Kosmidou Vivian, Oikonomou Eftychia, Vlassi Margarita, Avlonitis Spyros, Katseli Anastasia, Tsipras Iraklis, Mourtzoukou Despina, Kontogeorgos Georgios, Zografos Georgios, Pintzas Alexander
Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, 11635, Greece.
Hum Mutat. 2014 Mar;35(3):329-40. doi: 10.1002/humu.22496. Epub 2014 Jan 15.
Current clinical problems in colorectal cancer (CRC) diagnostics and therapeutics include the disease complexity, tumor heterogeneity, and resistance to targeted therapeutics. In the present study, we examined 171 CRC adenocarcinomas from Greek patients undergoing surgery for CRC to determine the frequency of KRAS, BRAF, and PIK3CA point mutations from different areas of tumors in heterogeneous specimens. Ninety two out of 171 (53.8%) patients were found to bear a KRAS mutation in codons 12/13. Of the 126 mutations found, 57.9% (73/126) were c.38G>A mutations (p.G13D) and 22.2% (28/126) were c.35G>T (p.G12V). Remarkably, RAS mutations in both codons 12 and 13 were recorded in the same tumor by pyrosequencing. Moreover, differences in KRAS mutations between tumor center and periphery revealed tumor heterogeneity in 50.7% of the specimens. BRAF c.1799T>A (V600E) mutations were moderately detected in 4/171 (2.3%) specimens, whereas most PIK3CA mutations were revealed by pyrosequencing 6/171 (3.5%). Remarkable tumor heterogeneity is revealed, where double mutations of KRAS in the same tumor and different KRAS mutation status between tumor core and margin are detected with high frequency. It is expected that these findings will have a major impact in cancer diagnosis and personalized therapies.
结直肠癌（CRC）诊断与治疗中的当前临床问题包括疾病复杂性、肿瘤异质性以及对靶向治疗的耐药性。在本研究中，我们检测了171例接受CRC手术的希腊患者的CRC腺癌，以确定异质性标本中肿瘤不同区域KRAS、BRAF和PIK3CA点突变的频率。171例患者中有92例（53.8%）被发现密码子12/13处存在KRAS突变。在发现的126个突变中，57.9%（73/126）为c.38G>A突变（p.G13D），22.2%（28/126）为c.35G>T（p.G12V）。值得注意的是，通过焦磷酸测序在同一肿瘤中记录到密码子12和13处均存在RAS突变。此外，肿瘤中心与周边KRAS突变的差异在50.7%的标本中显示出肿瘤异质性。在4/171（2.3%）的标本中中度检测到BRAF c.1799T>A（V600E）突变，而大多数PIK3CA突变通过焦磷酸测序在6/171（3.5%）的标本中被发现。结果显示出显著的肿瘤异质性，同一肿瘤中KRAS双突变以及肿瘤核心与边缘KRAS突变状态不同的情况被高频检测到。预计这些发现将对癌症诊断和个性化治疗产生重大影响。
