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The Regenerative Effects Of Reconstruction: An Analysis Of Cutaneous Gene Expression Changes In Irradiated Breast Reconstruction Patients
Kirsten A. Gunderson, BS1, Rebecca L. Farmer, MD, PhD1, Sarah M. Lyon, MD1, Jacqueline S. Israel, MD1, Sandra Splinter BonDurant, MS2, Katherine M. Gast, MD1, Samuel O. Poore, MD, PhD1, John W. Siebert, MD1.
1University of Wisconsin School of Medicine and Public Health, Madison, WI, USA, 2University of Wisconsin-Madison, Madison, WI, USA.

PURPOSE: The detrimental effects of radiation therapy on the skin and underlying tissues of breast cancer patients are well documented. While acute changes resolve with time, the overall quality of the skin is forever altered. Breast reconstruction in the context of radiation therapy has been shown to have higher rates of complications and failure, as well as unfavorable aesthetic outcomes. While the adverse effects of radiation are well known, the molecular mechanisms and genetic changes of radiation-induced skin injury are not yet described. Additionally, while there is often clinical improvement in the quality of irradiated tissue with the use of certain reconstructive techniques, the genetic alterations underlying these phenotypic changes are unknown. We utilized RNA Sequencing technology to analyze gene expression profiles of irradiated and non-irradiated breast skin to identify the major pathways that are affected by radiation therapy. Additionally, we used this technology to determine the genetic impact of commonly performed reconstructive breast procedures on these identified dysregulated pathways.
METHODS: Full thickness skin samples were collected from irradiated and non-irradiated breast cancer patients at the time of mastectomy and either autologous or alloplastic reconstruction. Cases performed in either delayed or immediate fashion were included. Additional samples were collected 3-6 months later at the time of secondary revision. Samples from patients undergoing non-oncologic breast surgery or prophylactic mastectomy were included as controls. Internal control samples were collected when symmetry procedures were performed. All samples were analyzed using RNA-Seq to determine the cellular transcriptome for irradiated versus non-irradiated breast skin, both before and after reconstruction. Gene expression was then analyzed via hierarchical clustering to determine the biologic pathways that were altered by radiation and reconstruction.
RESULTS: Gene expression profiles of 50 patients were analyzed. Irradiated samples were shown to have distinct profiles from non-irradiated and control samples. Genomic analysis demonstrated multiple dysregulated biologic pathways in irradiated tissue. In irradiated patients who underwent autologous reconstruction, a number of these dysregulated genetic pathways were reversed to near-normal levels post-reconstruction. This regenerative phenomenon was less clear in the alloplastic reconstruction group.
CONCLUSION: We utilized gene expression profiling to identify biologic pathways that are altered by radiation therapy and demonstrated that autologous reconstruction with microvascular free tissue transfer may restore these dysregulated pathways to resemble non-irradiated, control tissue. We have identified future targets for primary inhibition or pharmacologic rescue of radiation-induced tissue changes. Presently, plastic surgeons can use these findings to tailor reconstructive efforts in irradiated patients to reverse these detrimental phenotypic changes and improve overall reconstructive outcomes.


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