EGFR的第18至21外显子以及PIK3CA最常发生突变的第9和20外显子，并进行直接测序。
结果
评估EGFR时，在25/45（56%）的USC病例中观察到中度或强EGFR膜染色。因此，对35例病例进行了突变分析，包括所有中度和强EGFR染色的病例。未在EGFR中鉴定到突变。相比之下，在5/34（15%）的USC病例中证实存在PIK3CA突变。4例在第20外显子发生突变，1例在第9外显子发生突变。
结论
由于子宫浆液性癌的最佳治疗方法仍不明确，需要积极探索新的治疗方法。在当前对原发性USC肿瘤的研究中，15%的USC病例中发现了PIK3CA基因的致癌突变。这是USC中该基因突变的首次报道。此外，大多数病例中EGFR呈阳性染色，提示可能是一个靶蛋白。这些发现值得进一步研究，并提示针对PI3K - AKT - mTOR途径的治疗药物（如雷帕霉素）以及EGFR在子宫浆液性癌治疗中的潜在靶点作用。
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