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

Abstract

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 <i>v</i> 6; IQR, 4-10; <i>P</i> < .001), as was the MSIsensor score (median, 25.1; IQR, 17.9-31.2 <i>v</i> 0.03; IQR, 0-0.44; <i>P</i> < .001). Differences in the genetic landscape were observed between sporadic and LS-associated tumors. Alterations in <i>KMT2D</i>, <i>CREBBP</i>, or <i>ARID1A</i> or in DNA damage response and repair genes were present at a significantly higher frequency in LS-UTUC. <i>CIC</i>, <i>NOTCH1</i>, <i>NOTCH3</i>, <i>RB1</i>, and <i>CDKN1B</i> alterations were almost exclusive to LS-UTUC. Although <i>FGFR3</i> 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 <i>FGFR3</i> R248C mutation. Prospective molecular characterization of patients to identify those with LS-UTUC may help guide treatment.