Donner David B, Ruan Dan T, Toriguchi Kan, Bergsland Emily K, Nakakura Eric K, Lin Meng Hsun, Antonia Ricardo J, Warren Robert S
Department of Surgery, Division of Surgical Oncology, and The Comprehensive Cancer Center, The University of California San Francisco, San Francisco, CA. 94143; The Helen Diller Family Comprehensive Cancer Center, The University of California San Francisco, San Francisco, CA. 94143.
Department of Surgery, Division of Surgical Oncology, and The Comprehensive Cancer Center, The University of California San Francisco, San Francisco, CA. 94143; The Helen Diller Family Comprehensive Cancer Center, The University of California San Francisco, San Francisco, CA. 94143.
Transl Oncol. 2019 Mar;12(3):550-560. doi: 10.1016/j.tranon.2018.12.007. Epub 2019 Jan 9.
Prognostic schemes that rely on clinical variables to predict outcome after resection of colorectal metastases remain imperfect. We hypothesized that molecular markers can improve the accuracy of prognostic schemes.
We screened the transcriptome of matched colorectal liver metastases (CRCLM) and primary tumors from 42 patients with unresected CRCLM to identify differentially expressed genes. Among the differentially expressed genes identified, we looked for associations between expression and time to disease progression or overall survival. To validate such associations, mRNA levels of the candidate genes were assayed by qRT-PCR from CRCLM in 56 additional patients who underwent hepatectomy.
Seven candidate genes were selected for validation based on their differential expression between metastases and primary tumors and a correlation between expression and surgical outcome: lumican; tissue inhibitor metalloproteinase 1; basic helix-loop-helix domain containing class B2; fibronectin; transmembrane 4 superfamily member 1; mitogen inducible gene 6 (MIG-6); and serpine 2. In the hepatectomy group, only MIG-6 expression was predictive of poor survival after hepatectomy. Quantitative PCR of MIG-6 mRNA was performed on 25 additional hepatectomy patients to determine if MIG-6 expression could substratify patients beyond the clinical risk score. Patients within defined clinical risk score categories were effectively substratified into distinct groups by relative MIG-6 expression.
MIG-6 expression is inversely associated with survival after hepatectomy and may be used to improve traditional prognostic schemes that rely on clinicopathologic data such as the Clinical Risk Score.
依靠临床变量来预测结直肠癌肝转移切除术后预后的方案仍不完善。我们推测分子标志物可提高预后方案的准确性。
我们筛选了42例未切除的结直肠癌肝转移（CRCLM）患者的配对CRCLM和原发性肿瘤的转录组，以鉴定差异表达基因。在鉴定出的差异表达基因中，我们寻找表达与疾病进展时间或总生存期之间的关联。为验证这种关联，通过qRT-PCR对另外56例接受肝切除术的患者的CRCLM中的候选基因mRNA水平进行了检测。
基于转移灶与原发性肿瘤之间的差异表达以及表达与手术结果之间的相关性，选择了7个候选基因进行验证：亮蛋白聚糖；组织金属蛋白酶抑制剂1；含B2类碱性螺旋-环-螺旋结构域；纤连蛋白；跨膜4超家族成员1；丝裂原诱导基因6（MIG-6）；和丝氨酸蛋白酶抑制剂2。在肝切除组中，只有MIG-6表达可预测肝切除术后的不良生存。对另外25例肝切除患者进行了MIG-6 mRNA的定量PCR，以确定MIG-6表达是否可以在临床风险评分之外对患者进行分层。通过相对MIG-6表达，将定义的临床风险评分类别内的患者有效地分层为不同的组。
MIG-6表达与肝切除术后的生存率呈负相关，可用于改善依赖临床病理数据（如临床风险评分）的传统预后方案。
