Driver mutations associated with signatures of platinum sensitivity in germ cell tumors

Yun Cheng Sawa; Liwei Jia; Harris Krause; Margaret Meagher; Frederick Millard; Andrew Elliott; John T Lafin; Christina Jamieson; Emmanuel S Antonarakis; Anishka D'Souza; Krinio Giannikou; James F Amatruda; Siamak Daneshmand; Rana R McKay; Matthew Oberley; Chadi Nabhan; Aditya Bagrodia

doi:10.1038/s41698-024-00727-2

Driver mutations associated with signatures of platinum sensitivity in germ cell tumors

NPJ Precis Oncol. 2024 Nov 2;8(1):249. doi: 10.1038/s41698-024-00727-2.

Authors

Yun Cheng Sawa¹, Liwei Jia², Harris Krause³, Margaret Meagher¹, Frederick Millard¹, Andrew Elliott³, John T Lafin², Christina Jamieson¹, Emmanuel S Antonarakis⁴, Anishka D'Souza⁵, Krinio Giannikou⁵, James F Amatruda^{5

6}, Siamak Daneshmand⁵, Rana R McKay^{1

7}, Matthew Oberley³, Chadi Nabhan³, Aditya Bagrodia^{8

9}

Affiliations

¹ Department of Urology, University of California San Diego, La Jolla, CA, USA.
² Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
³ Caris Life Sciences, Irving, TX, USA.
⁴ University of Minnesota, Minneapolis, MN, USA.
⁵ Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
⁶ Departments of Paediatrics and Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷ Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁸ Department of Urology, University of California San Diego, La Jolla, CA, USA. Bagrodia@health.ucsd.edu.
⁹ Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Bagrodia@health.ucsd.edu.

Abstract

We sought to evaluate the genomic and transcriptomic landscapes in primary and metastatic germ cell tumors (GCTs; N = 138) to uncover factors that drive cisplatin resistance. Prevalence was calculated for platinum-resistant alterations (PRAs; KRAS, TP53, and KIT mutations, and MDM2 amplification) and high copy number amplifications (CNA ≥ 6 copies). Tumors were designated as chemo-naïve (PreC, N = 66) or post-chemotherapy (PostC, N = 17). A transcriptomic signature associated with platinum sensitivity (PSS, high suggests increased sensitivity) was applied. KIT mutations were observed in 14.5% of primary versus 1.8% of met and 0% of lymph. TP53 mutations were identified in 10% of primary GCTs versus 17% of met and 16.7% of lymph. MDM2 CNAs were similar between sites. PRA-positive PreC GCTs had significantly lower average PSS scores compared to PRA-negative tumors. Lower PSS scores in chemo-naïve tumors were associated with PRAs, suggesting a potential mechanism for platinum resistance.