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Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large‐Scale Data to Inform Therapeutic Directions

BACKGROUND: We describe the landscape of cyclin and interactive gene pathway alterations in 190,247 solid tumors. METHODS: Using comprehensive genomic profiling (315 genes, >500× coverage), samples were analyzed for alterations in activating/sensitizing cyclin genes (CDK4 amplification, CDK6 ampl...

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Autores principales: Jardim, Denis L., Millis, Sherri Z., Ross, Jeffrey S., Woo, Michelle Sue‐Ann, Ali, Siraj M., Kurzrock, Razelle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794175/
https://www.ncbi.nlm.nih.gov/pubmed/32885893
http://dx.doi.org/10.1634/theoncologist.2020-0509
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author Jardim, Denis L.
Millis, Sherri Z.
Ross, Jeffrey S.
Woo, Michelle Sue‐Ann
Ali, Siraj M.
Kurzrock, Razelle
author_facet Jardim, Denis L.
Millis, Sherri Z.
Ross, Jeffrey S.
Woo, Michelle Sue‐Ann
Ali, Siraj M.
Kurzrock, Razelle
author_sort Jardim, Denis L.
collection PubMed
description BACKGROUND: We describe the landscape of cyclin and interactive gene pathway alterations in 190,247 solid tumors. METHODS: Using comprehensive genomic profiling (315 genes, >500× coverage), samples were analyzed for alterations in activating/sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1), hormone genes (estrogen receptor 1 [ESR1], androgen receptor [AR]), and co‐alterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1). RESULTS: Alterations in at least one cyclin activating/sensitizing gene occurred in 24% of malignancies. Tumors that frequently harbored at least one cyclin alteration were brain gliomas (47.1%), esophageal (40.3%) and bladder cancer (37.9%), and mesotheliomas (37.9%). The most frequent alterations included CDKN2A (13.9%) and CDKN2B loss (12.5%). Examples of unique patterns of alterations included CCND1 amplification in breast cancer (17.3%); CDK4 alterations in sarcomas (12%); CCND2 in testicular cancer (23.4%), and SMARCB1 mutations in kidney cancer (3% overall, 90% in malignant rhabdoid tumors). Alterations in resistance genes RB1 and CCNE1 affected 7.2% and 3.6% of samples. Co‐occurrence analysis demonstrated a lower likelihood of concomitant versus isolated alterations in cyclin activating/sensitizing and resistance genes (odds ratio [OR], 0.35; p < .001), except in colorectal, cervical, and small intestine cancers. AR and cyclin activating/sensitizing alterations in prostate cancer co‐occurred more frequently (vs. AR alterations and wild‐type cyclin activating/sensitizing alterations) (OR, 1.79; p < .001) as did ESR1 and cyclin activating/sensitizing alterations in breast (OR, 1.62; p < .001) and cervical cancer (OR, 4.08; p = .04) (vs. ESR1 and cyclin wild‐type activating/sensitizing alterations). CONCLUSION: Cyclin pathway alterations vary according to tumor type/histology, informing opportunities for targeted therapy, including for rare cancers. IMPLICATIONS FOR PRACTICE: Cyclin pathway genomic abnormalities are frequent in human solid tumors, with substantial variation according to tumor site and histology. Opportunities for targeted therapy emerge with comprehensive profiling of this pathway.
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spelling pubmed-77941752021-01-15 Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large‐Scale Data to Inform Therapeutic Directions Jardim, Denis L. Millis, Sherri Z. Ross, Jeffrey S. Woo, Michelle Sue‐Ann Ali, Siraj M. Kurzrock, Razelle Oncologist Cancer Diagnostics and Molecular Pathology BACKGROUND: We describe the landscape of cyclin and interactive gene pathway alterations in 190,247 solid tumors. METHODS: Using comprehensive genomic profiling (315 genes, >500× coverage), samples were analyzed for alterations in activating/sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1), hormone genes (estrogen receptor 1 [ESR1], androgen receptor [AR]), and co‐alterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1). RESULTS: Alterations in at least one cyclin activating/sensitizing gene occurred in 24% of malignancies. Tumors that frequently harbored at least one cyclin alteration were brain gliomas (47.1%), esophageal (40.3%) and bladder cancer (37.9%), and mesotheliomas (37.9%). The most frequent alterations included CDKN2A (13.9%) and CDKN2B loss (12.5%). Examples of unique patterns of alterations included CCND1 amplification in breast cancer (17.3%); CDK4 alterations in sarcomas (12%); CCND2 in testicular cancer (23.4%), and SMARCB1 mutations in kidney cancer (3% overall, 90% in malignant rhabdoid tumors). Alterations in resistance genes RB1 and CCNE1 affected 7.2% and 3.6% of samples. Co‐occurrence analysis demonstrated a lower likelihood of concomitant versus isolated alterations in cyclin activating/sensitizing and resistance genes (odds ratio [OR], 0.35; p < .001), except in colorectal, cervical, and small intestine cancers. AR and cyclin activating/sensitizing alterations in prostate cancer co‐occurred more frequently (vs. AR alterations and wild‐type cyclin activating/sensitizing alterations) (OR, 1.79; p < .001) as did ESR1 and cyclin activating/sensitizing alterations in breast (OR, 1.62; p < .001) and cervical cancer (OR, 4.08; p = .04) (vs. ESR1 and cyclin wild‐type activating/sensitizing alterations). CONCLUSION: Cyclin pathway alterations vary according to tumor type/histology, informing opportunities for targeted therapy, including for rare cancers. IMPLICATIONS FOR PRACTICE: Cyclin pathway genomic abnormalities are frequent in human solid tumors, with substantial variation according to tumor site and histology. Opportunities for targeted therapy emerge with comprehensive profiling of this pathway. John Wiley & Sons, Inc. 2020-09-15 2021-01 /pmc/articles/PMC7794175/ /pubmed/32885893 http://dx.doi.org/10.1634/theoncologist.2020-0509 Text en © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Cancer Diagnostics and Molecular Pathology
Jardim, Denis L.
Millis, Sherri Z.
Ross, Jeffrey S.
Woo, Michelle Sue‐Ann
Ali, Siraj M.
Kurzrock, Razelle
Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large‐Scale Data to Inform Therapeutic Directions
title Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large‐Scale Data to Inform Therapeutic Directions
title_full Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large‐Scale Data to Inform Therapeutic Directions
title_fullStr Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large‐Scale Data to Inform Therapeutic Directions
title_full_unstemmed Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large‐Scale Data to Inform Therapeutic Directions
title_short Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large‐Scale Data to Inform Therapeutic Directions
title_sort cyclin pathway genomic alterations across 190,247 solid tumors: leveraging large‐scale data to inform therapeutic directions
topic Cancer Diagnostics and Molecular Pathology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794175/
https://www.ncbi.nlm.nih.gov/pubmed/32885893
http://dx.doi.org/10.1634/theoncologist.2020-0509
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