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Genomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome

PURPOSE: Patients with Lynch syndrome (LS) have a significantly increased risk of developing upper-tract urothelial carcinoma (UTUC). Here, we sought to identify differences in the patterns of mutational changes in LS-associated versus sporadic UTUCs. PATIENTS AND METHODS: We performed targeted sequ...

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Autores principales: Donahue, Timothy F., Bagrodia, Aditya, Audenet, François, Donoghue, Mark T.A., Cha, Eugene K., Sfakianos, John P., Sperling, Dahlia, Al-Ahmadie, Hikmat, Clendenning, Mark, Rosty, Christophe, Buchanan, Daniel D., Jenkins, Mark, Hopper, John, Winship, Ingrid, Templeton, Allyson S., Walsh, Michael F., Stadler, Zsofia K., Iyer, Gopa, Taylor, Barry, Coleman, Jonathan, Lindor, Noralane M., Solit, David B., Bochner, Bernard H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Clinical Oncology 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404976/
https://www.ncbi.nlm.nih.gov/pubmed/30854504
http://dx.doi.org/10.1200/PO.17.00143
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author Donahue, Timothy F.
Bagrodia, Aditya
Audenet, François
Donoghue, Mark T.A.
Cha, Eugene K.
Sfakianos, John P.
Sperling, Dahlia
Al-Ahmadie, Hikmat
Clendenning, Mark
Rosty, Christophe
Buchanan, Daniel D.
Jenkins, Mark
Hopper, John
Winship, Ingrid
Templeton, Allyson S.
Walsh, Michael F.
Stadler, Zsofia K.
Iyer, Gopa
Taylor, Barry
Coleman, Jonathan
Lindor, Noralane M.
Solit, David B.
Bochner, Bernard H.
author_facet Donahue, Timothy F.
Bagrodia, Aditya
Audenet, François
Donoghue, Mark T.A.
Cha, Eugene K.
Sfakianos, John P.
Sperling, Dahlia
Al-Ahmadie, Hikmat
Clendenning, Mark
Rosty, Christophe
Buchanan, Daniel D.
Jenkins, Mark
Hopper, John
Winship, Ingrid
Templeton, Allyson S.
Walsh, Michael F.
Stadler, Zsofia K.
Iyer, Gopa
Taylor, Barry
Coleman, Jonathan
Lindor, Noralane M.
Solit, David B.
Bochner, Bernard H.
author_sort Donahue, Timothy F.
collection PubMed
description PURPOSE: Patients with Lynch syndrome (LS) have a significantly increased risk of developing upper-tract urothelial carcinoma (UTUC). Here, we sought to identify differences in the patterns of mutational changes in LS-associated versus sporadic UTUCs. PATIENTS AND METHODS: We performed targeted sequencing of 17 UTUCs from patients with documented LS-associated germline mutations (LS-UTUCs) using the Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets targeted exon capture assay and compared the results with those from a recently characterized cohort of 82 patients with sporadic UTUC. RESULTS: Patients with LS-UTUC were significantly younger, had had less exposure to tobacco, and more often presented with a ureteral primary site compared with patients with sporadic UTUC. The median number of mutations per tumor was significantly greater in LS-UTUC tumors than in tumors from the sporadic cohort (58; interquartile range [IQR], 47-101 v 6; IQR, 4-10; P < .001), as was the MSIsensor score (median, 25.1; IQR, 17.9-31.2 v 0.03; IQR, 0-0.44; P < .001). Differences in the genetic landscape were observed between sporadic and LS-associated tumors. Alterations in KMT2D, CREBBP, or ARID1A or in DNA damage response and repair genes were present at a significantly higher frequency in LS-UTUC. CIC, NOTCH1, NOTCH3, RB1, and CDKN1B alterations were almost exclusive to LS-UTUC. Although FGFR3 mutations were identified in both cohorts, the R248C hotspot mutation was highly enriched in LS-UTUC. CONCLUSION: LS- and sporadic UTUCs have overlapping but distinct genetic signatures. LS-UTUC is associated with hypermutation and a significantly higher prevalence of FGFR3 R248C mutation. Prospective molecular characterization of patients to identify those with LS-UTUC may help guide treatment.
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spelling pubmed-64049762019-03-07 Genomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome Donahue, Timothy F. Bagrodia, Aditya Audenet, François Donoghue, Mark T.A. Cha, Eugene K. Sfakianos, John P. Sperling, Dahlia Al-Ahmadie, Hikmat Clendenning, Mark Rosty, Christophe Buchanan, Daniel D. Jenkins, Mark Hopper, John Winship, Ingrid Templeton, Allyson S. Walsh, Michael F. Stadler, Zsofia K. Iyer, Gopa Taylor, Barry Coleman, Jonathan Lindor, Noralane M. Solit, David B. Bochner, Bernard H. JCO Precis Oncol Original Reports PURPOSE: Patients with Lynch syndrome (LS) have a significantly increased risk of developing upper-tract urothelial carcinoma (UTUC). Here, we sought to identify differences in the patterns of mutational changes in LS-associated versus sporadic UTUCs. PATIENTS AND METHODS: We performed targeted sequencing of 17 UTUCs from patients with documented LS-associated germline mutations (LS-UTUCs) using the Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets targeted exon capture assay and compared the results with those from a recently characterized cohort of 82 patients with sporadic UTUC. RESULTS: Patients with LS-UTUC were significantly younger, had had less exposure to tobacco, and more often presented with a ureteral primary site compared with patients with sporadic UTUC. The median number of mutations per tumor was significantly greater in LS-UTUC tumors than in tumors from the sporadic cohort (58; interquartile range [IQR], 47-101 v 6; IQR, 4-10; P < .001), as was the MSIsensor score (median, 25.1; IQR, 17.9-31.2 v 0.03; IQR, 0-0.44; P < .001). Differences in the genetic landscape were observed between sporadic and LS-associated tumors. Alterations in KMT2D, CREBBP, or ARID1A or in DNA damage response and repair genes were present at a significantly higher frequency in LS-UTUC. CIC, NOTCH1, NOTCH3, RB1, and CDKN1B alterations were almost exclusive to LS-UTUC. Although FGFR3 mutations were identified in both cohorts, the R248C hotspot mutation was highly enriched in LS-UTUC. CONCLUSION: LS- and sporadic UTUCs have overlapping but distinct genetic signatures. LS-UTUC is associated with hypermutation and a significantly higher prevalence of FGFR3 R248C mutation. Prospective molecular characterization of patients to identify those with LS-UTUC may help guide treatment. American Society of Clinical Oncology 2018-01-23 /pmc/articles/PMC6404976/ /pubmed/30854504 http://dx.doi.org/10.1200/PO.17.00143 Text en © 2018 by American Society of Clinical Oncology http://creativecommons.org/licenses/by/4.0/ Licensed under the Creative Commons Attribution 4.0 License: http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Reports
Donahue, Timothy F.
Bagrodia, Aditya
Audenet, François
Donoghue, Mark T.A.
Cha, Eugene K.
Sfakianos, John P.
Sperling, Dahlia
Al-Ahmadie, Hikmat
Clendenning, Mark
Rosty, Christophe
Buchanan, Daniel D.
Jenkins, Mark
Hopper, John
Winship, Ingrid
Templeton, Allyson S.
Walsh, Michael F.
Stadler, Zsofia K.
Iyer, Gopa
Taylor, Barry
Coleman, Jonathan
Lindor, Noralane M.
Solit, David B.
Bochner, Bernard H.
Genomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome
title Genomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome
title_full Genomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome
title_fullStr Genomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome
title_full_unstemmed Genomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome
title_short Genomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome
title_sort genomic characterization of upper-tract urothelial carcinoma in patients with lynch syndrome
topic Original Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404976/
https://www.ncbi.nlm.nih.gov/pubmed/30854504
http://dx.doi.org/10.1200/PO.17.00143
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