Genomic Alterations during the In Situ to Invasive Ductal Breast Carcinoma Transition Shaped by the Immune System
Year: 2020
Type: article
Abstract: The drivers of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) transition are poorly understood. Here, we conducted an integrated genomic, transcriptomic, and whole-slide image analysis to evaluate changes in copy-number profiles, mutational profiles, expression, neoantigen load, and topology in 6 cases of matched pure DCIS and recurrent IDC. We demonstrate through combined copy-number and mutational analysis that recurrent IDC can be genetically related to its pure DCIS despite long latency periods and therapeutic interventions. Immune “hot” and “cold” tumors can arise as early as DCIS and are subtype-specific. Topologic analysis showed a similar degree of pan-leukocyte-tumor mixing in both DCIS and IDC but differ when assessing specific immune subpopulations such as CD4 T cells and CD68 macrophages. Tumor-specific copy-number aberrations in MHC-I presentation machinery and losses in 3p, 4q, and 5p are associated with differences in immune signaling in estrogen receptor (ER)-negative IDC. Common oncogenic hotspot mutations in genes including TP53 and PIK3CA are predicted to be neoantigens yet are paradoxically conserved during the DCIS-to-IDC transition, and are associated with differences in immune signaling. We highlight both tumor and immune-specific changes in the transition of pure DCIS to IDC, including genetic changes in tumor cells that may have a role in modulating immune function and assist in immune escape, driving the transition to IDC. Implications: We demonstrate that the in situ to IDC evolutionary bottleneck is shaped by both tumor and immune cells.
Source: Molecular Cancer Research
Institutions: Brigham and Women's Hospital, Harvard University, Dana-Farber Cancer Institute, Broad Institute, Massachusetts Institute of Technology, Oregon Health & Science University, The University of Texas MD Anderson Cancer Center, Seoul National University, Seoul National University Bundang Hospital, Yonsei University, Gangnam Severance Hospital, Yonsei University Health System
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Funder: National Cancer Institute
Awards: Evolution and Treatment Response of Brain, Breast, and Hematologic Malignancies, G3232288577, Intratumor heterogeneity underlying treatment resistance in HER2+ breast tumors, Measuring, Modeling and Controlling Heterogeneity, G4746443639, Immunogenomic analytical approaches for research and clinical applications, Targeting intratumor heterogeneity in breast cancer, Cancer Immune Monitoring and Analysis Center
OpenAlex ID: W3111432071