Relationship between genetic alterations and prognosis in sporadic colorectal cancer
Relationship between genetic alterations and prognosis in sporadic colorectal cancer
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DOI：
10.1002/ijc.21563
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发表时间：
2006-04-01
影响因子：
6.4
通讯作者：
Chi, CW
中科院分区：
文献类型：
--
作者：
Chang, SC;Lin, JK;Chi, CW
由于染色体不稳定性（CIN）和微卫星不稳定性（MSI）是结直肠癌中重要的遗传学改变，我们根据CIN和MSI的状态对散发性结直肠癌（CRC）进行分类，并探讨其分子特征。对213例大肠癌进行DNA倍体、MSI、杂合性丢失（洛）、p53（外显子5 ~ 9）、Ki-ras（外显子1和2）和BRAF（V599 E）突变分析。临床病理变量和分子分析之间的关系用卡方检验（Yates校正）进行分析。Kaplan-Meier生存曲线采用对数秩检验进行比较。将p < 0.1的变量输入考克斯回归风险模型进行多变量分析。高微卫星不稳定性（MSI-H）19例（8.9%），多位于右侧（31.6%），分化差（26.3%）。71例（33.3%）为二倍体，142例（66.7%）为异倍体。p53、Ki-ras和BRAF基因突变率分别为45.1%、41.8%和4.2%。基于MSI和CIN，定义了3种类型：（i）高微卫星不稳定性MSI-H肿瘤：年轻、高癌胚抗原（CEA）水平、右结肠、低分化、粘蛋白产生、高BRAF突变、较低等位基因丢失和相对良好的预后;（ii）微卫星稳定性（MSS）二倍体肿瘤：右结肠，低分化，较少浸润性肿瘤，粘蛋白产生，较低等位基因丢失和低p53，BRAF突变;（iii）MISS非整倍体肿瘤：更多浸润性浸润，更大等位基因丢失和高p53突变。多因素分析显示，肿瘤分期和p53突变与疾病进展显著相关。MISS二倍体和MISS非整倍体CRC可通过p53突变进行亚型分型，并具有不同的预后结果和分子特征。MSS-二倍体、野生型p53肿瘤患者的4年无病生存率（DFS）为67%，显著高于MSS-二倍体、突变型p53 CRC患者（30%，p = 0.003）。在患有MSS-非整倍体CRC的患者中发现了相同的趋势（野生型p53对突变型p53，64%对41%，p = 0.009）。我们认为CIN、MS 1和p53突变状态可作为散发性结直肠癌预后的多参数分析。(c)2005 Wiley-Liss，Inc.
Because chromosomal chromosomal instability (CIN) and microsatellite instability (MSI) are important genetic alterations in colorectal cancers, we classified the sporadic colorectal cancers (CRC) on the status of the CIN and MSI and explored their molecular profiles. A total or 213 colorectal tumors were collected for analysis of DNA ploidy, MSI, loss of heterozygosity (LOH), mutation of p53 (exons 5 to 9), Ki-ras (exons I and 2) and BRAF (V599E). Relationships between clinicopathological variables and molecular analyses were analyzed with the chi(2) test (Yates' correction). Kaplan-Meier survival curves were compared using log-rank test. Variables with p < 0.1 were entered into the Cox regression hazard model for multivariate analysis. High microsatellite instability (MSI-H) existed in 19 tumors (8.9%), which were more likely to be right-sided (31.6%) with poor differentiation (26.3%). Seventy-one (33.3%) tumors were diploid and 142 (66.7%) were aneuploid. Mutations in p53, Ki-ras and BRAF were found in 45.1%, 41.8% and 4.2% of tumors, respectively. Based on MSI, and CIN, 3 classes were defined: (i) High microsatellite instability MSI-H tumors: young age, high carcinoembryonic antigen (CEA) level, right colon, poorly differentiated, mucin production, high BRAF mutation, lower allelic loss and relatively good prognosis; (ii) Microsatellite stability (MSS) diploid tumors: right colon, poorly differentiated, less infiltrative tumor, mucin production, lower allelic loss and low p53, BRAF mutation; (iii) MISS aneuploid tumors: more infiltrative invasion, greater allelic loss and high p53 mutation. According to multivariate analysis, tumor stage and p53 mutation were significantly associated with disease progression. The MISS diploid and MISS aneuploid CRCs could be subtyped with p53 mutation and had different prognostic outcome and molecular profiles. The 4-year disease-free survival (DFS) of patients with MSS-diploid, wild-type p53 tumors was 67% and significantly higher than those of patients with MSS-diploid, mutant p53 CRC (30%, p = 0.003). The same trend was found in patients with MSS-aneuploid CRC(wild p53 vs. mutant p53, 64% vs. 41%, p = 0.009). We concluded that CIN, MS1 and p53 mutation status might be used as a multiple parameter profile for the prognosis of sporadic colorectal cancer. (c) 2005 Wiley-Liss, Inc.