Lawrence Ben, Blenkiron Cherie, Parker Kate, Tsai Peter, Fitzgerald Sandra, Shields Paula, Robb Tamsin, Yeong Mee Ling, Kramer Nicole, James Sarah, Black Mik, Fan Vicky, Poonawala Nooriyah, Yap Patrick, Coats Esther, Woodhouse Braden, Ramsaroop Reena, Yozu Masato, Robinson Bridget, Henare Kimiora, Koea Jonathan, Johnston Peter, Carroll Richard, Connor Saxon, Morrin Helen, Elston Marianne, Jackson Christopher, Reid Papaarangi, Windsor John, MacCormick Andrew, Babor Richard, Bartlett Adam, Damianovich Dragan, Knowlton Nicholas, Grimmond Sean, Findlay Michael, Print Cristin
1Discipline of Oncology, Faculty of Medicine and Health Sciences, University of Auckland, Auckland, New Zealand.
2Maurice Wilkins Centre hosted by the University of Auckland, Auckland, New Zealand.
NPJ Genom Med. 2018 Jul 20;3:18. doi: 10.1038/s41525-018-0058-3. eCollection 2018.
Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic inactivation and generally poor clinical outcome. Another ~40% of patients had pNETs that lacked this recurrent LoH pattern but had chromosome 11 LoH, bi-allelic inactivation, and universally good clinical outcome. The somatic aneuploidy allowed pathogenic germline variants (e.g., ) to be expressed unopposed, with RNA expression patterns showing inactivation of downstream tumor suppressor pathways. No prognostic associations were found with tumor morphology, single gene mutation, or expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. In pNETs, single gene mutations appear to be less important than aneuploidy, with the only statistically significant recurrently mutated driver gene. In addition, only one pNET in the series had clearly actionable single nucleotide variants (SNVs) (in and ) confirmed by corroborating RNA expression changes. The two clinically relevant patterns of LoH described here define a novel oncogenic mechanism and a plausible route to genomic precision oncology for this tumor type.
胰腺神经内分泌肿瘤（pNETs）是起源于胰岛细胞的罕见癌症。在此，我们报告了对57例散发性高分化pNETs的基因突变、拷贝数和RNA表达的分析。pNET基因组以非整倍体为主，导致全染色体和染色体片段水平上RNA表达的一致变化。我们观察到两种不同的体细胞pNET非整倍体模式，它们与肿瘤病理学和患者预后相关。在该系列中，约26%的患者患有pNETs，其基因组特征为10条特定染色体的杂合性反复缺失（LoH），伴有双等位基因失活，临床结果通常较差。另外约40%的患者患有pNETs，其缺乏这种反复LoH模式，但存在11号染色体LoH、双等位基因失活，临床结果普遍良好。体细胞非整倍体使得致病性种系变异（例如）得以不受抑制地表达，RNA表达模式显示下游肿瘤抑制途径失活。未发现肿瘤形态、单基因突变或反映免疫、分化、增殖或肿瘤抑制途径活性的RNA表达与预后相关。在pNETs中，单基因突变似乎不如非整倍体重要，是唯一具有统计学意义的反复突变驱动基因。此外，该系列中只有一个pNET具有经RNA表达变化证实的明确可操作的单核苷酸变异（SNV）（在和中）。这里描述的两种与临床相关的LoH模式定义了一种新的致癌机制以及针对这种肿瘤类型的基因组精准肿瘤学的合理途径。
