SUN-069 - Distinct Lineage-Specific Transcriptional Landscapes of Human Endogenous Retroviruses in Pituitary Neuroendocrine Tumors

Introduction: Pituitary neuroendocrine tumors (PitNETs) remain challenging to stratify molecularly and to manage in aggressive/recurrent settings, where targeted options are limited. Human endogenous retroviruses (HERVs) comprise ~8% of the human genome and can be transcriptionally reactivated in cancer, generating tumor-associated transcripts and candidate antigens. However, locus-level HERV activity in PitNETs and its relationship with transcription factor–defined lineage remain poorly characterized. We mapped HERV expression programs across PitNET lineages and assessed reproducibility across independent cohorts.

Methods: We integrated RNA-seq from a published cohort (n=41) and an independent local cohort (n=140). Tumors were assigned to TPIT, PIT1, and SF1 lineages by immunohistochemistry for lineage-defining transcription factors with confirmatory lineage-marker PCR/qPCR. Locus-specific HERV expression was quantified with Telescope, enabling resolution within repetitive regions, and differential expression was tested using DESeq2. Selected loci were validated by orthogonal RT-PCR in clinically characterized tumors.

Results: HERV expression programs were strongly lineage-dependent and reproducible across cohorts. TPIT-lineage tumors showed preferential activation of HERV-K and HERV-H loci, whereas SF1-lineage tumors exhibited enrichment of ERVL/ERV1 elements. In contrast, PIT1-lineage tumors displayed broad relative repression across these loci. We additionally observed consistent downregulation of stem cell–associated HERVH loci in PIT1 tumors, supporting epigenetic remodeling accompanying lineage specification. Collectively, these findings define non-random, lineage-linked retroviral transcriptional programs that add a distinct layer to PitNET molecular heterogeneity.

Conclusion: Locus-level HERV profiles are intrinsically linked to PitNET lineage identity and nominate lineage-associated HERV loci as candidate biomarkers compatible with contemporary pathology workflows. Re-expressed retroviral transcripts in defined subtypes prioritize specific loci for downstream functional and immunogenicity studies, with potential implications for future therapeutic development

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