The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas
Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome seque...
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| Veröffentlicht in: | Clinical cancer research Jg. 27; H. 5; S. 1516 |
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| Format: | Journal Article |
| Sprache: | Englisch |
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01.03.2021
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| ISSN: | 1557-3265, 1557-3265 |
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| Abstract | Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous (
= 3), uveal (
= 2), and acral (
= 2) melanoma subtypes.
Primary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression.
For each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance.
In 4 patients who received immunotherapy, we found 1-3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective. |
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| AbstractList | Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous (n = 3), uveal (n = 2), and acral (n = 2) melanoma subtypes.PURPOSEMelanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous (n = 3), uveal (n = 2), and acral (n = 2) melanoma subtypes.Primary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression.EXPERIMENTAL DESIGNPrimary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression.For each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance.RESULTSFor each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance.In 4 patients who received immunotherapy, we found 1-3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective.CONCLUSIONSIn 4 patients who received immunotherapy, we found 1-3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective. Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous ( = 3), uveal ( = 2), and acral ( = 2) melanoma subtypes. Primary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression. For each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance. In 4 patients who received immunotherapy, we found 1-3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective. |
| Author | Riaz, Nadeem Tokheim, Collin Solit, David B Topalian, Suzanne L Chapman, Paul B Hong, Jungeui Hooper, Jody E Baez, Priscilla Karchin, Rachel Zucker, Amanda Postow, Michael A Socci, Nicholas D Lipson, Evan J Kohutek, Zachary Makarov, Vladimir Makohon-Moore, Alvin P Bielski, Craig M Taylor, Barry S Chan, Timothy A Hayashi, Akimasa Kappagantula, Rajya Iacobuzio-Donahue, Christine A |
| Author_xml | – sequence: 1 givenname: Alvin P surname: Makohon-Moore fullname: Makohon-Moore, Alvin P organization: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 2 givenname: Evan J orcidid: 0000-0003-2976-0911 surname: Lipson fullname: Lipson, Evan J organization: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland – sequence: 3 givenname: Jody E surname: Hooper fullname: Hooper, Jody E organization: Department of Pathology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland – sequence: 4 givenname: Amanda orcidid: 0000-0002-9283-7072 surname: Zucker fullname: Zucker, Amanda organization: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 5 givenname: Jungeui surname: Hong fullname: Hong, Jungeui organization: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 6 givenname: Craig M surname: Bielski fullname: Bielski, Craig M organization: Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 7 givenname: Akimasa surname: Hayashi fullname: Hayashi, Akimasa organization: Department of Pathology, Kyorin University, Mitaka City, Tokyo, Japan – sequence: 8 givenname: Collin orcidid: 0000-0003-1395-5378 surname: Tokheim fullname: Tokheim, Collin organization: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts – sequence: 9 givenname: Priscilla surname: Baez fullname: Baez, Priscilla organization: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 10 givenname: Rajya surname: Kappagantula fullname: Kappagantula, Rajya organization: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 11 givenname: Zachary surname: Kohutek fullname: Kohutek, Zachary organization: Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee – sequence: 12 givenname: Vladimir surname: Makarov fullname: Makarov, Vladimir organization: Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 13 givenname: Nadeem surname: Riaz fullname: Riaz, Nadeem organization: Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 14 givenname: Michael A orcidid: 0000-0002-3367-7961 surname: Postow fullname: Postow, Michael A organization: Weill Cornell Medical College, New York, New York – sequence: 15 givenname: Paul B surname: Chapman fullname: Chapman, Paul B organization: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 16 givenname: Rachel surname: Karchin fullname: Karchin, Rachel organization: Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland – sequence: 17 givenname: Nicholas D orcidid: 0000-0002-8254-6925 surname: Socci fullname: Socci, Nicholas D organization: Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 18 givenname: David B surname: Solit fullname: Solit, David B organization: Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 19 givenname: Timothy A surname: Chan fullname: Chan, Timothy A organization: Center for Immunotherapy and Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio – sequence: 20 givenname: Barry S surname: Taylor fullname: Taylor, Barry S organization: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 21 givenname: Suzanne L orcidid: 0000-0002-0821-8587 surname: Topalian fullname: Topalian, Suzanne L email: iacobuzc@mskcc.org, stopali1@jhmi.edu organization: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland – sequence: 22 givenname: Christine A orcidid: 0000-0002-4672-3023 surname: Iacobuzio-Donahue fullname: Iacobuzio-Donahue, Christine A email: iacobuzc@mskcc.org, stopali1@jhmi.edu organization: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York |
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| Snippet | Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of... |
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| SubjectTerms | Biomarkers, Tumor Drug Resistance, Neoplasm - genetics Evolution, Molecular Humans Immunotherapy - methods Melanoma - drug therapy Melanoma - genetics Melanoma - immunology Melanoma - pathology Mutation Prognosis Skin Neoplasms - drug therapy Skin Neoplasms - genetics Skin Neoplasms - immunology Skin Neoplasms - pathology Uveal Neoplasms - drug therapy Uveal Neoplasms - genetics Uveal Neoplasms - immunology Uveal Neoplasms - pathology |
| Title | The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas |
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