Synapse - RAS/MAPK pathway driver alterations are significantly associated with oncogenic KIT mutations in germ-cell tumors

RAS/MAPK pathway driver alterations are significantly associated with oncogenic KIT mutations in germ-cell tumors Journal Article

Authors:	Mata, D. A.; Yang, S. R.; Ferguson, D. C.; Liu, Y.; Sharma, R.; Benhamida, J. K.; Al-Ahmadie, H. A.; Chakravarty, D.; Solit, D. B.; Tickoo, S. K.; Gupta, S.; Arcila, M. E.; Ladanyi, M.; Feldman, D. R.; Reuter, V. E.; Vanderbilt, C. M.
Article Title:	RAS/MAPK pathway driver alterations are significantly associated with oncogenic KIT mutations in germ-cell tumors
Abstract:	Objective: To report the mutational profile and clinical outcomes of a cohort of patients with KIT-mutant seminomas and nonseminomatous germ-cell tumors (SGCT/NSGCTs). Patients and Methods: Retrospective cohort study of all patients with KIT-mutant GCTs sequenced at Memorial Sloan Kettering between March 2014 and March 2020. Tumors were assessed with MSK-IMPACT, a DNA next-generation sequencing assay for targeted sequencing of up to 468 key cancer genes. Results: Among 568 patients with GCTs, 8.1% had somatic KIT mutations, including 28 seminomas and 18 mixed/NSGCTs. Exons 17 (67.3%), 11 (22.4%), and 13 (6.1%) were most commonly affected. KIT-mutant cases were enriched for oncogenic RAS/MAPK pathway alterations compared to KIT-wildtype cases (34.8% vs 19.2%, P =.02). Among KIT-mutant cases, concurrent mutations were noted in KRAS (21.7%), RRAS2 (11.8%), CBL (6.5%), NRAS (4.3%), MAP2K1 (2.2%), and RAC1 (2.2%). Mutations in KRAS, RRAS2, and NRAS were mutually exclusive. In all, 73.9% of patients developed metastases and 95.7% received chemotherapy. No patients received KIT-directed tyrosine kinase inhibitors (TKIs). Classification as a NSGCT rather than a SGCT was associated with an increased risk of death (hazard ratio 9.1, 95% confidence interval 1.1-78.4, P =.04) while the presence of a concurrent RAS/MAPK pathway alteration was not (hazard ratio 0.8, 95% confidence interval 0.1-4.3, P =.76). Conclusion: Mitogenic driver alterations can co-occur with activating KIT mutations, which may explain the lack of efficacy of KIT-directed TKIs in prior trials. Novel KIT-directed TKIs that target exon 17 mutations may benefit chemotherapy-refractory patients with KIT-mutant GCTs without RAS/MAPK alterations. Dual MEK/KIT inhibitor therapy in KIT-mutant GCTs with concurrent RAS/MAPK alterations could also be a plausible therapeutic strategy. © 2020 Elsevier Inc.
Keywords:	mitogen activated protein kinase; adolescent; adult; cancer chemotherapy; child; human tissue; gene mutation; major clinical study; somatic mutation; exon; gene; stem cell factor receptor; metastasis; cohort analysis; retrospective study; wild type; risk factor; protein tyrosine kinase inhibitor; ras protein; oncogene k ras; cbl protein; germ cell tumor; tumor classification; yolk sac tumor; non seminomatous germinoma; mutant; kit gene; oncogene n ras; clinical outcome; rac1 protein; map2k1 gene; human; male; female; priority journal; article; cbl gene; cobimetinib; atezolizumab; mortality risk; rac1 gene; rras2 gene; seminomatous germinoma
Journal Title:	Urology
Volume:	144
ISSN:	0090-4295
Publisher:	Elsevier Science, Inc.
Date Published:	2020-10-01
Start Page:	111
End Page:	116
Language:	English
DOI:	10.1016/j.urology.2020.07.027
PUBMED:	32721511
PROVIDER:	scopus
PMCID:	PMC8276690
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85089355815&doi=10.1016%2fj.urology.2020.07.027&partnerID=40&md5=9e81b8fbb282b4adeec72d4cd3cf44ec
Notes:	Article -- Export Date: 2 November 2020 -- Source: Scopus