TY - JOUR
T1 - Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma
AU - Audenet, François
AU - Isharwal, Sumit
AU - Cha, Eugene K.
AU - Donoghue, Mark T.A.
AU - Drill, Esther N.
AU - Ostrovnaya, Irina
AU - Pietzak, Eugene J.
AU - Sfakianos, John P.
AU - Bagrodia, Aditya
AU - Murugan, Paari
AU - Dalbagni, Guido
AU - Donahue, Timothy F.
AU - Rosenberg, Jonathan E.
AU - Bajorin, Dean F.
AU - Arcila, Maria E.
AU - Hechtman, Jaclyn F.
AU - Berger, Michael F.
AU - Taylor, Barry S.
AU - Al-Ahmadie, Hikmat
AU - Iyer, Gopa
AU - Bochner, Bernard H.
AU - Coleman, Jonathan A.
AU - Solit, David B.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-18-2039
DO - 10.1158/1078-0432.CCR-18-2039
M3 - Article
C2 - 30352907
AN - SCOPUS:85060149623
SN - 1078-0432
VL - 25
SP - 967
EP - 976
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -