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Abstract：
BACKGROUND: Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related mortality worldwide. Mesenchymal-epithelial transition factor (MET) gene participates in multiple tumor biology and shows clinical potential for pharmacological manipulation in tumor treatment. MET amplification has been reported in CRC, but data are very limited. Investigating pathological values of MET in CRC may provide new therapeutic and genetic screening options in future clinical practice.
OBJECTIVE: To determine the pathological significance of MET amplification in CRC and to propose a feasible screening strategy.
METHODS: A number of 205 newly diagnosed CRC patients undergoing surgical resection without any preoperative therapy at Shenzhen Cancer Hospital of Chinese Academy of Medical Sciences were recruited. All patients were without RAS/RAF mutation or microsatellite instability-high. MET amplification and c-MET protein expression were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. Correlations between MET aberration and pathological features were detected using the chi-squared test. Progression free survival (PFS) during the two-year follow-up was detected using the Kaplan-Meier method and log rank test. The results of MET FISH and IHC were compared using one-way ANOVA.
RESULTS: Polysomy-induced MET amplification was observed in 14.4% of cases, and focal MET amplification was not detected. Polysomy-induced MET amplification was associated with a higher frequency of lymph node metastasis (LNM) (P < 0.001) and higher tumor budding grade (P = 0.02). In the survival analysis, significant difference was detected between patients with amplified- and non-amplified MET in a two-year follow-up after the first diagnosis (P = 0.001). C-MET scores of 0, 1+, 2+, and 3+ were observed in 1.4%, 24.9%, 54.7%, and 19.0% of tumors, respectively. C-MET overexpression correlated with higher frequency of LNM (P = 0.002), but no significant difference of PFS was detected between patients with different protein levels. In terms of concordance between MET FISH and IHC results, MET copy number showed no difference in c-MET IHC 0/1+ (3.35 ± 0.18), 2+ (3.29 ± 0.11) and 3+ (3.58 ± 0.22) cohorts, and the MET-to-CEP7 ratio showed no difference in three groups (1.09 ± 0.02, 1.10 ± 0.01, and 1.09 ± 0.03).
CONCLUSIONS: In CRC, focal MET amplification was a rare event. Polysomy-induced MET amplification correlated with adverse pathological characteristics and poor prognosis. IHC was a poor screening tool for MET amplification.
OBJECTIVE: To determine the pathological significance of MET amplification in CRC and to propose a feasible screening strategy.
METHODS: A number of 205 newly diagnosed CRC patients undergoing surgical resection without any preoperative therapy at Shenzhen Cancer Hospital of Chinese Academy of Medical Sciences were recruited. All patients were without RAS/RAF mutation or microsatellite instability-high. MET amplification and c-MET protein expression were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. Correlations between MET aberration and pathological features were detected using the chi-squared test. Progression free survival (PFS) during the two-year follow-up was detected using the Kaplan-Meier method and log rank test. The results of MET FISH and IHC were compared using one-way ANOVA.
RESULTS: Polysomy-induced MET amplification was observed in 14.4% of cases, and focal MET amplification was not detected. Polysomy-induced MET amplification was associated with a higher frequency of lymph node metastasis (LNM) (P < 0.001) and higher tumor budding grade (P = 0.02). In the survival analysis, significant difference was detected between patients with amplified- and non-amplified MET in a two-year follow-up after the first diagnosis (P = 0.001). C-MET scores of 0, 1+, 2+, and 3+ were observed in 1.4%, 24.9%, 54.7%, and 19.0% of tumors, respectively. C-MET overexpression correlated with higher frequency of LNM (P = 0.002), but no significant difference of PFS was detected between patients with different protein levels. In terms of concordance between MET FISH and IHC results, MET copy number showed no difference in c-MET IHC 0/1+ (3.35 ± 0.18), 2+ (3.29 ± 0.11) and 3+ (3.58 ± 0.22) cohorts, and the MET-to-CEP7 ratio showed no difference in three groups (1.09 ± 0.02, 1.10 ± 0.01, and 1.09 ± 0.03).
CONCLUSIONS: In CRC, focal MET amplification was a rare event. Polysomy-induced MET amplification correlated with adverse pathological characteristics and poor prognosis. IHC was a poor screening tool for MET amplification.
摘要：
背景：结直肠癌（CRC）是全球第三大常见癌症，也是癌症相关死亡的第二大常见原因。间充质-上皮转化因子（MET）基因参与多种肿瘤生物学，并显示出在肿瘤治疗中的药理操作的临床潜力。在CRC中已经报道了MET扩增，但是数据非常有限。研究CRC中MET的病理学价值可能为未来的临床实践提供新的治疗和遗传筛查选择。
目的：确定MET扩增在CRC中的病理学意义，并提出可行的筛查策略。
方法：选择在中国医学科学院肿瘤医院接受手术切除治疗的205例初诊CRC患者。所有患者均无RAS/RAF突变或微卫星不稳定性高。使用荧光原位杂交（FISH）和免疫组织化学（IHC）分析MET扩增和c-MET蛋白表达，分别。使用卡方检验检测MET畸变与病理特征之间的相关性。使用Kaplan-Meier方法和对数秩检验检测两年随访期间的无进展生存期（PFS）。使用单向方差分析比较METFISH和IHC的结果。
结果：在14.4％的病例中观察到多体性引起的MET扩增，未检测到局灶性MET扩增。多体分裂诱导的MET扩增与较高的淋巴结转移（LNM）频率（P<0.001）和较高的肿瘤出芽分级（P=0.02）相关。在生存分析中，在首次诊断后的2年随访中,扩增和非扩增MET患者之间存在显著差异(P=0.001).C-MET评分为0，1+，2+,在1.4%中观察到3+，24.9%,54.7%,和19.0%的肿瘤，分别。C-MET过表达与LNM发生频率相关(P=0.002),但不同蛋白水平患者的PFS差异无统计学意义。就METFISH和IHC结果之间的一致性而言，MET拷贝数显示c-METIHC0/1+(3.35±0.18),2+(3.29±0.11)和3+(3.58±0.22)组，MET与CEP7的比值在三组中没有差异（1.09±0.02，1.10±0.01和1.09±0.03）。
结论：在CRC中，局灶性MET扩增是罕见事件.多体分体引起的MET扩增与不良病理特征和不良预后相关。IHC是用于MET扩增的差的筛选工具。
目的：确定MET扩增在CRC中的病理学意义，并提出可行的筛查策略。
方法：选择在中国医学科学院肿瘤医院接受手术切除治疗的205例初诊CRC患者。所有患者均无RAS/RAF突变或微卫星不稳定性高。使用荧光原位杂交（FISH）和免疫组织化学（IHC）分析MET扩增和c-MET蛋白表达，分别。使用卡方检验检测MET畸变与病理特征之间的相关性。使用Kaplan-Meier方法和对数秩检验检测两年随访期间的无进展生存期（PFS）。使用单向方差分析比较METFISH和IHC的结果。
结果：在14.4％的病例中观察到多体性引起的MET扩增，未检测到局灶性MET扩增。多体分裂诱导的MET扩增与较高的淋巴结转移（LNM）频率（P<0.001）和较高的肿瘤出芽分级（P=0.02）相关。在生存分析中，在首次诊断后的2年随访中,扩增和非扩增MET患者之间存在显著差异(P=0.001).C-MET评分为0，1+，2+,在1.4%中观察到3+，24.9%,54.7%,和19.0%的肿瘤，分别。C-MET过表达与LNM发生频率相关(P=0.002),但不同蛋白水平患者的PFS差异无统计学意义。就METFISH和IHC结果之间的一致性而言，MET拷贝数显示c-METIHC0/1+(3.35±0.18),2+(3.29±0.11)和3+(3.58±0.22)组，MET与CEP7的比值在三组中没有差异（1.09±0.02，1.10±0.01和1.09±0.03）。
结论：在CRC中，局灶性MET扩增是罕见事件.多体分体引起的MET扩增与不良病理特征和不良预后相关。IHC是用于MET扩增的差的筛选工具。
