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Integrated analysis highlights APC11 protein expression as a likely new independent predictive marker for colorectal cancer

Abstract : After a diagnosis of colorectal cancer (CRC), approximately 50% of patients will present distant metastasis. Although significant progress has been made in treatments, most of them will die from the disease. We investigated the predictive and prognostic potential of APC11, the catalytic subunit of APC/C, which has never been examined in the context of CRC. The expression of APC11 was assessed in CRC cell lines, in tissue microarrays (TMAs) and in public datasets. Overexpression of APC11 mRNA was associated with chromosomal instability, lymphovascular invasion and residual tumor. Regression models accounting for the effects of well-known protein markers highlighted association of APC11 protein expression with residual tumor (odds ratio: OR = 6.51; 95% confidence intervals: CI = 1.54-27.59; P = 0.012) and metastasis at diagnosis (OR = 3.87; 95% CI = 1.20-2.45; P = 0.024). Overexpression of APC11 protein was also associated with worse distant relapse-free survival (hazard ratio: HR = 2.60; 95% CI = 1.26-5.37; P = 0.01) and worse overall survival (HR = 2.69; 95% CI = 1.31-5.51; P = 0.007). APC11 overexpression in primary CRC thus represents a potentially novel theranostic marker of metastatic CRC. Colorectal cancer (CRC) is the third most frequent cancer and the fourth cause of cancer-related mortality worldwide 1. Patient survival is highly dependent on the stage of CRC at the time of diagnosis but approximately 50% of the patients will be concerned by distant metastasis development, either present at diagnosis (20%) or occurring after the curative-intent surgery of the primary tumor. The most frequent sites affected by metastatic CRC (mCRC) are the liver and lung 1. The current first-line standard-of-care for mCRC relies on the combination of cytotoxic chemotherapy (5FU/FA, oxaliplatin, irinotecan) and biologic agents (anti VEGF(R) or anti-EGFR mon-oclonal antibodies) guided by the molecular profile of the tumor. Surgery or local tumor ablation may also play a role in the treatment of mCRC patients, especially those with oligometastatic disease. Several biomarkers, mostly predictive, are routinely used for mCRC 2,3. Activating RAS mutations (KRAS and NRAS), present in nearly 50% of mCRC cases, are negative predictive markers of anti-EGFR inhibitor efficacy (cetuximab, panitumumab) and RAS testing is now mandatory in all mCRC patients, from the first-line meta-static setting. V600E-BRAF mutation is a significant negative poor-prognostic marker for patients with mCRC and may be a negative predictive factor for anti-EGFR therapies.
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Submitted on : Tuesday, November 13, 2018 - 1:05:48 PM
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Youenn Drouet, Isabelle Treilleux, Alain Viari, Sophie Léon, Mojgan Devouassoux-Shisheboran, et al.. Integrated analysis highlights APC11 protein expression as a likely new independent predictive marker for colorectal cancer. Scientific Reports, Nature Publishing Group, 2018, 8 (1), ⟨10.1038/s41598-018-25631-1⟩. ⟨hal-01920572⟩



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