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

被引：47

作者：

Elfandy, Habiba ^{[1
,2
]}

Armenia, Joshua ^{[3
]}

Pederzoli, Filippo ^{[4
]}

Pullman, Eli ^{[5
]}

Pertega-Gomes, Nelma ^{[1
]}

Schultz, Nikolaus ^{[6
]}

Viswanathan, Kartik ^{[7
]}

Vosoughi, Aram ^{[7
,8
]}

Blattner, Mirjam ^{[8
,9
]}

Stopsack, Konrad H. ^{[10
]}

Zadra, Giorgia ^{[1
,11
]}

Penney, Kathryn L. ^{[12
,13
,14
]}

Mosquera, Juan Miguel ^{[7
,8
]}

Tyekucheva, Svitlana ^{[15
,16
]}

Mucci, Lorelei A. ^{[12
]}

Barbieri, Christopher ^{[8
,9
]}

Loda, Massimo ^{[1
,11
,17
]}

机构：

[1] Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02115 USA

[2] Cairo Univ, Natl Canc Inst, Dept Pathol, Cairo, Egypt

[3] Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, 1275 York Ave, New York, NY 10021 USA

[4] Univ Vita Salute San Raffaele, Milan, Italy

[5] George Washington Univ, Washington, DC USA

[6] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[7] Weill Cornell Med, Dept Pathol, New York, NY USA

[8] Weill Cornell Med, Englander Inst Precis Med, New York, NY USA

[9] Weill Cornell Med, Dept Urol, New York, NY USA

[10] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[11] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA

[12] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[13] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA

[14] Harvard Med Sch, Boston, MA USA

[15] Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA

[16] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA

[17] Broad Inst, Cambridge, MA USA

来源：

MOLECULAR CANCER RESEARCH | 2019年 / 17卷 / 02期

关键词：

2014 INTERNATIONAL SOCIETY; INTRADUCTAL CARCINOMA; GLEASON SCORE; CANCER; METHYLATION; BIOPSY; SPOP; ARCHITECTURE; ASSOCIATION; PROGRESSION;

D O I：

10.1158/1541-7786.MCR-18-0440

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 (n = 164) had distinctive molecular features when compared with NC4 (n = 102). These include: (i) increased somatic copy number variations (SCNV), specifically deletions at 6q, 8p and 10q, which encompassed PTEN and MAP3K7 losses and gains at 3q; (ii) increased SPOPmut and ATM(mut); (iii) enrichment for mTORC1 and MYC 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 SPOPmut (n = 38) and PTENloss (n = 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; n = 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.

引用

页码：446 / 456

页数：11

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