Genomic alterations during the in situ to invasive ductal breast carcinoma transition shaped by the immune system

Anne Trinh, Carlos R. Gil Del Alcazar, Sachet A. Shukla, Koei Chin, Young Hwan Chang, Guillaume Thibault, Jennifer Eng, Bojana Jovanovic, C. Marcelo Aldaz, So Yeon Park, Joon Jeong, Catherine Wu, Joe Gray, Kornelia Polyak

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)623-635
Number of pages13
JournalMolecular Cancer Research
Issue number4
Publication statusPublished - 2021 Apr

Bibliographical note

Funding Information:
A. Trinh reports grants from Helen Gurley Brown Pussycat Foundation during the conduct of the study. S.A. Shukla reports non-financial support from Bristol-Myers Squibb, other from Agenus Inc, other from Agios Pharmaceuticals, other from BreakBio Corp, other from Bristol-Myers Squibb, and other from Lumos Pharma outside the submitted work. K. Chin reports grants from NIH/NCI, grants from Prospect Creek Foundation, and grants from OHSU Foundation during the conduct of the study. J. Eng reports grants from NIH/NCI during the conduct of the study; grants from Komen Foundation, grants from Prospect Creek Foundation, and grants from SBIR outside the submitted work. C. Wu reports other from BioNTech outside the submitted work. J. Gray reports personal fees from New Leaf Ventures during the conduct of the study; personal fees from PDX Pharmaceuticals, personal fees from KromaTid, personal fees from Quantitative Imaging, personal fees from Health Technologies, and personal fees from Convergent Genomics outside the submitted work; in addition, Dr Gray has a patent for FISH Patent licensed to Abbott Diagnostics. K. Polyak reports other from Scorpion Therapeutics, other from Acrivon Therapuetics, and other from twoXAR outside the submitted work. No disclosures were reported by the other authors..

Funding Information:
We thank Drs. Deborah Dillon, Paul Spellman, Doris Tabassum, Michalina Janiszewska, and members of the Polyak lab for their critical reading of our manuscript. We thank Drs. Thomas O. McDonald, Hua-Jun Wu, and Daniel Temko for their useful suggestions with computational analyses. This work was supported by the National Cancer Institute R35CA197623 (to K. Polyak), U01CA195469 (to K. Polyak and J. Gray), NIH-U24CA224331 (to C. Wu), R50RCA211482 (to S.A. Shukla), U54CA209988 (to K. Polyak and J. Gray), DFCI Helen Gurley Brown Presidential Initiative Award (to A. Trinh), and the Breast Cancer Research Foundation (to K. Polyak).

Publisher Copyright:
© 2020 American Association for Cancer Research.

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research


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