Oncotarget

Research Papers:

FBXW7 missense mutation: a novel negative prognostic factor in metastatic colorectal adenocarcinoma

Krittiya Korphaisarn, Van Karlyle Morris, Michael J. Overman, David R. Fogelman, Bryan K. Kee, Kanwal Pratap Singh Raghav, Shanequa Manuel, Imad Shureiqi, Robert A. Wolff, Cathy Eng, David Menter, Stanley R. Hamilton, Scott Kopetz and Arvind Dasari _

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Oncotarget. 2017; 8:39268-39279. https://doi.org/10.18632/oncotarget.16848

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Abstract

Krittiya Korphaisarn1,2, Van Karlyle Morris1, Michael J. Overman1, David R. Fogelman1, Bryan K. Kee1, Kanwal Pratap Singh Raghav1, Shanequa Manuel1, Imad Shureiqi1, Robert A. Wolff1, Cathy Eng1, David Menter1, Stanley R. Hamilton3, Scott Kopetz1 and Arvind Dasari1

1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

2Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Bangkok, Thailand

3Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence to:

Arvind Dasari, email: adasari@mdanderson.org

Keywords: colorectal cancer, FBXW7, mutation, missense, prognosis

Received: January 25, 2017    Accepted: March 02, 2017    Published: April 05, 2017

ABSTRACT

Background: 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. However, the clinicopathologic factors and outcomes associated with FBXW7 missense mutations in metastatic colorectal cancer (mCRC) have not been described.

Methods: Data 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.

Results: Of 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).

Conclusions: In the largest clinical dataset of mCRC to date, FBXW7 missense mutations showed a strong negative prognostic association.


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