野生型APC预示微卫星稳定的近端结肠癌预后不良。

Wild-type APC predicts poor prognosis in microsatellite-stable proximal colon cancer.

作者信息

Jorissen Robert N, Christie Michael, Mouradov Dmitri, Sakthianandeswaren Anuratha, Li Shan, Love Christopher, Xu Zheng-Zhou, Molloy Peter L, Jones Ian T, McLaughlin Stephen, Ward Robyn L, Hawkins Nicholas J, Ruszkiewicz Andrew R, Moore James, Burgess Antony W, Busam Dana, Zhao Qi, Strausberg Robert L, Lipton Lara, Desai Jayesh, Gibbs Peter, Sieber Oliver M

机构信息

Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.

Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.

出版信息

Br J Cancer. 2015 Sep 15;113(6):979-88. doi: 10.1038/bjc.2015.296. Epub 2015 Aug 25.

DOI:10.1038/bjc.2015.296

PMID:26305864

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4578087/

Abstract

BACKGROUND

APC mutations (APC-mt) occur in ∼70% of colorectal cancers (CRCs), but their relationship to prognosis is unclear.

METHODS

APC prognostic value was evaluated in 746 stage I-IV CRC patients, stratifying for tumour location and microsatellite instability (MSI). Microarrays were used to identify a gene signature that could classify APC mutation status, and classifier ability to predict prognosis was examined in an independent cohort.

RESULTS

Wild-type APC microsatellite stable (APC-wt/MSS) tumours from the proximal colon showed poorer overall and recurrence-free survival (OS, RFS) than APC-mt/MSS proximal, APC-wt/MSS distal and APC-mt/MSS distal tumours (OS HR⩾1.79, P⩽0.015; RFS HR⩾1.88, P⩽0.026). APC was a stronger prognostic indicator than BRAF, KRAS, PIK3CA, TP53, CpG island methylator phenotype or chromosomal instability status (P⩽0.036). Microarray analysis similarly revealed poorer survival in MSS proximal cancers with an APC-wt-like signature (P=0.019). APC status did not affect outcomes in MSI tumours. In a validation on 206 patients with proximal colon cancer, APC-wt-like signature MSS cases showed poorer survival than APC-mt-like signature MSS or MSI cases (OS HR⩾2.50, P⩽0.010; RFS HR⩾2.14, P⩽0.025). Poor prognosis APC-wt/MSS proximal tumours exhibited features of the sessile serrated neoplasia pathway (P⩽0.016).

CONCLUSIONS

APC-wt status is a marker of poor prognosis in MSS proximal colon cancer.

摘要

背景

约70%的结直肠癌（CRC）中存在腺瘤性息肉病基因（APC）突变（APC-mt），但其与预后的关系尚不清楚。

方法

对746例I-IV期CRC患者的APC预后价值进行评估，根据肿瘤位置和微卫星不稳定性（MSI）进行分层。利用微阵列鉴定可对APC突变状态进行分类的基因特征，并在独立队列中检验该分类器预测预后的能力。

结果

近端结肠的野生型APC微卫星稳定（APC-wt/MSS）肿瘤，其总生存期和无复发生存期（OS，RFS）比APC-mt/MSS近端、APC-wt/MSS远端和APC-mt/MSS远端肿瘤更差（OS风险比[HR]⩾1.79，P⩽0.015；RFS HR⩾1.88，P⩽0.026）。与BRAF、KRAS、PIK3CA、TP53、CpG岛甲基化表型或染色体不稳定状态相比，APC是更强的预后指标（P⩽0.036）。微阵列分析同样显示，具有APC-wt样特征的MSS近端癌症患者生存率较低（P=0.019）。APC状态不影响MSI肿瘤的预后。在对206例近端结肠癌患者的验证中，具有APC-wt样特征的MSS病例比具有APC-mt样特征的MSS或MSI病例生存率更差（OS HR⩾2.50，P⩽0.010；RFS HR⩾2.14，P⩽0.025）。预后不良的APC-wt/MSS近端肿瘤表现出无蒂锯齿状肿瘤发生途径的特征（P⩽0.016）。