Molecular Genetics Laboratory, Humanitas Clinical and Research Center, Milan, Italy.
Cancer. 2013 Jan 15;119(2):266-76. doi: 10.1002/cncr.27722. Epub 2012 Jul 11.
Colorectal cancer (CRC) prognosis and survival are strictly related to the development of distant metastases. New targeted therapies have increased patient survival, but the objective response rate is still very limited, partially because of a traditional focus on designing treatment according to the molecular profile of the primary tumor regardless the diversity between the primary tumor and metastases. The objective of this study was to evaluate the presence of molecular heterogeneity during metastatic progression and its potential impact on clinical treatment.
The authors analyzed v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) codon 12 mutations, the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) thymine to adenine substitution at codon 1788, and tumor protein 53 (p53) mutations and investigated promoter methylation of Ras association (RalGDS/AF-6) domain family member 1 protein (RASSF1a), E-cadherin, and cyclin-dependent kinase inhibitor 2A (p16INK4a) in 101 primary CRCs (67 stage III and 34 stage IV) and related lymph node and liver metastases.
Lymph node metastases were characterized by fewer alterations compared with primary tumors and liver metastases, especially KRAS (P = .03) and p16INK4a (P = .05). Genetic changes, when detectable in metastases, mostly were retained from the primary tumor, whereas epigenetic changes more frequently were acquired de novo. Overall, 31 distinct CRC molecular profiles were detected, none of which characterized a particular tumor stage. When the metastatic lesions also were included in the profiles, there were 53 distinct molecular profiles in 67 patients with stage III disease and 34 distinct molecular profiles in 34 patients with stage IV disease.
Lymph node and liver metastases appear to originate in clonally different processes, with more molecular alterations occurring in distant metastases than in lymph node metastases and with elevated heterogeneity of the primary tumor. Thus, potential prognostic targets should be carefully evaluated for their heterogeneity in both primary tumors and distant metastases to avoid erroneous misclassification.
结直肠癌（CRC）的预后和生存与远处转移的发展密切相关。新的靶向治疗方法提高了患者的生存率，但客观缓解率仍然非常有限，部分原因是传统上侧重于根据原发性肿瘤的分子谱设计治疗方案，而忽略了原发性肿瘤和转移瘤之间的多样性。本研究的目的是评估转移进展过程中分子异质性的存在及其对临床治疗的潜在影响。
作者分析了 v-Ki-ras2 Kirsten 大鼠肉瘤病毒癌基因同源物（KRAS）密码子 12 突变、v-Raf 鼠肉瘤病毒癌基因同源物 B1（BRAF）胸腺嘧啶到腺嘌呤取代密码子 1788 以及肿瘤蛋白 53（p53）突变，并研究了 Ras 相关（RalGDS/AF-6）域家族成员 1 蛋白（RASSF1a）、E-钙黏蛋白和细胞周期蛋白依赖性激酶抑制剂 2A（p16INK4a）在 101 例原发性 CRC（67 例 III 期和 34 例 IV 期）及其相关淋巴结和肝转移灶中的启动子甲基化。
与原发性肿瘤和肝转移灶相比，淋巴结转移灶的改变较少，尤其是 KRAS（P =.03）和 p16INK4a（P =.05）。在转移灶中可检测到的遗传变化主要来自原发性肿瘤，而表观遗传变化更常是新获得的。总体而言，检测到 31 种不同的 CRC 分子谱，没有一种谱特征与特定的肿瘤分期有关。当将转移性病变也纳入这些谱中时，在 67 例 III 期疾病患者中发现了 53 种不同的分子谱，在 34 例 IV 期疾病患者中发现了 34 种不同的分子谱。
淋巴结和肝转移似乎起源于克隆不同的过程，与淋巴结转移相比，远处转移的分子变化更多，且原发性肿瘤的异质性增加。因此，为了避免错误的分类，应仔细评估潜在的预后靶点在原发性肿瘤和远处转移中的异质性。
