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.

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.

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.

LSand 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.

JCO precision oncology. 2018 Jan [Epub]

Timothy F Donahu, Aditya Bagrodia, François Audenet, Mark T A Donoghue, Eugene K Cha, John P Sfakianos, Dahlia Sperling, Hikmat Al-Ahmadie, Mark Clendenning, Christophe Rosty, Daniel D Buchanan, Mark Jenkins, John Hopper, Ingrid Winship, Allyson S Templeton, Michael F Walsh, Zsofia K Stadler, Gopa Iyer, Barry Taylor, Jonathan Coleman, Noralane M Lindor, David B Solit, Bernard H Bochner

Memorial Sloan Kettering Cancer Center., University of Texas Southwest Medical Center, Dallas, TX., Mount Sinai Hospital., University of Melbourne, Parkville, Victoria, Australia., Fred Hutchinson Cancer Research Center, Seattle, WA., Mayo Clinic, Scottsdale, AZ.