Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA.
Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Breast Cancer Res. 2024 May 14;26(1):76. doi: 10.1186/s13058-024-01835-4.
Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer death among women globally. Despite advances, there is considerable variation in clinical outcomes for patients with non-luminal A tumors, classified as difficult-to-treat breast cancers (DTBC). This study aims to delineate the proteogenomic landscape of DTBC tumors compared to luminal A (LumA) tumors.
We retrospectively collected a total of 117 untreated primary breast tumor specimens, focusing on DTBC subtypes. Breast tumors were processed by laser microdissection (LMD) to enrich tumor cells. DNA, RNA, and protein were simultaneously extracted from each tumor preparation, followed by whole genome sequencing, paired-end RNA sequencing, global proteomics and phosphoproteomics. Differential feature analysis, pathway analysis and survival analysis were performed to better understand DTBC and investigate biomarkers.
We observed distinct variations in gene mutations, structural variations, and chromosomal alterations between DTBC and LumA breast tumors. DTBC tumors predominantly had more mutations in TP53, PLXNB3, Zinc finger genes, and fewer mutations in SDC2, CDH1, PIK3CA, SVIL, and PTEN. Notably, Cytoband 1q21, which contains numerous cell proliferation-related genes, was significantly amplified in the DTBC tumors. LMD successfully minimized stromal components and increased RNA-protein concordance, as evidenced by stromal score comparisons and proteomic analysis. Distinct DTBC and LumA-enriched clusters were observed by proteomic and phosphoproteomic clustering analysis, some with survival differences. Phosphoproteomics identified two distinct phosphoproteomic profiles for high relapse-risk and low relapse-risk basal-like tumors, involving several genes known to be associated with breast cancer oncogenesis and progression, including KIAA1522, DCK, FOXO3, MYO9B, ARID1A, EPRS, ZC3HAV1, and RBM14. Lastly, an integrated pathway analysis of multi-omics data highlighted a robust enrichment of proliferation pathways in DTBC tumors.
This study provides an integrated proteogenomic characterization of DTBC vs LumA with tumor cells enriched through laser microdissection. We identified many common features of DTBC tumors and the phosphopeptides that could serve as potential biomarkers for high/low relapse-risk basal-like BC and possibly guide treatment selections.
乳腺癌（BC）是最常见的癌症，也是全球女性癌症死亡的主要原因。尽管取得了进展，但非腔 A 型肿瘤（被归类为难治疗的乳腺癌[DTBC]）患者的临床结果仍存在相当大的差异。本研究旨在描绘 DTBC 肿瘤与腔 A 型（LumA）肿瘤相比的蛋白质基因组景观。
我们回顾性收集了总共 117 例未经治疗的原发性乳腺癌标本，重点是 DTBC 亚型。通过激光显微切割（LMD）处理乳腺癌组织以富集肿瘤细胞。从每个肿瘤制剂中同时提取 DNA、RNA 和蛋白质，随后进行全基因组测序、配对末端 RNA 测序、全局蛋白质组学和磷酸蛋白质组学。进行差异特征分析、通路分析和生存分析，以更好地了解 DTBC 并研究生物标志物。
我们观察到 DTBC 和 LumA 乳腺癌肿瘤之间在基因突变、结构变异和染色体改变方面存在明显差异。DTBC 肿瘤中 TP53、PLXNB3、锌指基因的突变较多，而 SDC2、CDH1、PIK3CA、SVIL 和 PTEN 的突变较少。值得注意的是，包含许多细胞增殖相关基因的 Cytoband 1q21 在 DTBC 肿瘤中显著扩增。LMD 成功地最小化了基质成分，并通过基质评分比较和蛋白质组学分析增加了 RNA-蛋白质一致性。通过蛋白质组学和磷酸蛋白质组学聚类分析观察到明显的 DTBC 和 LumA 富集聚类，其中一些具有生存差异。磷酸蛋白质组学为高复发风险和低复发风险基底样肿瘤鉴定了两种不同的磷酸蛋白质组学特征，涉及几个已知与乳腺癌发生和进展相关的基因，包括 KIAA1522、DCK、FOXO3、MYO9B、ARID1A、EPRS、ZC3HAV1 和 RBM14。最后，多组学数据的综合通路分析突出了 DTBC 肿瘤中增殖途径的稳健富集。
本研究通过激光微切割富集肿瘤细胞，对 DTBC 与 LumA 进行了综合蛋白质基因组学描述。我们鉴定了 DTBC 肿瘤的许多共同特征以及可能作为高/低复发风险基底样 BC 的潜在生物标志物的磷酸肽，并可能指导治疗选择。
