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Genomic and Expression Analyses Define MUC17 and PCNX1 as Predictors of Chemotherapy Response in Breast Cancer.
Al Amri, Waleed S; Allinson, Lisa M; Baxter, Diana E; Bell, Sandra M; Hanby, Andrew M; Jones, Stacey J; Shaaban, Abeer M; Stead, Lucy F; Verghese, Eldo T; Hughes, Thomas A.
Afiliação
  • Al Amri WS; School of Medicine, University of Leeds, Leeds, United Kingdom.
  • Allinson LM; Department of Histopathology and Cytopathology, The Royal Hospital, Muscat, Oman.
  • Baxter DE; School of Medicine, University of Leeds, Leeds, United Kingdom.
  • Bell SM; School of Medicine, University of Leeds, Leeds, United Kingdom.
  • Hanby AM; School of Medicine, University of Leeds, Leeds, United Kingdom.
  • Jones SJ; School of Medicine, University of Leeds, Leeds, United Kingdom.
  • Shaaban AM; Department of Histopathology, St. James's University Hospital, Leeds, United Kingdom.
  • Stead LF; Department of Breast Surgery, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
  • Verghese ET; Histopathology and Cancer Sciences, Queen Elizabeth Hospital Birmingham and University of Birmingham, Birmingham, United Kingdom.
  • Hughes TA; School of Medicine, University of Leeds, Leeds, United Kingdom.
Mol Cancer Ther ; 19(3): 945-955, 2020 03.
Article em En | MEDLINE | ID: mdl-31879365
ABSTRACT
Poor-prognosis breast cancers are treated with cytotoxic chemotherapy, but often without any guidance from therapy predictive markers because universally accepted markers are not currently available. Treatment failure, in the form of recurrences, is relatively common. We aimed to identify chemotherapy predictive markers and resistance pathways in breast cancer. Our hypothesis was that tumor cells remaining after neoadjuvant chemotherapy (NAC) contain somatic variants causing therapy resistance, while variants present pre-NAC but lost post-NAC cause sensitivity. Whole-exome sequencing was performed on matched pre- and post-NAC cancer cells, which were isolated by laser microdissection, from 6 cancer cases, and somatic variants selected for or against by NAC were identified. Somatic variant diversity was significantly reduced after therapy (P < 0.05). MUC17 variants were identified in 3 tumors and were selected against by NAC in each case, while PCNX1 variants were identified in 2 tumors and were selected for in both cases, implicating the function of these genes in defining chemoresponse. In vitro knockdown of MUC17 or PCNX1 was associated with significantly increased or decreased chemotherapy sensitivity, respectively (P < 0.05), further supporting their roles in chemotherapy response. Expression was tested for predictive value in two independent cohorts of chemotherapy-treated breast cancers (n = 53, n = 303). Kaplan-Meier analyses revealed that low MUC17 expression was significantly associated with longer survival after chemotherapy, whereas low PCNX1 was significantly associated with reduced survival. We concluded that therapy-driven selection of somatic variants allows identification of chemotherapy response genes. With respect to MUC17 and PCNX1, therapy-driven selection acting on somatic variants, in vitro knockdown data concerning drug sensitivity, and survival analysis of expression levels in patient cohorts all define the genes as mediators of and predictive markers for chemotherapy response in breast cancer.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Protocolos de Quimioterapia Combinada Antineoplásica / Biomarcadores Tumorais / Proteínas de Ciclo Celular / Resistencia a Medicamentos Antineoplásicos / Mucinas / Mutação Tipo de estudo: Guideline / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans Idioma: En Revista: Mol Cancer Ther Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Protocolos de Quimioterapia Combinada Antineoplásica / Biomarcadores Tumorais / Proteínas de Ciclo Celular / Resistencia a Medicamentos Antineoplásicos / Mucinas / Mutação Tipo de estudo: Guideline / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans Idioma: En Revista: Mol Cancer Ther Ano de publicação: 2020 Tipo de documento: Article