Genomic and Expression Analyses Define MUC17 and PCNX1 as Predictors of Chemotherapy Response in Breast Cancer
| العنوان: | Genomic and Expression Analyses Define MUC17 and PCNX1 as Predictors of Chemotherapy Response in Breast Cancer |
|---|---|
| المؤلفون: | Lucy F. Stead, Abeer M Shaaban, Stacey J. Jones, Lisa M. Allinson, Thomas A. Hughes, Sandra M. Bell, Andrew M. Hanby, Waleed S. Al Amri, Diana E. Baxter, Eldo T. Verghese |
| المصدر: | Molecular Cancer Therapeutics. 19:945-955 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Somatic cell, medicine.medical_treatment, Breast Neoplasms, Cell Cycle Proteins, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Text mining, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, medicine, Humans, Laser capture microdissection, Chemotherapy, business.industry, Carcinoma, Ductal, Breast, Mucins, Cancer, Genomics, Prognosis, medicine.disease, Neoadjuvant Therapy, Gene Expression Regulation, Neoplastic, Survival Rate, Carcinoma, Lobular, 030104 developmental biology, Chemotherapy, Adjuvant, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Mutation, Cancer cell, Female, business, Chemotherapy response, Follow-Up Studies |
| الوصف: | 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. |
| تدمد: | 1538-8514 1535-7163 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::64df56d9e890c9b40aa368142d63158e https://doi.org/10.1158/1535-7163.mct-19-0940 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....64df56d9e890c9b40aa368142d63158e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
|---|