Abstract
BackgroundFBXW7 functions as a ubiquitin ligase tagging multiple dominant oncogenic proteins and commonly mutates in colorectal cancer. Data suggest missense mutations lead to greater loss of FBXW7 function than other gene aberrations do. However, the clinicopathologic factors and outcomes associated with FBXW7 missense mutations in metastatic colorectal cancer (mCRC) have not been described.MethodsData were obtained from mCRC patients whose tumors were evaluated by next-generation sequencing for hotspot mutations at The University of Texas MD Anderson Cancer Center. Alterations in FBXW7 were identified, and their associations with clinicopathologic features and overall survival (OS) were evaluated.ResultsOf 855 mCRC patients, 571 had data on FBXW7 status; 43 (7.5%) had FBXW7 mutations, including 37 with missense mutations. R465C mutations in exon 9 were the most common missense mutations (18.6%). PIK3CA mutations were associated with FBXW7 missense mutations (p=0.012). On univariate analysis, patients with FBXW7 missense mutations had significantly worse OS (median 28.7 mo) than those with wild-type FBXW7 (median 46.6 mo; p=0.003). On multivariate analysis including other known prognostic factors such as BRAF mutations, FBXW7 missense mutations were the strongest negative prognostic factor for OS (hazard ratio 2.0; p=0.003).ConclusionsIn the largest clinical dataset of mCRC to date, FBXW7 missense mutations showed a strong negative prognostic association.
Highlights
Colorectal cancer (CRC) is the third most common cancer worldwide and the second most common cause of cancer-related mortality
PIK3CA mutations were associated with FBXW7 missense mutations (p=0.012)
A total of 855 metastatic colorectal cancer (mCRC) patients were included in the Assessment of Targeted Therapies Against Colorectal Cancer program at The University of Texas MD Anderson Cancer Center between February 13, 2009, and November 18, 2015
Summary
Colorectal cancer (CRC) is the third most common cancer worldwide and the second most common cause of cancer-related mortality. It has been well established that colorectal tumorigenesis is a multistep process with an accumulation of multiple, successive genetic alterations, including chromosomal abnormalities, gene mutations, and/or epigenetic changes transforming normal colonic epithelium to colorectal carcinoma [1]. APC, TP53, RAS, RAF, and PIK3CA gene mutations are the most commonly noted aberrations in metastatic CRC (mCRC). F-box proteins, the substrate-recognition subunit of SKP1–Cullin1–F-box protein ubiquitin E3 ligase complexes, have been well characterized and shown to play important roles in degradation of proteins regulating cell cycle progression. FBXW7 functions as a ubiquitin ligase tagging multiple dominant oncogenic proteins and commonly mutates in colorectal cancer. Data suggest missense mutations lead to greater loss of FBXW7 function than other gene aberrations do. The clinicopathologic factors and outcomes associated with FBXW7 missense mutations in metastatic colorectal cancer (mCRC) have not been described
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