小柯机器人

英国伦敦大学学院Nicholas McGranahan等研究人员合作揭示肺癌和转移中的基因组-转录组演变。相关论文于2023年4月12日在线发表于国际学术期刊《自然》。

利用配对的全外显子组和RNA测序数据，研究人员揭示了354个非小细胞肺癌肿瘤的瘤内转录组多样性，这些肿瘤来自TRACERx研究中前瞻性招募的首批421名患者中的347人。对代表原发性和转移性疾病的947个肿瘤区域以及96个与肿瘤相邻的正常组织样本的分析表明，转录组是表型变化的主要来源。基因表达水平和瘤内异质性（ITH）与肿瘤演变过程中的正负选择模式有关。研究人员观察到频繁的与拷贝数无关的等位基因特异性表达，这与表观基因组功能障碍有关。等位基因特异性表达也会导致基因组-转录组的平行演化，从而汇聚到癌症基因的破坏上。

研究人员提取了RNA单碱基替换的特征，并将其病因与RNA编辑酶ADAR和APOBEC3A的活性联系起来，从而揭示了肿瘤中其他未被发现的持续的APOBEC活动。在描述原发-转移性肿瘤对的转录组时，研究人员结合了多种机器学习方法，利用基因组和转录组变量将转移-繁殖潜力与原发肿瘤区域内突变和增殖的演化背景联系起来。这些结果突出了基因组和转录组在影响ITH、肺癌进化和转移中的相互作用。

据悉，ITH助长了肺癌的演变，导致免疫规避和治疗耐受。

附：英文原文

Title: Genomic–transcriptomic evolution in lung cancer and metastasis

Author: Martnez-Ruiz, Carlos, Black, James R. M., Puttick, Clare, Hill, Mark S., Demeulemeester, Jonas, Larose Cadieux, Elizabeth, Thol, Kerstin, Jones, Thomas P., Veeriah, Selvaraju, Naceur-Lombardelli, Cristina, Toncheva, Antonia, Prymas, Paulina, Rowan, Andrew, Ward, Sophia, Cubitt, Laura, Athanasopoulou, Foteini, Pich, Oriol, Karasaki, Takahiro, Moore, David A., Salgado, Roberto, Colliver, Emma, Castignani, Carla, Dietzen, Michelle, Huebner, Ariana, Al Bakir, Maise, Tani, Miljana, Watkins, Thomas B. K., Lim, Emilia L., Al-Rashed, Ali M., Lang, Danny, Clements, James, Cook, Daniel E., Rosenthal, Rachel, Wilson, Gareth A., Frankell, Alexander M., de Carn Trcesson, Sophie, East, Philip, Kanu, Nnennaya, Litchfield, Kevin, Birkbak, Nicolai J., Hackshaw, Allan, Beck, Stephan, Van Loo, Peter, Jamal-Hanjani, Mariam, Swanton, Charles, McGranahan, Nicholas

Issue&Volume: 2023-04-12

Abstract: Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.

DOI: 10.1038/s41586-023-05706-4

Source: https://www.nature.com/articles/s41586-023-05706-4

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html