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

• 成果类型: Article
• 署名作者: Shah, Osama Shiraz; Nasrazadani, Azadeh; Foldi, Julia; Atkinson, Jennifer M.; Kleer, Celina G.; McAuliffe, Priscilla F.; Johnston, Tyler J.; Stallaert, Wayne; da Silva, Edaise M.; Selenica, Pier; Dopeso, Higinio; Pareja, Fresia; Mandelker, Diana; Weigelt, Britta; Reis-Filho, Jorge S.; Bhargava, Rohit; Lucas, Peter C.; Lee, Adrian V.; Oesterreich, Steffi
• 署名单位: Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Magee-Womens Research Institute; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Memorial Sloan Kettering Cancer Center; Mayo Clinic
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10452
• DOI: 10.1073/pnas.2322068121
• 发表日期: 2024-07-30
• 关键词: clinicopathological features; single-cell; e-cadherin; carcinoma; neoplasms; defects; pattern

摘要

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.