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 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 6; IQR, 4-10; < .001), as was the MSIsensor score (median, 25.1; IQR, 17.9-31.2 0.03; IQR, 0-0.44; < .001). Differences in the genetic landscape were observed between sporadic and LS-associated tumors. Alterations in , , or or in DNA damage response and repair genes were present at a significantly higher frequency in LS-UTUC. , , , , and alterations were almost exclusive to LS-UTUC. Although mutations were identified in both cohorts, the R248C hotspot mutation was highly enriched in LS-UTUC.

CONCLUSION

LSand sporadic UTUCs have overlapping but distinct genetic signatures. LS-UTUC is associated with hypermutation and a significantly higher prevalence of R248C mutation. Prospective molecular characterization of patients to identify those with LS-UTUC may help guide treatment.