A Gene Signature Identifying CIN3 Regression and Cervical Cancer Survival

SIMPLE SUMMARY: Through implementation of HPV testing as standard primary screening method, the number of women diagnosed with high-grade cervical intraepithelial neoplasia (CIN2-3) has increased. Although only one third of CIN3 will progress to cancer, conization is standard treatment in high-income countries. The aim of this study was to identify tools with which to predict CIN regression relevant for individualizing treatment within this patient group. We compared the transcriptomic immune-profile from 21 lesions with confirmed regression and 28 lesions with confirmed persistent CIN3. A gene signature with high sensitivity to identify CIN3 lesions that regressed during follow-up was identified. When tested in a cervical cancer cohort (n = 239) with available transcriptomic data, a high regression signature score was associated with favorable survival, small tumors, and immune infiltration. This study presents a gene signature with the capacity to predict CIN regression, that may potentially guide treatment, and identifies common disease drivers in CIN and cervical cancer. ABSTRACT: The purpose of this study was to establish a gene signature that may predict CIN3 regression and that may aid in selecting patients who may safely refrain from conization. Oncomine mRNA data including 398 immune-related genes from 21 lesions with confirmed regression and 28 with persistent CIN3 were compared. L1000 mRNA data from a cervical cancer cohort was available for validation (n = 239). Transcriptomic analyses identified TDO2 (p = 0.004), CCL5 (p < 0.001), CCL3 (p = 0.04), CD38 (p = 0.02), and PRF1 (p = 0.005) as upregulated, and LCK downregulated (p = 0.01) in CIN3 regression as compared to persistent CIN3 lesions. From these, a gene signature predicting CIN3 regression with a sensitivity of 91% (AUC = 0.85) was established. Transcriptomic analyses revealed proliferation as significantly linked to persistent CIN3. Within the cancer cohort, high regression signature score associated with immune activation by Gene Set enrichment Analyses (GSEA) and immune cell infiltration by histopathological evaluation (p < 0.001). Low signature score was associated with poor survival (p = 0.007) and large tumors (p = 0.01). In conclusion, the proposed six-gene signature predicts CIN regression and favorable cervical cancer prognosis and points to common drivers in precursors and cervical cancer lesions.