Genetic Progression of High Grade Prostatic Intraepithelial Neoplasia to Prostate Cancer

Abstract

BackgroundAlthough high grade prostatic intraepithelial neoplasia (HGPIN) is considered a neoplastic lesion that precedes prostate cancer (PCA), the genomic structures of HGPIN remain unknown. ObjectiveIdentification of the genomic landscape of HGPIN and the genomic differences between HGPIN and PCA that may drive the progression to PCA. Design, settings, and participantsWe analyzed 20 regions of paired HGPIN and PCA from six patients using whole-exome sequencing and array-comparative genomic hybridization. Outcome measurements and statistical analysisSomatic mutation and copy number alteration (CNA) profiles of paired HGPIN and PCA were measured and compared. Results and limitationsThe number of total mutations and CNAs of HGPINs were significantly fewer than those of PCAs. Mutations in FOXA1 and CNAs (1q and 8q gains) were detected in both HGPIN and PCA (‘common’), suggesting their roles in early PCA development. Mutations in SPOP, KDM6A, and KMT2D were ‘PCA-specific’, suggesting their roles in HGPIN progression to PCA. The 8p loss was either ‘common’ or ‘PCA-specific’. In-silico estimation of evolutionary ages predicted that HGPIN genomes were much younger than PCA genomes. Our data show that PCAs are direct descendants of HGPINs in most cases that require more genomic alterations to progress to PCA. The nature of heterogeneous HGPIN population that might attenuate genomic signals should further be studied. ConclusionsHGPIN genomes harbor relatively fewer mutations and CNAs than PCA but require additional hits for the progression. Patient summaryIn this study, we suggest a systemic diagram from high grade prostatic intraepithelial neoplasia (HGPIN) to prostate cancer (PCA). Our results provide a clue to explain the long latency from HGPIN to PCA and provide useful information for the genetic diagnosis of HGPIN and PCA.