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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 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.

SUBMITTER: Zong X

PROVIDER: S-EPMC8196104 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Zong Xuan X Zhang Ying Y Peng Xinxin X Cao Dongyan D Yu Mei M Wang Jinhui J Li Hongyue H Guo Xuejiao X Liang Han H Yang Jiaxin J

Nature communications 20210611 1

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 ...[more]

PMID: 34117242

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Project description:ObjectivesYolk sac tumors (YSTs) are rare and highly malignant ovarian malignancies that have a very poor prognosis. The aim of this study is to delineate the ultrasound and clinicopathological features of female pelvic YSTs to better understand the disease.MethodsThis study was a retrospective analysis of the clinicopathological and ultrasound imaging data from 16 YST patients who received treatment at our hospital between January 2012 and August 2023. Then, the ultrasound imaging characteristics were compared with pathological findings.ResultsAmong the 16 patients, various degrees of serum AFP increase were observed, and CA125 levels increased in 58.33% (7 out of 12) of patients. Thirteen patients (81.25%) had tumors located in ovary, two patients (12.5%) had tumors located in the sacrococcygeal region, and one patient (6.25%) had tumors located in the mesentery. Pathologically, nine patients presented with simple yolk sac tumors and seven with mixed germ cell tumors. According to the ultrasound manifestations, YST lesions can be classified into three types. (1) the cystic type, was diagnosed in two patients who presented with a large cystic mass with regular morphology and clear boundary and dense liquid within the cyst; and (2) the cystic-solid mixed type, was diagnosed in 4 patients. On 2D ultrasound, the lesions showed a cystic-solid mixed echo, and color Doppler showed a rich blood flow signal in the solid region and cystic separation. made up of four cases. (3) In ten patients with the solid type, 2D ultrasound showed solid uniform echoes with clear boundaries. The "fissure sign" was observed in the lesion. Color Doppler displayed rich blood flow in the solid part, and PW showed low to moderate resistance index of artery (RI:0.21-0.63). On contrast-enhanced ultrasound (CEUS), rapid and high enhancement in the solid part and cystic separation was observed in 2 patients.ConclusionsCombining ultrasound features with clinical information and tumor markers provides reliable clues for the diagnosis of YST. The application of two-dimensional ultrasound and CEUS combined with patient tumor marker levels can provide a robust reference for determining the necessity of fertility-preserving surgery and postoperative chemotherapy, which can improve clinical decision-making and patient consultation.

Project description:BackgroundThe yolk sac (YS) is an extra-embryonic tissue that surrounds the yolk and absorbs, digests and transports nutrients during incubation of the avian embryo as well as during early term mammalian embryonic development. Understanding YS functions and development may enhance the efficient transfer of nutrients and optimize embryo development. To identify temporal large-scale patterns of gene expression and gain insights into processes and mechanisms in the YS, we performed a transcriptome study of the YS of chick embryos on embryonic days (E) E13, E15, E17, E19, and E21 (hatch).Results3547 genes exhibited a significantly changed expression across days. Clustering and functional annotation of these genes as well as histological sectioning of the YS revealed that we monitored two cell types: the epithelial cells and the erythropoietic cells of the YS. We observed a significant up-regulation of epithelial genes involved in lipid transport and metabolism between E13 and E19. YS epithelial cells expressed a vast array of lipoprotein receptors and fatty acid transporters. Several lysosomal genes (CTSA, PSAP, NPC2) and apolipoproteins genes (apoA1, A2, B, C3) were among the highest expressed, reflecting the intensive digestion and re-synthesis of lipoproteins in YS epithelial cells. Genes associated with cytoskeletal structure were down-regulated between E17 and E21 supporting histological evidence of a degradation of YS epithelial cells towards hatch. Expression patterns of hemoglobin synthesis genes indicated a high erythropoietic capacity of the YS between E13 and E15, which decreased towards hatch. YS histological sections confirmed these results. We also observed that YS epithelial cells expressed high levels of genes coding for plasma carrier proteins (ALB, AFP, LTF, TTR), normally produced by the liver.ConclusionsHere we expand current knowledge on developmental, nutritional and molecular processes in the YS. We demonstrate that in the final week of chick embryonic development, the YS plays different roles to support or replace the functions of several organs that have not yet reached their full functional capacity. The YS has a similar functional role as the intestine in digestion and transport of nutrients, the liver in producing plasma carrier proteins and coagulation factors, and the bone marrow in synthesis of blood cells.

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

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

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