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Abstract Purpose: Despite all the knowledge we have concerning cancer cells’ immunesuppressive ability, we still don’t understand whether the mechanisms upregulatingimmune suppression in cancer cells are patient specific. This information is critical forthe generation of tailored treatments that recruit the immune system for the eradicationof cancer disease. In the past, we showed that super-enhancers, composed of cluster ofenhancers spanning over long genomic regions characterized by having potent generegulatory activity, are critical for the upregulation of immune suppressive genes, including CD47, within the tumor. Recently we found a DNA insertion/deletion variant (8bp in size) within a super-enhancer located between the CD47 and Linc00636 genes, that is present more often in European (53%) than Asian (12%) populations and whichassociates with breast cancer. Moreover, sequence analyses of patient-derived breasttumors (44) and gynecological tumor samples (23) demonstrated a significantassociation of this insert with breast cancer and not with gynecological cancer. Thus, wehypothesize that the insertion variant regulates genes that drive immune escape andbreast cancer specifically in patient populations that carry the insert version. Methods: To test this, we CRISPR deleted the variant’s insertion and CRISPR-VP64induced its activation and quantified its effect on target genes and encoded proteinsusing high throughput RNA sequencing and immunofluorescence flow cytometryanalyses respectively. Results: CRISPR-VP64 induction of the 8bp insertion confirmed that the insertion issufficient to regulate gene expression of CD47 and of an anti-tumor, long intergenicnon-coding RNA (Linc00636) in breast cancer cells. Furthermore, we observed thatCRISPR deletion of the 8bp insertion increases CD47 levels, while dramaticallyincreasing expression of Linc00636 and reducing the expression of CD44, CXCL14, MUC1 genes involved in invasion and migration. Our work shows that the insertion ofan 8bp is responsible for stabilizing upregulation of CD47 (an immune suppressivesignal), downregulating Linc00636 (a modulator of tumor metastasis), and upregulating, as a result, the expression of cell surface receptors involved in metastasis andtumorigenesis. Conclusions: Here we found a genomic insert within a super-enhancer that unleashesthe upregulation of Linc00636 and of a program that promotes breast cancer, mostlikely in populations of patients carrying this variant. Our findings are important tounderstand patient specific genomic bifunctional modulators of immune suppressionand tumor progression for the design of more personalized treatments geared towardprecision medicine. Citation Format: Paola Betancur, Carolina DiBenedetto, Daniza Diane Acenas, Anthony Rodriguez, Alysia Thach. A genomic insertion/deletion variant activates immune escape and tumor promoting programs in breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4402.
Betancur et al. (Fri,) studied this question.