Spatial molecular profiling of mixed invasive ductal and lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations.

Autor:	Shah OS; Womens Cancer Research Center at University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center and Magee Women's Research Institute, Pittsburgh, PA 15213.; Integrative Systems Biology Program, University of Pittsburgh School of Medicine, Pittsburgh PA 15260., Nasrazadani A; Womens Cancer Research Center at University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center and Magee Women's Research Institute, Pittsburgh, PA 15213.; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213., Foldi J; Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260., Atkinson JM; Womens Cancer Research Center at University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center and Magee Women's Research Institute, Pittsburgh, PA 15213.; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260., Kleer CG; Department of Pathology and Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109., McAuliffe PF; Womens Cancer Research Center at University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center and Magee Women's Research Institute, Pittsburgh, PA 15213.; Division of Surgical Oncology, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232., Johnston TJ; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213., Stallaert W; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213., da Silva EM; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Selenica P; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Dopeso H; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Pareja F; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Mandelker D; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Weigelt B; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Reis-Filho JS; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Bhargava R; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213., Lucas PC; Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, MN 55902., Lee AV; Womens Cancer Research Center at University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center and Magee Women's Research Institute, Pittsburgh, PA 15213.; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260., Oesterreich S; Womens Cancer Research Center at University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center and Magee Women's Research Institute, Pittsburgh, PA 15213.; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jul 30; Vol. 121 (31), pp. e2322068121. Date of Electronic Publication: 2024 Jul 23.
DOI:	10.1073/pnas.2322068121
Abstrakt:	Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive ductal and E-cadherin negative lobular morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct morphologies also have distinct biology and risk of recurrence. Our spatially resolved transcriptomic, genomic, and single-cell profiling revealed clinically significant differences between ductal and lobular tumor regions including distinct intrinsic subtype heterogeneity - e.g., MDLC with triple-negative breast cancer (TNBC) or basal ductal and estrogen receptor positive (ER+) luminal lobular regions, distinct enrichment of cell cycle arrest/senescence and oncogenic (ER and MYC ) signatures, genetic and epigenetic CDH1 inactivation in lobular but not ductal regions, and single-cell ductal and lobular subpopulations with unique oncogenic signatures further highlighting intraregional heterogeneity. Altogether, we demonstrated that the intratumoral morphological/histological heterogeneity within MDLC is underpinned by intrinsic subtype and oncogenic heterogeneity which may result in prognostic uncertainty and therapeutic dilemma. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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