Department of Clinical Sciences, Division of Pathology, Lund University, Skåne University Hospital, Lund, Sweden.
Diagn Pathol. 2013 Jan 21;8:10. doi: 10.1186/1746-1596-8-10.
Despite their pivotal roles in colorectal carcinogenesis, the interrelationship and prognostic significance of beta-catenin alterations and microsatellite instability (MSI) in colorectal cancer (CRC) needs to be further clarified. In this paper, we studied the associations between beta-catenin overexpression and MSI status with survival from CRC, and with expression of p21, p27, cyclin D1 and p53, in a large, prospective cohort study.
Immunohistochemical MSI-screening status and expression of p21, p27 and p53 was assessed in tissue microarrays with tumours from 557 cases of incident CRC in the Malmö Diet and Cancer Study. Chi Square and Spearman's correlation tests were used to explore the associations between beta-catenin expression, MSI status, clinicopathological characteristics and investigative parameters. Kaplan-Meier analysis and Cox proportional hazards modelling were used to assess the relationship between beta-catenin overexpression, MSI status and cancer specific survival (CSS).
Positive MSI screening status was significantly associated with older age, female sex, proximal tumour location, non-metastatic disease, and poor differentiation, and inversely associated with beta-catenin overexpression. Beta-catenin overexpression was significantly associated with distal tumour location, low T-stage and well-differentiated tumours. Patients with MSI tumours had a significantly prolonged CSS in the whole cohort, and in stage III-IV disease, also in multivariable analysis, but not in stage I-II disease. Beta-catenin overexpression was associated with a favourable prognosis in the full cohort and in patients with stage III-IV disease. Neither MSI nor beta-catenin status were predictive for response to adjuvant chemotherapy in curatively treated stage III patients. P53 and p27 expression was positively associated with beta-catenin overexpression and inversely associated with MSI. Cyclin D1 expression was positively associated with MSI and beta-catenin overexpression, and p21 expression was positively associated with MSI but not beta-catenin overexpression.
Findings from this large, prospective cohort study demonstrate that MSI screening status in colorectal cancer is an independent prognostic factor, but not in localized disease, and does not predict response to adjuvant chemotherapy. Beta-catenin overexpression was also associated with favourable outcome but not a treatment predictive factor. Associations of MSI and beta-catenin alterations with other investigative and clinicopathological factors were in line with the expected.
The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8778585058652609.
尽管β-连环蛋白改变和微卫星不稳定性（MSI）在结直肠癌（CRC）的发生中起着关键作用，但它们之间的相互关系和预后意义仍需进一步阐明。在本文中，我们通过对来自马尔默饮食与癌症研究中的 557 例 CRC 患者的组织微阵列进行免疫组织化学 MSI 筛查状态和 p21、p27 和 p53 的表达分析，研究了β-连环蛋白过表达与 CRC 患者的生存和 p21、p27、细胞周期蛋白 D1 和 p53 的表达之间的关系。卡方检验和斯皮尔曼相关分析用于探索β-连环蛋白表达、MSI 状态、临床病理特征和研究参数之间的关系。Kaplan-Meier 分析和 Cox 比例风险模型用于评估β-连环蛋白过表达、MSI 状态与癌症特异性生存（CSS）之间的关系。
MSI 筛查阳性状态与年龄较大、女性、肿瘤位置较近、非转移性疾病和分化不良显著相关，与β-连环蛋白过表达呈负相关。β-连环蛋白过表达与肿瘤位置较远、T 分期较低和分化较好的肿瘤显著相关。在整个队列中，MSI 肿瘤患者的 CSS 明显延长，在 III-IV 期疾病中，在多变量分析中也是如此，但在 I-II 期疾病中则不然。β-连环蛋白过表达与全队列和 III-IV 期疾病患者的良好预后相关。MSI 状态和β-连环蛋白过表达均不能预测可切除 III 期患者的辅助化疗反应。P53 和 p27 的表达与β-连环蛋白过表达呈正相关，与 MSI 呈负相关。Cyclin D1 的表达与 MSI 和β-连环蛋白过表达呈正相关，p21 的表达与 MSI 呈正相关，但与β-连环蛋白过表达无关。
这项大型前瞻性队列研究的结果表明，结直肠癌的 MSI 筛查状态是一个独立的预后因素，但在局限性疾病中不是，也不能预测辅助化疗的反应。β-连环蛋白过表达也与良好的预后相关，但不是治疗预测因素。MSI 和β-连环蛋白改变与其他研究和临床病理因素的关联与预期相符。
