Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
Department of Cancer Pathomorphology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
J Transl Med. 2024 Nov 4;22(1):994. doi: 10.1186/s12967-024-05736-0.
Somatotroph neuroendocrine pituitary tumors (sPitNET) are a subtype of pituitary tumors that commonly cause acromegaly. Our study aimed to determine the spectrum of DNA copy number abnormalities (CNAs) in sPitNETs and their relevance.
A landscape of CNAs in sPitNETs was determined using combined whole-genome approaches involving low-pass whole genome sequencing and SNP microarrays. Fluorescent in situ hybridization (FISH) was used for microscopic validation of CNAs. The tumors were also subjected to transcriptome and DNA methylation analyses with RNAseq and microarrays, respectively.
We observed a wide spectrum of cytogenetic changes ranging from multiple deletions, recurrent chromosome 11 loss, stable genomes, to duplication of the majority of the chromosomes. The identified CNAs were confirmed with FISH. sPitNETs with multiple duplications were characterized by intratumoral heterogeneity in chromosome number variation in individual tumor cells, as determined with FISH. These tumors were separate CNA-related sPitNET subtype in clustering analyses with CNA signature specific for whole genome doubling-related etiology. This subtype encompassed GNAS-wild type, mostly densely granulated tumors with favorable expression level of known prognosis-related genes, notably enriched with POUF1/NR5A1-double positive PitNETs. Chromosomal deletions in sPitNETs are functionally relevant. They occurred in gene-dense DNA regions and were related to genes downregulation and increased DNA methylation in the CpG island and promoter regions in the affected regions. Recurrent loss of chromosome 11 was reflected by lowered MEN1 and AIP. No such unequivocal relevance was found for chromosomal gains. Comparisons of transcriptomes of selected most cytogenetically stable sPitNETs with tumors with recurrent loss of chromosome 11 showed upregulation of processes related to gene dosage compensation mechanism in tumors with deletion. Comparison of stable tumors with those with multiple duplications showed upregulation of processes related to mitotic spindle, DNA repair, and chromatin organization. Both comparisons showed upregulation of the processes related to immune infiltration in cytogenetically stable tumors and deconvolution of DNA methylation data indicated a higher content of specified immune cells and lower tumor purity in these tumors.
sPitNETs fall into three relevant cytogenetic groups: highly aneuploid tumors characterized by known prognostically favorable features and low aneuploidy tumors including specific subtype with chromosome 11 loss.
生长激素细胞神经内分泌垂体肿瘤（sPitNET）是一种常见引起肢端肥大症的垂体肿瘤亚型。我们的研究旨在确定 sPitNET 中 DNA 拷贝数异常（CNAs）的图谱及其相关性。
采用低通全基因组测序和 SNP 微阵列相结合的全基因组方法，确定 sPitNET 中的 CNA 图谱。使用荧光原位杂交（FISH）对 CNA 进行微观验证。肿瘤还分别进行了转录组和 DNA 甲基化分析，分别使用 RNAseq 和微阵列。
我们观察到广泛的细胞遗传学变化，从多个缺失、染色体 11 反复丢失、稳定的基因组到大多数染色体的重复。用 FISH 验证了所鉴定的 CNA。用 FISH 检测到，具有多个重复的 sPitNET 肿瘤细胞内存在肿瘤内染色体数目变异的异质性。这些肿瘤在聚类分析中是单独的与 CNA 相关的 sPitNET 亚型，具有全基因组倍增相关病因的 CNA 特征。这种亚型包含 GNAS 野生型，主要是密集颗粒状肿瘤，具有已知预后相关基因的有利表达水平，特别是富含 POUF1/NR5A1-双阳性 PitNET。sPitNET 中的染色体缺失具有功能相关性。它们发生在基因密集的 DNA 区域，与受影响区域中基因下调和 CpG 岛和启动子区域的 DNA 甲基化增加有关。染色体 11 的反复丢失反映了 MEN1 和 AIP 的降低。对于染色体获得，没有发现如此明确的相关性。对选定的大多数细胞遗传学稳定的 sPitNET 肿瘤与反复染色体 11 缺失的肿瘤进行转录组比较显示，缺失肿瘤中与基因剂量补偿机制相关的过程上调。稳定肿瘤与多个重复肿瘤的比较显示，有丝分裂纺锤体、DNA 修复和染色质组织相关过程上调。这两个比较都显示出细胞遗传学稳定肿瘤中与免疫浸润相关的过程上调，并且去卷积 DNA 甲基化数据表明这些肿瘤中特定免疫细胞含量较高，肿瘤纯度较低。
sPitNET 分为三个相关的细胞遗传学组：以已知预后良好特征为特征的高度非整倍体肿瘤和包括具有染色体 11 缺失的特定亚型的低度非整倍体肿瘤。
