Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, Munich, Germany.
Ann Surg. 2012 Nov;256(5):763-71; discussion 771. doi: 10.1097/SLA.0b013e318272de87.
Individualized risk assessment in patients with UICC stage II colon cancer based on a panel of molecular genetic alterations.
Risk assessment in patients with colon cancer and localized disease (UICC stage II) is not sufficiently reliable. Development of metachronous metastasis is assumed to be governed largely by individual tumor genetics.
Fresh frozen tissue from 232 patients (T3-4, N0, M0) with complete tumor resection and a median follow-up of 97 months was analyzed for microsatellite stability, KRAS exon 2, and BRAF exon 15 mutations. Gene expression of the WNT-pathway surrogate marker osteopontin and the metastasis-associated genes SASH1 and MACC1 was determined for 179 patients. The results were correlated with metachronous distant metastasis risk (n = 22 patients).
Mutations of KRAS were detected in 30% patients, mutations of BRAF in 15% patients, and microsatellite instability in 26% patients. Risk of recurrence was associated with KRAS mutation (P = 0.033), microsatellite stable tumors (P = 0.015), decreased expression of SASH1 (P = 0.049), and increased expression of MACC1 (P < 0.001). MACC1 was the only independent parameter for recurrence prediction (hazard ratio: 6.2; 95% confidence interval: 2.4-16; P < 0.001). Integrative 2-step cluster analysis allocated patients into 4 groups, according to their tumor genetics. KRAS mutation, BRAF wild type, microsatellite stability, and high MACC1 expression defined the group with the highest risk of recurrence (16%, 7 of 43), whereas BRAF wild type, microsatellite instability, and low MACC1 expression defined the group with the lowest risk (4%, 1 of 26).
MACC1 expression predicts development of metastases, outperforming microsatellite stability status, as well as KRAS/BRAF mutation status.
基于分子遗传学改变的小组，对 UICC 分期 II 期结肠癌患者进行个体化风险评估。
对结肠癌和局部疾病（UICC 分期 II）患者的风险评估并不足够可靠。假定结直肠肿瘤的转移主要由个体肿瘤遗传学决定。
分析了 232 例完全肿瘤切除的患者（T3-4，N0，M0）的新鲜冷冻组织，中位随访时间为 97 个月，分析了微卫星不稳定性、KRAS 外显子 2 和 BRAF 外显子 15 突变。对 179 例患者进行了 WNT 通路替代标志物骨桥蛋白和转移相关基因 SASH1 和 MACC1 的基因表达检测。结果与 22 例患者的远处转移复发风险相关。
30%的患者检测到 KRAS 突变，15%的患者检测到 BRAF 突变，26%的患者检测到微卫星不稳定。复发风险与 KRAS 突变（P = 0.033）、微卫星稳定肿瘤（P = 0.015）、SASH1 表达降低（P = 0.049）和 MACC1 表达增加（P <0.001）相关。MACC1 是唯一独立的复发预测参数（危险比：6.2；95%置信区间：2.4-16；P <0.001）。综合两步聚类分析根据肿瘤遗传学将患者分为 4 组。KRAS 突变、BRAF 野生型、微卫星稳定性和高 MACC1 表达定义了复发风险最高的组（16%，43 例中有 7 例），而 BRAF 野生型、微卫星不稳定和低 MACC1 表达定义了复发风险最低的组（4%，26 例中有 1 例）。
MACC1 表达预测转移的发展，优于微卫星不稳定性状态以及 KRAS/BRAF 突变状态。
