Genotype-phenotype landscape of pituitary adrenocorticotroph hormone adenoma
10.3760/cma.j.cn311282-20210520-00315
- VernacularTitle:垂体促肾上腺皮质激素腺瘤基因型与临床表型的相关性研究
- Author:
Hui MIAO
1
;
Luo WANG
;
Fengying GONG
;
Lian DUAN
;
Linjie WANG
;
Yong YAO
;
Ming FENG
;
Kan DENG
;
Renzhi WANG
;
Yanfang GUAN
;
Huijuan ZHU
;
Lin LU
Author Information
1. 中国医学科学院，北京协和医学院，北京协和医院内分泌科，卫健委内分泌重点实验室，疑难重症及罕见病国家重点实验室，协和转化医学中心 100730
- Keywords:
Pituitary adenomas;
ACTH;
Whole genome sequencing;
USP8
- From:
Chinese Journal of Endocrinology and Metabolism
2022;38(2):125-131
- CountryChina
- Language:Chinese
-
Abstract:
Objective:Cushing′s disease(CD) is caused by the pituitary adrenocorticotroph hormone(ACTH) secreting adenomas, leading to increased serum cortisol levels and various abnormal metabolic processes. Untreated CD is linked to high mortality, thus it is critical to elucidate its pathogenesis. This study aims to explore the pathogenesis of pituitary ACTH adenomas using whole-genome sequencing analysis.Methods:Fresh tumor tissues and peripheral blood samples were collected in 9 confirmed cases of pituitary ACTH adenomas who underwent surgery. Whole genome sequencing was then performed, followed by analysis and verification of single nucleotide mutations, copy number variation(CNV) and chromosome structure variations.Results:Somatic USP8 mutations(p.Ser718del, p. Ser718Pro, p. Pro720Arg, p. Pro720Gln) were found in 5 patients, with a rate of 55.6%; CNV of USP8 was detected in 1 patient; TP53(p.Cys135Tyr), NF1(p.Val1049Glufs*11) and KMT2C(c.3323+ 1G>A) mutations were identified in 1 patient harboring wild-type USP8. CNV analysis showed a loss of heterozygosity in multiple chromosomes in a wild-type USP8 patient. Structural variations were found in 2 with unknown significance. No germline gene mutations were detected in this study.Conclusion:Somatic USP8 mutations, increased copy number of USP8, variations of tumor-related genes such as TP53 and extensive somatic CNV all contribute to pathogenesis of CD. Chromosomal structure variations may suggest high-risk pituitary ACTH adenomas, and call for frequent follow-up and aggressive treatment.
