Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate.

TitleGenetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate.
Publication TypeJournal Article
Year of Publication2019
AuthorsElfandy H, Armenia J, Pederzoli F, Pullman E, Pertega-Gomes N, Schultz N, Viswanathan K, Vosoughi A, Blattner M, Stopsack KH, Zadra G, Penney KL, Mosquera JMiguel, Tyekucheva S, Mucci LA, Barbieri C, Loda M
JournalMol Cancer Res
Volume17
Issue2
Pagination446-456
Date Published2019 02
ISSN1557-3125
KeywordsAdenocarcinoma, Animals, Epigenomics, Humans, Male, Mice, Prostatic Neoplasms
Abstract

Among prostate cancers containing Gleason pattern 4, cribriform morphology is associated with unfavorable clinicopathologic factors, but its genetic features and association with long-term outcomes are incompletely understood. In this study, genetic, transcriptional, and epigenetic features of invasive cribriform carcinoma (ICC) tumors were compared with non-cribriform Gleason 4 (NC4) in The Cancer Genome Atlas (TCGA) cohort. ICC ( = 164) had distinctive molecular features when compared with NC4 ( = 102). These include: (i) increased somatic copy number variations (SCNV), specifically deletions at 6q, 8p and 10q, which encompassed and losses and gains at 3q; (ii) increased and ; (iii) enrichment for and pathways by gene expression; and (iv) increased methylation of selected genes. In addition, when compared with the metastatic prostate cancer, ICC clustered more closely to metastatic prostate cancer than NC4. Validation in clinical cohorts and genomically annotated murine models confirmed the association with ( = 38) and ( = 818). The association of ICC with lethal disease was evaluated in the Health Professionals Follow-up Study (HPFS) and Physicians' Health Study (PHS) prospective prostate cancer cohorts (median follow-up, 13.4 years; = 818). Patients with ICC were more likely to develop lethal cancer [HR, 1.62; 95% confidence interval (CI), 1.05-2.49], independent from Gleason score (GS). IMPLICATIONS: ICC has a distinct molecular phenotype that resembles metastatic prostate cancer and is associated with progression to lethal disease.

DOI10.1158/1541-7786.MCR-18-0440
Alternate JournalMol Cancer Res
PubMed ID30333152
PubMed Central IDPMC6359952
Grant ListP50 CA090381 / CA / NCI NIH HHS / United States
R01 CA187918 / CA / NCI NIH HHS / United States
U01 CA167552 / CA / NCI NIH HHS / United States
R37 CA215040 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA131945 / CA / NCI NIH HHS / United States
K08 CA187417 / CA / NCI NIH HHS / United States
P50 CA211024 / CA / NCI NIH HHS / United States
UM1 CA167552 / CA / NCI NIH HHS / United States
Related Faculty: 
Juan Miguel Mosquera, M.D. Massimo Loda, M.D.

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