Genomes and epigenomes of matched normal and tumor breast tissue reveal diverse evolutionary trajectories and tumor-host interactions.

IF 8.1 1区 生物学 Q1 GENETICS & HEREDITY American journal of human genetics Pub Date : 2024-10-29 DOI:10.1016/j.ajhg.2024.10.005
Bin Zhu, Avraam Tapinos, Hela Koka, Priscilla Ming Yi Lee, Tongwu Zhang, Wei Zhu, Xiaoyu Wang, Alyssa Klein, DongHyuk Lee, Gary M Tse, Koon-Ho Tsang, Cherry Wu, Min Hua, Chad A Highfill, Petra Lenz, Weiyin Zhou, Difei Wang, Wen Luo, Kristine Jones, Amy Hutchinson, Belynda Hicks, Montserrat Garcia-Closas, Stephen Chanock, Lap Ah Tse, David C Wedge, Xiaohong R Yang
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Abstract

Normal tissues adjacent to the tumor (NATs) may harbor early breast carcinogenesis events driven by field cancerization. Although previous studies have characterized copy-number (CN) and transcriptomic alterations, the evolutionary history of NATs in breast cancer (BC) remains poorly characterized. Utilizing whole-genome sequencing (WGS), methylation profiling, and RNA sequencing (RNA-seq), we analyzed paired germline, NATs, and tumor samples from 43 individuals with BC in Hong Kong (HK). We found that single-nucleotide variants (SNVs) were common in NATs, with one-third of NAT samples exhibiting SNVs in driver genes, many of which were present in paired tumor samples. The most frequently mutated genes in both tumor and NAT samples were PIK3CA, TP53, GATA3, and AKT1. In contrast, large-scale aberrations such as somatic CN alterations (SCNAs) and structural variants (SVs) were rarely detected in NAT samples. We generated phylogenetic trees to investigate the evolutionary history of paired NAT and tumor samples. They could be categorized into tumor only, shared, and multiple-tree groups, the last of which is concordant with non-genetic field cancerization. These groups exhibited distinct genomic and epigenomic characteristics in both NAT and tumor samples. Specifically, NAT samples in the shared-tree group showed higher number of mutations, while NAT samples belonging to the multiple-tree group showed a less inflammatory tumor microenvironment (TME), characterized by a higher proportion of regulatory T cells (Tregs) and lower presence of CD14 cell populations. In summary, our findings highlight the diverse evolutionary history in BC NAT/tumor pairs and the impact of field cancerization and TME in shaping the genomic evolutionary history of tumors.

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匹配的正常和肿瘤乳腺组织的基因组和表观基因组揭示了不同的进化轨迹和肿瘤-宿主相互作用。
与肿瘤相邻的正常组织(NATs)可能蕴藏着由现场癌化驱动的早期乳腺癌发生事件。尽管以前的研究已经描述了拷贝数(CN)和转录组的改变,但对乳腺癌(BC)中NATs的进化史仍然缺乏描述。利用全基因组测序(WGS)、甲基化分析和 RNA 测序(RNA-seq),我们分析了香港 43 名乳腺癌患者的配对种系、NATs 和肿瘤样本。我们发现,单核苷酸变异(SNVs)在NATs中很常见,三分之一的NAT样本显示出驱动基因中的SNVs,其中许多变异出现在配对的肿瘤样本中。肿瘤和 NAT 样本中最常见的突变基因是 PIK3CA、TP53、GATA3 和 AKT1。相比之下,NAT样本中很少检测到体细胞CN改变(SCNA)和结构变异(SV)等大规模畸变。我们生成了系统发生树来研究配对的 NAT 和肿瘤样本的进化史。它们可被分为仅肿瘤组、共享组和多树组,其中最后一组与非基因领域的癌症化是一致的。这些组别在 NAT 和肿瘤样本中都表现出不同的基因组和表观基因组特征。具体来说,共享树组的 NAT 样本突变较多,而多树组的 NAT 样本炎症性肿瘤微环境(TME)较低,调节性 T 细胞(Tregs)比例较高,CD14 细胞群较少。总之,我们的研究结果凸显了BC NAT/肿瘤配对的多样化进化史,以及野外癌化和TME在塑造肿瘤基因组进化史方面的影响。
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来源期刊
CiteScore
14.70
自引率
4.10%
发文量
185
审稿时长
1 months
期刊介绍: The American Journal of Human Genetics (AJHG) is a monthly journal published by Cell Press, chosen by The American Society of Human Genetics (ASHG) as its premier publication starting from January 2008. AJHG represents Cell Press's first society-owned journal, and both ASHG and Cell Press anticipate significant synergies between AJHG content and that of other Cell Press titles.
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