Short Communication| Volume 220, P38-43, January 2018

Assessment of a FBXW8 frameshift mutation, c.1312_1313delGT, in breast cancer patients and controls from Central Europe


      • A frameshift mutation in FBXW8 occurs at near-polymorphic frequencies in two European populations.
      • Case-control association studies rule out clinically actionable breast cancer risks.
      F-box proteins participate in multiple cellular processes through ubiquitylation and subsequent degradation of target proteins, such as cyclin D1 as target of FBXW8. To investigate the spectrum of FBXW8 germ-line mutations in patients with breast cancer and healthy controls, we analyzed the whole FBXW8 coding region and flanking untranslated portions in germ-line DNA samples of 91 breast cancer patients and 277 healthy controls using next-generation amplicon sequencing. Five missense variants, one splice site variant, one frameshift variant, one synonymous variant, and one variant in the 3′-UTR were identified. Frameshift mutation FBXW8 c.1312_1313delGT was considered functionally relevant and was investigated for its potential association with breast cancer risk through subsequent genotyping in two hospital-based breast cancer case-control series from Belarus and Germany, respectively, comprising a total of 2740 breast cancer cases and 2174 controls. The mutation was found in 30 cases and 23 controls with an adjusted Odds Ratio 1.02 (95% CI 0.59–1.77; p = 0.94) in the combined analysis. There was no statistically significant difference when patients were stratified by ER status, PR status, age at diagnosis, ductal histology, contralateral status, family history or tumor grade. Altogether, our data exclude clinically actionable breast cancer risks above two-fold for the FBXW8 c.1312_1313delGT mutation, although larger studies would be needed to exclude low-penetrance associations.


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        • Wang Z.
        • Liu P.
        • Inuzuka H.
        • et al.
        Roles of F-box proteins in cancer.
        Nat Rev Cancer. 2014; 14: 233-247
        • Akhoondi S.
        • Sun D.
        • von der Lehr N.
        • et al.
        FBXW7/hCDC4 is a general tumor suppressor in human cancer.
        Cancer Res. 2007; 67: 9006-9012
        • Akhoondi S.
        • Lindstrom L.
        • Widschwendter M.
        • et al.
        Inactivation of FBXW7/hCDC4-beta expression by promoter hypermethylation is associated with favorable prognosis in primary breast cancer.
        Breast Cancer Res. 2010; 12: R105
        • Crusio K.M.
        • King B.
        • Reavie L.B.
        • et al.
        The ubiquitous nature of cancer. The role of the SCF(Fbw7) complex in development and transformation.
        Oncogene. 2010; 29: 4865-4873
        • Welcker M.
        • Clurman B.E.
        FBW7 ubiquitin ligase. A tumour suppressor at the crossroads of cell division, growth and differentiation.
        Nat Rev Cancer. 2008; 8: 83-93
        • Tsunematsu R.
        • Nishiyama M.
        • Kotoshiba S.
        • et al.
        Fbxw8 is essential for Cul1-Cul7 complex formation and for placental development.
        Mol Cell Biol. 2006; 26: 6157-6169
        • Tsutsumi T.
        • Kuwabara H.
        • Arai T.
        • et al.
        Disruption of the Fbxw8 gene results in pre- and postnatal growth retardation in mice.
        Mol Cell Biol. 2008; 28: 743-751
        • Lin P.
        • Fu J.
        • Zhao B.
        • et al.
        Fbxw8 is involved in the proliferation of human choriocarcinoma JEG-3 cells.
        Mol Biol Rep. 2011; 38: 1741-1747
        • Okabe H.
        • Lee S.H.
        • Phuchareon J.
        • et al.
        A critical role for FBXW8 and MAPK in cyclin D1 degradation and cancer cell proliferation.
        PLoS ONE. 2006; 1: e128
        • Zhang Q.
        • Sakamoto K.
        • Wagner K.U.
        D-type cyclins are important downstream effectors of cytokine signaling that regulate the proliferation of normal and neoplastic mammary epithelial cells.
        Mol Cell Endocrinol. 2014; 382: 583-592
        • French J.D.
        • Ghoussaini M.
        • Edwards S.L.
        • et al.
        Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers.
        Am J Hum Genet. 2013; 92: 489-503
        • Bogdanova N.
        • Cybulski C.
        • Bermisheva M.
        • et al.
        A nonsense mutation (E1978X) in the ATM gene is associated with breast cancer.
        Breast Cancer Res Treat. 2009; 118: 207-211
        • Bogdanova N.V.
        • Antonenkova N.N.
        • Rogov Y.I.
        • et al.
        High frequency and allele-specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus.
        Clin Genet. 2010; 78: 364-372
        • Noskowicz M.
        • Bogdanova N.
        • Bermisheva M.
        • et al.
        Prevalence of PALB2 mutation c.509_510delGA in unselected breast cancer patients from Central and Eastern Europe.
        Fam Cancer. 2014; 13: 137-142
        • Bogdanova N.
        • Pfeifer K.
        • Schürmann P.
        • et al.
        Analysis of a RECQL splicing mutation, c.1667_1667+3delAGTA, in breast cancer patients and controls from Central Europe.
        Fam Cancer. 2017; 16: 181-186
        • Breast Cancer Association Consortium
        Commonly studied single-nucleotide polymorphisms and breast cancer. Results from the Breast Cancer Association Consortium.
        J Natl Cancer Inst. 2006; 98: 1382-1396
        • Easton D.F.
        • Pooley K.A.
        • Dunning A.M.
        • et al.
        Genome-wide association study identifies novel breast cancer susceptibility loci.
        Nature. 2007; 447: 1087-1093
        • Michailidou K.
        • Hall P.
        • Gonzalez-Neira A.
        • et al.
        Large-scale genotyping identifies 41 new loci associated with breast cancer risk.
        Nat Genet. 2013; 45: 353-361
        • Milne R.L.
        • Kuchenbaecker K.B.
        • Michailidou K.
        • et al.
        Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.
        Nat Genet. 2017; (in press; Epub ahead of print on Oct 23, 2017)
        • Michailidou K.
        • Lindström S.
        • Dennis J.
        • et al.
        Association analysis identifies 65 new breast cancer risk loci.
        Nature. 2017; 551: 92-94
        • Maleva Kostovska I.
        • Wang J.
        • Bogdanova N.
        • et al.
        Rare ATAD5 missense variants in breast and ovarian cancer patients.
        Cancer Lett. 2016; 376: 173-177
        • Eng L.
        • Coutinho G.
        • Nahas S.
        • et al.
        Nonclassical splicing mutations in the coding and noncoding regions of the ATM Gene. maximum entropy estimates of splice junction strengths.
        Hum Mutat. 2004; 23: 67-76
        • Frescas D.
        • Pagano M.
        Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP. tipping the scales of cancer.
        Nat Rev Cancer. 2008; 8: 438-449
        • Nakayama K.I.
        • Nakayama K.
        Regulation of the cell cycle by SCF-type ubiquitin ligases.
        Semin Cell Dev Biol. 2005; 16: 323-333
        • Xu C.
        • Min J.
        Structure and function of WD40 domain proteins.
        Protein Cell. 2011; 2: 202-214