Volante Marco, Monica Valentina, Birocco Nadia, Brizzi Maria Pia, Busso Simone, Daniele Lorenzo, La Rosa Stefano, Righi Luisella, Sapino Anna, Berruti Alfredo, Scagliotti Giorgio V, Papotti Mauro
Department of Oncology, University of Turin at San Luigi Hospital, Orbassano, Italy.
Neuroendocrinology. 2015;101(2):151-60. doi: 10.1159/000375449. Epub 2015 Jan 29.
Mixed neuroendocrine/nonneuroendocrine carcinomas are heterogeneous tumors with poorly defined diagnostic and clinical features and without pathological or molecular markers of prognosis or markers predicting their response to therapy. We aimed at analyzing the pathological features and the expression of genes involved in DNA repair or synthesis in a cohort of patients with mixed carcinomas from different sites as compared to the patients' outcome.
Relative cDNA quantification of ribonucleotide reductase, large subunit 1, excision repair cross-complementation group 1, thymidylate synthase and topoisomerase IIa genes was tested using real-time PCR on microdissected neuroendocrine and nonneuroendocrine tumor components of 42 mixed cases (from the lung as well as the gastrointestinal and genitourinary tracts) and on 45 control cases of pure neuroendocrine and nonneuroendocrine carcinomas.
The expression levels of all genes were stable comparing nonneuroendocrine and neuroendocrine components of mixed cases (except for topoisomerase IIa in lung samples) but significantly different as compared to control nonneuroendocrine and neuroendocrine tumors. In the multivariate analysis including all clinical and pathological parameters and gene expression levels available, a predominant nonneuroendocrine component, the administration of additional therapy other than surgery and a high thymidylate synthase expression in nonneuroendocrine tumor tissue were significantly associated with a lower risk of a patient's death.
Our data show that mixed neuroendocrine/nonneuroendocrine carcinomas are different at the molecular level from their pure neuroendocrine and nonneuroendocrine counterparts, and detailed analyses of their clinical, pathological and molecular features may improve the clinical strategies for the treatment of these rare and underestimated tumors.
混合性神经内分泌/非神经内分泌癌是一种异质性肿瘤，其诊断和临床特征尚不明确，且缺乏预后的病理或分子标志物，也没有预测其对治疗反应的标志物。我们旨在分析来自不同部位的混合性癌患者队列中与DNA修复或合成相关基因的病理特征及表达情况，并与患者的预后进行比较。
使用实时PCR对42例混合性病例（来自肺、胃肠道和泌尿生殖道）的微切割神经内分泌和非神经内分泌肿瘤成分以及45例纯神经内分泌和非神经内分泌癌对照病例，检测核糖核苷酸还原酶大亚基1、切除修复交叉互补组1、胸苷酸合成酶和拓扑异构酶IIα基因的相对cDNA定量。
与对照非神经内分泌和神经内分泌肿瘤相比，混合性病例的非神经内分泌和神经内分泌成分中所有基因的表达水平均稳定（肺样本中的拓扑异构酶IIα除外），但存在显著差异。在包括所有可用临床和病理参数以及基因表达水平的多变量分析中，非神经内分泌成分占主导、接受手术以外的其他附加治疗以及非神经内分泌肿瘤组织中胸苷酸合成酶高表达与患者较低的死亡风险显著相关。
我们的数据表明，混合性神经内分泌/非神经内分泌癌在分子水平上与其纯神经内分泌和非神经内分泌对应物不同，对其临床、病理和分子特征进行详细分析可能会改善这些罕见且被低估肿瘤的临床治疗策略。
