Proteogenomic characterization of difficult-to-treat breast cancer with tumor cells enriched through laser microdissection.

Autor:	Raj-Kumar PK; 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., Lin X; 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., Liu T; Pacific Northwest National Laboratory, Richland, WA, USA., Sturtz LA; 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., Gritsenko MA; Pacific Northwest National Laboratory, Richland, WA, USA., Petyuk VA; Pacific Northwest National Laboratory, Richland, WA, USA., Sagendorf TJ; Pacific Northwest National Laboratory, Richland, WA, USA., Deyarmin B; Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA., Liu J; Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA., Praveen-Kumar A; Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA., Wang G; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA., McDermott JE; Pacific Northwest National Laboratory, Richland, WA, USA., Shukla AK; Pacific Northwest National Laboratory, Richland, WA, USA., Moore RJ; Pacific Northwest National Laboratory, Richland, WA, USA., Monroe ME; Pacific Northwest National Laboratory, Richland, WA, USA., Webb-Robertson BM; Pacific Northwest National Laboratory, Richland, WA, USA., Hooke JA; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA., Fantacone-Campbell L; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA., Mostoller B; Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA., Kvecher L; 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., Kane J; Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA., Melley J; Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA., Somiari S; Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA., Soon-Shiong P; NantWorks, Culver City, CA, USA., Smith RD; Pacific Northwest National Laboratory, Richland, WA, USA., Mural RJ; Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA., Rodland KD; Pacific Northwest National Laboratory, Richland, WA, USA., Shriver CD; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. craig.shriver@usuhs.edu.; Department of Surgery, Walter Reed National Military Medical Center, Bethesda, MD, USA. craig.shriver@usuhs.edu., Kovatich AJ; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA., Hu H; Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA, USA. h.hu@wriwindber.org.; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. h.hu@wriwindber.org.
Jazyk:	angličtina
Zdroj:	Breast cancer research : BCR [Breast Cancer Res] 2024 May 14; Vol. 26 (1), pp. 76. Date of Electronic Publication: 2024 May 14.
DOI:	10.1186/s13058-024-01835-4
Abstrakt:	Background: 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. Methods: 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. Results: 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. Conclusions: 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. (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze:	MEDLINE
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