Abstract 3532: Genetic insights into clonal evolution from normal prostate epithelium to cancer via HighGradePIN

Abstract Background Prostate cancer (PC) is one of the most prevalent cancers in the developed world, where its incidence is still increasing. Most PCs are thought to arise from high-grade prostatic intraepithelial neoplasia (HGPIN), a well-recognized precursor lesion. However, the genetic landscape of HGPIN and its relationship with normal prostate epithelium (NPE) and PC remains to be fully explored. To clarify the early genetic events and clonal dynamics underlying PC development, we performed comprehensive genomic profiling of NPE, HGPIN, and PC. Methods We performed laser-capture microdissection (LMD) to obtain samples from PC (n = 49), HGPIN (n = 77), and NEP (n =393), which were subjected to whole-exome sequencing (WES). We measured genome-wide mutation burdens in normal prostate epithelium from 5 patients using a highly accurate sequencing platform, Nanoseq. Results In NanoSeq, a total of 10,047 SNVs & indels were detected across 393 NPE samples, based on which the mutation accumulation rate in NPE was estimated to be 0.205 mutations/year/exon. Several mutations were shared between NPE and HGPIN as well as between HGPIN and PC, suggesting a common clonal origin. Pathogenic FOXA1 mutations were frequently detected in both HGPIN and PC. Although pathogenic FOXA1 mutations were also found in NPE, they did not overlapped with those in HGPIN or PC and therefore, likely represent independent mutational events. In one case, spatially distinct multifocal cancers exhibited multiple FOXA1 mutations, each of which was shared with corresponding adjacent HGPIN. In additional cases, 12 mutations were shared across PCa, HGPIN, and NPE samples, although no known driver mutations were detected therein. These findings suggest that PCa may arise from clones with apparently normal histology, which progress through HGPIN to PC. Phylogenetic analysis of these samples revealed that PC and HGPIN diverged from a common normal ancestor approximately 45 years earlier. Conclusions We successfully characterized somatic mutations and CNVs in apparently normal prostate epithelium, which were shared between HGPIN and adjacent PC in some cases. The presence of shared somatic mutations supports a clonal continuum from normal epithelium to precursor lesions and invasive carcinoma. These insights enhance our understanding of early prostate carcinogenesis and highlight potential avenues for early detection and intervention. Citation Format: Kohsuke Hishiki, Nobuyuki Kakiuchi, Yuki Teramoto, Koichi Watanabe, Kosuke Ieiri, Hirona Maeda, Tomonori Hirano, Yuki Kita, Takashi Kobayashi, Seishi Ogawa. Genetic insights into clonal evolution from normal prostate epithelium to cancer via HighGradePIN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3532.