Genomic characterization of upper-tract urothelial carcinoma in patients with Lynch syndrome Journal Article
| Authors: | Donahue, T. F.; Bagrodia, A.; Audenet, F.; Donoghue, M. T. A.; Cha, E. K.; Sfakianos, J. P.; Sperling, D.; Al-Ahmadie, H.; Clendenning, M.; Rosty, C.; Buchanan, D. D.; Jenkins, M.; Hopper, J.; Winship, I.; Templeton, A. S.; Walsh, M. F.; Stadler, Z. K.; Iyer, G.; Taylor, B.; Coleman, J.; Lindor, N. M.; Solit, D. B.; Bochner, B. H. |
| Article Title: | Genomic characterization of upper-tract urothelial carcinoma in patients with Lynch syndrome |
| Abstract: | 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 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. Conclusion LS-and 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. © 2019 American Society of Clinical Oncology. |
| Keywords: | adult; clinical article; aged; unclassified drug; human cell; somatic mutation; frameshift mutation; dna repair; cohort analysis; fibroblast growth factor receptor 3; protein p53; carcinogenesis; lung metastasis; cyclin dependent kinase inhibitor 1b; mismatch repair; microsatellite instability; breast carcinoma; hamartin; tumor protein; genomics; dna damage response; heterozygosity loss; mutation rate; cyclin dependent kinase inhibitor 2a; transitional cell carcinoma; tongue carcinoma; genomic dna; notch1 receptor; hereditary nonpolyposis colorectal cancer; notch3 receptor; molecular pathology; copy number variation; germline mutation; brg1 protein; crebbp protein; kdm6a protein; human; male; female; priority journal; article; arid1a protein; squamous cell lung carcinoma; rb1 protein; stag2 protein; apolipoprotein b mrna editing enzyme catalytic polypeptide like; pik3ca protein; genetic profile; kmt2d protein; cic protein; fat1 protein; foxp1 protein; kmt2c protein; sporadic transitional cell carcinoma |
| Journal Title: | JCO Precision Oncology |
| Volume: | 2 |
| ISSN: | 2473-4284 |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2018-01-01 |
| Language: | English |
| DOI: | 10.1200/po.17.00143 |
| PROVIDER: | scopus |
| PMCID: | PMC6404976 |
| PUBMED: | 30854504 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2020 -- Source: Scopus |
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