Ciani Yari, Fedrizzi Tarcisio, Prandi Davide, Lorenzin Francesca, Locallo Alessio, Gasperini Paola, Franceschini Gian Marco, Benelli Matteo, Elemento Olivier, Fava Luca L, Inga Alberto, Demichelis Francesca
Department of Cellular, Computational and Integrative Biology, University of Trento, 38123 Trento, Italy.
Department of Cellular, Computational and Integrative Biology, University of Trento, 38123 Trento, Italy; Bioinformatics Unit, Hospital of Prato, 59100 Prato, Italy.
Cell Syst. 2022 Feb 16;13(2):183-193.e7. doi: 10.1016/j.cels.2021.10.001. Epub 2021 Nov 2.
Pan-cancer studies sketched the genomic landscape of the tumor types spectrum. We delineated the purity- and ploidy-adjusted allele-specific profiles of 4,950 patients across 27 tumor types from the Cancer Genome Atlas (TCGA). Leveraging allele-specific data, we reclassified as loss of heterozygosity (LOH) 9% and 7% of apparent copy-number wild-type and gain calls, respectively, and overall observed more than 18 million allelic imbalance somatic events at the gene level. Reclassification of copy-number events revealed associations between driver mutations and LOH, pointing out the timings between the occurrence of point mutations and copy-number events. Integrating allele-specific genomics and matched transcriptomics, we observed that allele-specific gene status is relevant in the regulation of TP53 and its targets. Further, we disclosed the role of copy-neutral LOH in the impairment of tumor suppressor genes and in disease progression. Our results highlight the role of LOH in cancer and contribute to the understanding of tumor progression.
泛癌研究勾勒出了肿瘤类型谱的基因组格局。我们描绘了来自癌症基因组图谱（TCGA）的27种肿瘤类型中4950名患者经纯度和倍性调整后的等位基因特异性图谱。利用等位基因特异性数据，我们分别将9%的表观拷贝数野生型和7%的增益调用重新分类为杂合性缺失（LOH），并且在基因水平上总体观察到超过1800万个等位基因不平衡体细胞事件。拷贝数事件的重新分类揭示了驱动突变与LOH之间的关联，指出了点突变与拷贝数事件发生之间的时间关系。整合等位基因特异性基因组学和匹配的转录组学，我们观察到等位基因特异性基因状态在TP53及其靶标的调控中具有相关性。此外，我们揭示了拷贝中性LOH在肿瘤抑制基因损伤和疾病进展中的作用。我们的结果突出了LOH在癌症中的作用，并有助于理解肿瘤进展。
