Clinical cancer research : an official journal of the American Association for Cancer Research · 2018
Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Audenet François, Isharwal Sumit, Cha Eugene K, Donoghue Mark T A, Drill Esther N, Ostrovnaya Irina, Pietzak Eugene J, Sfakianos John P, Bagrodia Aditya, Murugan Paari, Dalbagni Guido, Donahue Timothy F, Rosenberg Jonathan E, Bajorin Dean F, Arcila Maria E, Hechtman Jaclyn F, Berger Michael F, Taylor Barry S, Al-Ahmadie Hikmat, Iyer Gopa, Bochner Bernard H, Coleman Jonathan A, Solit David B
Аннотация
PURPOSE: To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors.
EXPERIMENTAL DESIGN: We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness.
RESULTS: With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared with UCB, TP53, RB1, and ERBB2 were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; Q < 0.001), whereas FGFR3 and HRAS were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; Q < 0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in FGFR3, KDM6A, CCND1, and TP53. Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness.
CONCLUSIONS: UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome.
EXPERIMENTAL DESIGN: We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness.
RESULTS: With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared with UCB, TP53, RB1, and ERBB2 were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; Q < 0.001), whereas FGFR3 and HRAS were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; Q < 0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in FGFR3, KDM6A, CCND1, and TP53. Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness.
CONCLUSIONS: UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome.
Предметные рубрики MeSH
AgedBiomarkers, TumorCarcinoma, Transitional CellClone CellsColorectal Neoplasms, Hereditary NonpolyposisFemaleGenetic Predisposition to DiseaseGenomicsHigh-Throughput Nucleotide SequencingHumansMaleMiddle AgedMutationProspective StudiesReceptor, Fibroblast Growth Factor, Type 3Tumor Suppressor Protein p53Urinary BladderUrinary Bladder NeoplasmsUrinary Tract