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RAC3 As A Novel Marker Of Breast Implant-Associated Anaplastic Large Cell Lymphoma
Dharshan Sivaraj, BS1, Kento Takaya, MD PhD
2, Debrah Thompson, PhD
3, Jeffrey L. Medeiros, MD
4, Ash A. Alizadeh, MD PhD
1, Roberto N. Miranda, MD
4, David P. Perrault, MD
1, Gordon K. Lee, MD
5, Dominic Henn, MD
6, Kellen Chen, PhD
2, Mark W. Clemens, MD
4, Geoffrey C. Gurtner, MD
2.
1Stanford University, Stanford, CA, USA,
2University of Arizona, Tucson, AZ, USA,
3Metfora, Tucson, AZ, USA,
4MD Anderson Cancer Center, Houston, TX, USA,
5University of California Irvine, Irvine, CA, USA,
6UT Southwestern Medical Center, Dallas, TX, USA.
PURPOSE:Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare T-cell lymphoma that arises in the fibrous capsule surrounding breast implants, almost exclusively with macro-textured devices. Although most cases are curable, the molecular drivers of disease initiation and progression remain unclear. We investigated transcriptomic alterations in BIA-ALCL to define its molecular landscape and identify potential biomarkers.
METHODS:Capsule tissue from five patients with confirmed BIA-ALCL underwent RNA sequencing using the HTG Transcriptome Panel. Contralateral non-tumor capsule tissue served as matched controls. Differential gene expression and gene-set enrichment analyses were performed, and key findings were validated by immunofluorescence staining.
RESULTS:RAC3 was among the most upregulated genes across both early and invasive BIA-ALCL (log₂FC = 5.69-9.98, p < 0.01). BIA-ALCL capsules showed a shift from a dense fibrillar matrix to a remodeled basement membrane profile, with increased
COL4A3,
COL4A4,
COL6A5, and
COL6A6, and reduced
COL1A1 and
FN1 expression. Focal adhesion and ECM-receptor interaction pathways were significantly enriched in BIA-ALCL capsules compared to contralateral controls (p < 0.01). Invasive samples demonstrated elevated
BCL2 and decreased
BAD, consistent with apoptosis resistance. Transcriptomic findings were confirmed at the protein level, showing increased RAC and pFAK expression in BIA-ALCL capsules compared to controls (p < 0.01).
CONCLUSION:BIA-ALCL exhibits a distinct molecular signature characterized by RAC3 overexpression, extracellular matrix remodeling of the capsule, and regulation of focal adhesion pathways. These findings identify RAC3 as a potential biomarker and indicate that mechanical signaling within the implant capsule microenvironment may drive BIA-ALCL onset and progression.
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