FBXW7 Mutation Analysis and its Correlation with Clinicopathological Features and Prognosis in Colorectal Cancer Patients

Chang, Chi-Ching; Lin, Hung Hsin; Lin, Jen Kou; Lin, Chun Chi; Lan, Yuan Tzu; Wang, Huann Sheng; Yang, Shung Haur; Chen, Wei Shone; Lin, Tzu Chen; Jiang, Jeng Kai; Chang, Shih Ching

doi:10.5301/jbm.5000125

Cited by 36 publications

(34 citation statements)

References 41 publications

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“…Low FBXW7 expressions in tumor as compared to normal tissues were significantly correlated with poor prognosis of overall survival in CRCs and esophageal cancer (EC) patients (Iwatsuki et al, 2010; Kurashige et al, 2012). A similar pattern of low overall survival was also found in early stage CRC patients with FBXW7 mutants but the results was not significant when compare to wild type patients (Chang et al, 2015). About 10 to 11% of FBWX7 alterations were found in most of CRCs studies (Eliana et al, 2013; Grim, 2014; Cai Z.X.…”

Section: Discussionsupporting

confidence: 62%

Molecular Characterization of Somatic Alterations in Dukes’ B and C Colorectal Cancers by Targeted Sequencing

Abdul

Mutalib

Sean³

et al. 2017

Front. Pharmacol.

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Despite global progress in research, improved screening and refined treatment strategies, colorectal cancer (CRC) remains as the third most common malignancy. As each type of cancer is different and exhibits unique alteration patterns, identifying and characterizing gene alterations in CRC that may serve as biomarkers might help to improve diagnosis, prognosis and predict potential response to therapy. With the emergence of next generation sequencing technologies (NGS), it is now possible to extensively and rapidly identify the gene profile of individual tumors. In this study, we aimed to identify actionable somatic alterations in Dukes’ B and C in CRC via NGS. Targeted sequencing of 409 cancer-related genes using the Ion AmpliseqTM Comprehensive Cancer Panel was performed on genomic DNA obtained from paired fresh frozen tissues, cancer and normal, of Dukes’ B (n = 10) and Dukes’ C (n = 9) CRC. The sequencing results were analyzed using Torrent Suite, annotated using ANNOVAR and validated using Sanger sequencing. A total of 141 somatic non-synonymous sequence variations were identified in 86 genes. Among these, 64 variants (45%) were predicted to be deleterious, 38 variants (27%) possibly deleterious while the other 39 variants (28%) have low or neutral protein impact. Seventeen genes have alterations with frequencies of ≥10% in the patient cohort and with 14 overlapped genes in both Dukes’ B and C. The adenomatous polyposis coli gene (APC) was the most frequently altered gene in both groups (n = 6 in Dukes’ B and C). In addition, TP53 was more frequently altered in Dukes’ C (n = 7) compared to Dukes’ B (n = 4). Ten variants in APC, namely p.R283∗, p.N778fs, p.R805∗, p.Y935fs, p.E941fs, p.E1057∗, p.I1401fs, p.Q1378∗, p.E1379∗, and p.A1485fs were predicted to be driver variants. APC remains as the most frequently altered gene in the intermediate stages of CRC. Wnt signaling pathway is the major affected pathway followed by P53, RAS, TGF-β, and PI3K signaling. We reported the alteration profiles in each of the patient which has the potential to affect the clinical decision. We believe that this study will add further to the understanding of CRC molecular landscape.

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Section: Discussionsupporting

confidence: 62%

Molecular Characterization of Somatic Alterations in Dukes’ B and C Colorectal Cancers by Targeted Sequencing

Abdul

Mutalib

Sean³

et al. 2017

Front. Pharmacol.

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“…Mutations in the FBXW7 gene are thought to impair cyclin E degradation resulting in unchecked cellular growth, and subsequently in progression of CRC (115)(116)(117). The frequency of FBXW7 mutation in the present study was 3% in Arab patients, none were found in the matched Western cohort.…”

Section: Discussionmentioning

confidence: 60%

Molecular spectrum of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC somatic gene mutations in Arab patients with colorectal cancer: determination of frequency and distribution pattern

Al-Shamsi¹,

Jones²,

Fahmawi³

et al. 2016

J. Gastrointest. Oncol.

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Background: The frequency rates of mutations such as KRAS, NRAS, BRAF, and PIK3CA in colorectal cancer (CRC) differ among populations. The aim of this study was to assess mutation frequencies in the Arab population and determine their correlations with certain clinicopathological features. Methods: Arab patients from the Arab Gulf region and a population of age-and sex-matched Western patients with CRC whose tumors were evaluated with next-generation sequencing (NGS) were identified and retrospectively reviewed. The mutation rates of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC were recorded, along with clinicopathological features. Other somatic mutation and their rates were also identified. Fisher's exact test was used to determine the association between mutation status and clinical features. Results: A total of 198 cases were identified; 99 Arab patients and 99 Western patients. Fifty-two point seven percent of Arab patients had stage IV disease at initial presentation, 74.2% had left-sided tumors.Eighty-nine point two percent had tubular adenocarcinoma and 10.8% had mucinous adenocarcinoma. The prevalence rates of KRAS, NRAS, BRAF, PIK3CA, TP53, APC, SMAD, FBXW7 mutations in Arab population were 44.4%, 4%, 4%, 13.1%, 52.5%, 27.3%, 2% and 3% respectively. Compared to 48.4%, 4%, 4%, 12.1%, 47.5%, 24.2%, 11.1% and 0% respectively in matched Western population. Associations between these mutations and patient clinicopathological features were not statistically significant.Conclusions: This is the first study to report comprehensive hotspot mutations using NGS in Arab patients with CRC. The frequency of KRAS, NRAS, BRAF, TP53, APC and PIK3CA mutations were similar to reported frequencies in Western population except SMAD4 that had a lower frequency and higher frequency of FBXW7 mutation.

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“…S582L was noted in six cases (14%) and was the third most common FBXW7 mutation in our study. Chang et al [33] reported a similar frequency of FBXW7 mutations (7.5%, 114/1519) in CRC patients but noted that Ser 582 (S582L) was the most frequent type (19.3%), ahead of Arg 465 (R465H, 16.6%), Arg 505 (R505C, 14.9%), and Arg 479 (R479Q, 14.9%). These variations are slight and within the realm of inter-study statistical variations.…”

Section: Discussionmentioning

confidence: 96%

“…In a study of 1,519 patients with CRC at all stages, Chang et al [33] showed that FBXW7 mutations did not impact prognosis. In fact, in that study, subgroup analyses of FBXW7 mutations showed that R465H, R465C, and R479Q were associated with better 5-year OS rates than other FBXW7 mutation types were (76.9% vs 56.0%; p=0.012).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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FBXW7 Mutation Analysis and its Correlation with Clinicopathological Features and Prognosis in Colorectal Cancer Patients

Abstract: There was no strong association between patient prognosis and FBXW7 mutations in our large-scale study.

Cited by 36 publications

References 41 publications

Molecular Characterization of Somatic Alterations in Dukes’ B and C Colorectal Cancers by Targeted Sequencing

Molecular Characterization of Somatic Alterations in Dukes’ B and C Colorectal Cancers by Targeted Sequencing

Molecular spectrum of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC somatic gene mutations in Arab patients with colorectal cancer: determination of frequency and distribution pattern

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

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