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

Xuan Zong,Hongyue Li,Ying Zhang,Jinhui Wang,Jiaxin Yang,Xinxin Peng,Han Liang,Xuejiao Guo,Dongyan Cao,Mei Yu

doi:10.1038/s41467-021-23681-0

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 genes KRAS and KIT and copy-number alteration drivers, including deleted ARID1A and PARK2, and amplified ZNF217, CDKN1B, and KRAS. YSTs have very infrequent TP53 mutations, whereas the tumors from patients with abnormal gonadal development contain both KRAS and TP53 mutations. We further reveal a role of OVOL2 overexpression in YST resistance to cisplatin. This study lays a critical foundation for understanding key molecular aberrations in YSTs and developing related therapeutic strategies.

Highlights

Yolk sac tumors (YSTs) are a major histological subtype of malignant ovarian germ cell tumors with a relatively poor prognosis
Focusing on a set of well-established somatic copy-number alterations (SCNAs) driver genes[25], we found that ARID1A and PARK2 were the most frequently deleted genes, whereas ZNF217, CDKN1B, and KRAS were amongst the most frequent amplifications (Fig. 3D)
We found that OVOL2 was a top candidate; this gene showed a significantly higher expression level in relapsed tumors than in sensitive tumors (Fig. 6C), and a high expression of OVOL2 was associated with cisplatin resistance in cancer cell lines of different lineages (Wilcoxon rank-sum test, p = 4.8 × 10−9, Fig. 6D), and in ovarian cancer cell lines (Wilcoxon rank-sum test, p = 6.7 × 10−3, Fig. 6E)

Summary

Introduction

Yolk sac tumors (YSTs) are a major histological subtype of malignant ovarian germ cell tumors with a relatively poor prognosis. We perform whole-exome and RNA sequencing on 41 clinical tumor samples from 30 YST patients, with distinct responses to cisplatin-based chemotherapy. Similar to other MOGCTs, the standard management for patients with YST is surgery, followed by adequate cisplatin-based chemotherapy. It is clinically important to elucidate the molecular mechanisms associated with the YST resistance to chemotherapy. The genomic landscape, evolutionary pattern, and chemoresistance-related mechanisms of this disease are largely unknown, resulting in a critical knowledge gap for developing diagnostic, prognostic, and therapeutic strategies. We perform whole-exome and RNA-sequencing on a large collection of clinical YST samples to systematically identify molecular drivers and key features related to chemoresistance in this disease

Methods

Results

Conclusion