Analysis of the genomic landscape of yolk sac tumors reveals mechanisms of evolution and chemoresistance

Abstract

Yolk sac tumors (YSTs) are a major histological subtype of malignant ovarian germ cell tumors with a relatively poor prognosis. The molecular basis of this disease has not been thoroughly characterized at the genomic level. Here we perform whole-exome and RNA sequencing on 41 clinical tumor samples from 30 YST patients, with distinct responses to cisplatin-based chemotherapy. We show that microsatellite instability status and mutational signatures are informative of chemoresistance. We identify somatic driver candidates, including significantly mutated genesKRASandKITand copy-number alteration drivers, including deletedARID1AandPARK2, and amplifiedZNF217,CDKN1B, andKRAS. YSTs have very infrequentTP53mutations, whereas the tumors from patients with abnormal gonadal development contain bothKRASandTP53mutations. We further reveal a role ofOVOL2overexpression in YST resistance to cisplatin. This study lays a critical foundation for understanding key molecular aberrations in YSTs and developing related therapeutic strategies.