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

نویسندگان

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

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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Cytokeratin7 expression in gastric and colorectal adenocarcinoma: Correlation with prognostic factors

 Background: Gastric and colorectal adenocarcinoma are the second and the fifth most common cancers in Iran, respectively. Expression of cytokeratin 7 (CK7) is established in most malignancies including gastric and colorectal adenocarcinoma. Demonstration of Ck7 could be related to prognostic factors and help to the better management of the patients. The objective of our study was to evalu...

متن کامل

Investigation of the atypical FBXW7 mutation spectrum in human tumours by conditional expression of a heterozygous propellor tip missense allele in the mouse intestines

OBJECTIVE FBXW7 encodes the substrate recognition component of a ubiquitin ligase that degrades targets such as Notch1, c-Jun, c-Myc and cyclin E. FBXW7 mutations occur in several tumour types, including colorectal cancers. The FBXW7 mutation spectrum in cancers is unusual. Some tumours have biallelic loss of function mutations but most have monoallelic missense mutations involving specific arg...

متن کامل

The Report of KRAS Mutation and NRAS Wild-Type in a Patient with Thyroid Metastasis from Colon Cancer: a Rare Case Report

Colorectal cancer (CRC) metastasis to the thyroid gland is rare. Here wereport a 45 yr-old man in western Iran referred to Hematology Clinic, Kermanshah city, Iran in March 2014 with complaint of exertional dyspnea, multi-nodular goiter as well as complaint of exertional dyspnea, and multi-nodular goiter. His history included a low anterior resection of rectum in 9 months ago for a high-risk st...

متن کامل

Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer.

Biomarkers for predicting chemotherapy response are important to the treatment of colorectal cancer patients. Cryptochrome 2 (CRY2) is a circadian clock protein involved in cell cycle, but the biologic consequences of this activity in cancer are poorly understood. We set up biochemical and cell biology analyses to analyze CRY2 expression and chemoresistance. Here, we report that CRY2 is overexp...

متن کامل

Mutational analysis of primary and metastatic colorectal cancer samples underlying the resistance to cetuximab-based therapy

PURPOSE Although several molecular markers predicting resistance to cetuximab- or panitumumab-based therapy of metastatic colorectal cancer were described, mutations in RAS proto-oncogenes remain the only predictors being used in daily clinical practice. However, 35%-45% of wild-type RAS patients still do not respond to this anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody-...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره 8  شماره 

صفحات  -

تاریخ انتشار 2017