晚期肾上腺皮质癌的全基因组和转录组分析强调了影响表观基因组和DNA修复途径的多种改变

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2022-04-01 DOI:10.1101/mcs.a006148
J. Lavoie, V. Csizmok, L. Williamson, Luka Culibrk, G. Wang, M. Marra, J. Laskin, Steven J. M. Jones, D. Renouf, C. Kollmannsberger
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引用次数: 3

摘要

肾上腺皮质癌(ACC)是一种罕见的肾上腺癌。在原发性和转移性acc中已经发现了几个驱动突变,但治疗选择仍然有限。我们对7例转移性ACC患者进行了全基因组和转录组测序。进行突变综合分析、RNA表达变化、突变特征和同源重组缺陷(HRD)分析。在我们的队列中观察到影响CTNNB1和TP53的突变和频繁的杂合性丢失(LOH)事件。还观察到影响细胞周期基因(RB1, CDKN2A, CDKN2B), DNA修复途径(MUTYH, BRCA2, ATM, RAD52, MLH1, MSH6)和端粒维持(TERF2和TERT)的改变,包括体细胞和种系突变,结构变异和表达异常值。HRDetect收集了6个与HRD相关的突变特征,确定了一小部分HRD病例。研究还发现了影响表观遗传调控基因的基因组改变,包括结构变异(SWI/SNF基因和组蛋白甲基转移酶)、拷贝增益和KDM5A的同时高表达,这可能有助于表观基因组失调。这项研究的结果强调了HRD和表观基因组通路是潜在的治疗靶点,并表明一亚组患者可能受益于ACC的多种分子靶向治疗,这是一种迫切需要治疗策略的罕见疾病。
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Whole-genome and transcriptome analysis of advanced adrenocortical cancer highlights multiple alterations affecting epigenome and DNA repair pathways
Adrenocortical cancer (ACC) is a rare cancer of the adrenal gland. Several driver mutations have been identified in both primary and metastatic ACCs, but the therapeutic options are still limited. We performed whole-genome and transcriptome sequencing on seven patients with metastatic ACC. Integrative analysis of mutations, RNA expression changes, mutation signature, and homologous recombination deficiency (HRD) analysis was performed. Mutations affecting CTNNB1 and TP53 and frequent loss of heterozygosity (LOH) events were observed in our cohort. Alterations affecting genes involved in cell cycle (RB1, CDKN2A, CDKN2B), DNA repair pathways (MUTYH, BRCA2, ATM, RAD52, MLH1, MSH6), and telomere maintenance (TERF2 and TERT) consisting of somatic and germline mutations, structural variants, and expression outliers were also observed. HRDetect, which aggregates six HRD-associated mutation signatures, identified a subset of cases as HRD. Genomic alterations affecting genes involved in epigenetic regulation were also identified, including structural variants (SWI/SNF genes and histone methyltransferases), and copy gains and concurrent high expression of KDM5A, which may contribute to epigenomic deregulation. Findings from this study highlight HRD and epigenomic pathways as potential therapeutic targets and suggest a subgroup of patients may benefit from a diverse array of molecularly targeted therapies in ACC, a rare disease in urgent need of therapeutic strategies.
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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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