PO.MCB05.01 · 分子与细胞生物学
Li-Fraumeni综合征乳腺癌中独特的基因组重塑
Distinct genomic remodeling in Li Fraumeni Syndrome breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：TP53的致病性胚系变异（PGVs）可引起Li-Fraumeni综合征（LFS），这是一种遗传性多癌易感综合征。在患有LFS的女性中，乳腺癌（BC）是最常见的恶性肿瘤，影响80-90%的携带者，通常发病年龄远早于散发病例，且常表现为HER2阳性。有趣的是，LFS-BC表现出高负荷的短片段扩增性非整倍体节段（SAAS），提示胚系TP53缺失可能通过尚不明确的独特基因组机制驱动肿瘤发生。
方法：为阐明这些独特基因组特征背后的基因型-表型关联，我们对LFS个体的浸润性导管癌（IDC）、导管原位癌（DCIS）以及配对的邻近和对侧正常乳腺组织进行了全基因组测序（WGS）和靶向测序。数据与早发性非LFS-BC以及携带野生型或体细胞TP53突变的癌症基因组图谱（TCGA）肿瘤进行了比较。
结果：在各激素受体（HR）亚型中，如预期所见，三阴性相较于ER+非LFS-BC出现基因组不稳定性升高。然而，LFS-BC的总体不稳定性指标相似或更低。具体而言，在ER+肿瘤中，LFS-BC的微卫星不稳定性（MSI）和非整倍体评分显著低于非LFS-BC。相比之下，LFS-BC表现出节段性等位基因失衡（AI）的显著增加，并伴有高水平扩增——尤其是在HER2+亚型中。这些扩增区域显著短于非LFS-BC中的区域，并常包含如ERBB2等癌基因，定义了一种独特的SAAS表型。与TCGA中散发性TP53突变型乳腺癌（表现为全局性非整倍体和HRD升高）不同，LFS-BC独特地积累了局灶性短扩增。对LFS的DCIS和浸润性肿瘤进行WGS，揭示了以染色体不稳定性（CN9）和染色体碎裂（CN5）拷贝数特征为主，全基因组加倍极少。Amplicon Architect分析在19个肿瘤中的14个中鉴定出ecDNA结构，包括在3/6的DCIS和5/9的HER2+ IDC中含ERBB2的ecDNA，两类中每例分别含4个和8个ecDNA结构。我们的研究与既往报道一致，即约23%的乳腺癌以及高达46%的HER2+病例中存在ecDNA。
结论：LFS相关乳腺癌以一种独特的基因组重塑模式为特征，表现为短的非整倍体扩增节段（SAAS）内的局灶性高水平扩增及频繁的ecDNA形成。这些特征使LFS-BC区别于散发性TP53突变型肿瘤，并凸显了一种由胚系TP53驱动的癌基因扩增和结构性基因组演化机制。
查看英文原文 English abstract
Background: Pathogenic germline variants (PGVs) in TP53 cause Li-Fraumeni Syndrome (LFS), a hereditary multicancer predisposition syndrome. Among females with LFS, breast cancer (BC) is the most prevalent malignancy, affecting 80-90% of carriers, typically at a much earlier age than sporadic cases and frequently exhibiting HER2 positivity. Interestingly, LFS-BC displays a high burden of short- amplified segments of aneuploidy (SAAS), suggesting that germline TP53 loss may drive tumorigenesis through distinct genomic mechanisms that remain poorly understood.
Methods: To elucidate genotype-phenotype correlations underlying these unique genomic features, we performed whole-genome sequencing (WGS) and targeted sequencing on invasive ductal carcinoma (IDC), ductal carcinoma in situ (DCIS), and matched adjacent and contralateral normal breast tissues from individuals with LFS. Data were compared to early-onset nonLFS-BC and to The Cancer Genome Atlas (TCGA) tumors harboring either wild-type or somatic TP53 mutations.
Results: Across hormone receptor (HR) subtypes, expected increases in genomic instability were observed in triple-negative versus ER+ nonLFS-BC. However, overall instability measures were similar or lower in LFS-BC. Specifically, in ER+ tumors, microsatellite instability (MSI) and aneuploidy scores were significantly lower in LFS-BC compared to nonLFS-BC. In contrast, LFS-BC exhibited a notable increase in segmental allelic imbalance (AI) with high-level amplifications-particularly within HER2+ subtypes. These amplified regions were significantly shorter than those in nonLFS-BC and often encompassed oncogenes such as ERBB2 , defining a distinct SAAS phenotype. Unlike sporadic TP53 -mutant breast cancers in TCGA, which showed globally elevated aneuploidy and HRD, LFS-BC uniquely accumulated focal, short amplifications. WGS of LFS DCIS and invasive tumors revealed predominant chromosomal instability (CN9) and chromothripsis (CN5) copy number signatures, with minimal whole-genome doubling. Amplicon Architect analysis identified ecDNA structures in 14 of 19 tumors, including ERBB2 -containing ecDNA in 3/6 DCIS and 5/9 HER2+ IDCs with 4 and 8 number of ecDNA structure in each category respevtively. Our work is consistent with prior reports of ecDNA in ~23% of breast cancers and up to 46% of HER2+ cases.
Conclusion: LFS-associated breast cancers are defined by a unique genomic remodeling pattern characterized by focal, high-level amplifications within short aneuploid amplified segments (SAAS) and frequent ecDNA formation. These features distinguish LFS-BC from sporadic TP53 -mutant tumors and highlight a germline TP53 -driven mechanism of oncogene amplification and structural genome evolution.
利益披露 Disclosure
N. Boruah, None..
R. Hausler, None..
H. Desai, None..
M. Tayab, None..
A. Le, None..
G. Kelly, None..
A. Nayak, None..
K. Maxwell, None.