CHEK2 Mutations Affecting Kinase Activity Together With Mutations in TP53 Indicate a Functional Pathway Associated with Resistance to Epirubicin in Primary Breast Cancer
AuthorChrisanthar, Ranjan; Knappskog, Stian; Løkkevik, Erik; Anker, Gun; Østenstad, Bjørn; Lundgren, Steinar; Berge, Elisabet O.; Risberg, Terje; Mjaaland, Ingvil; Mæhle, Lovise; Engebretsen, Lars Fredrik; Lillehaug, Johan Richard; Lønning, Per Eystein
Methods and Findings Snap-frozen biopsies from 109 patients collected prior to epirubicin (as preoperative therapy were investigated for TP53, CHEK2 and p14(ARF) mutations by sequencing the coding region and p14(ARF) promoter methylations. TP53 mutastions were associated with chemoresistance, defined as progressive disease on therapy (p = 0.0358; p = 0.0136 for mutations affecting p53 loop domains L2/L3). Germline CHEK2 mutations (n = 3) were associated with therapy resistance (p = 0.0226). Combined, mutations affecting either CHEK2 or TP53 strongly predicted therapy resistance (p = 0.0101; TP53 mutations restricted to the L2/L3 domains: p = 0.0032). Two patients progressing on therapy harbored the CHEK2 mutation, Arg95Ter, completely abrogating Chk2 protein dimerization and kinase activity. One patient (Epi132) revealed family cancer occurrence resembling families harboring CHEK2 mutations in general, the other patient (epi203) was non-conclusive. No mutation or promoter hypermethylation in p14(ARF) were detected.
Conclusion This study is the first reporting an association between CHEK2 mutations and therapy resistance in human cancers and to document mutations in two genes acting direct up / down-stream to each other to cause therapy failure, emphasizing the need to investigate functional cascades in future studies.
PublisherPublic Library of Science (PLoS)
CitationPLoS ONE 3(2008) nr. 8 s. 3062-3079
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