The mutational landscape of lethal  castration-resistant prostate cancer.
Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approximately one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signalling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signalling and increases tumour growth. Proteins that physically interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signalling deregulated in prostate cancer, and prioritize candidates for future study.
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Catherine S
CS
Grasso
Yi-Mi
YM
Wu
Dan R
DR
Robinson
Xuhong
X
Cao
Saravana M
SM
Dhanasekaran
Amjad P
AP
Khan
Michael J
MJ
Quist
Xiaojun
X
Jing
Robert J
RJ
Lonigro
J Chad
JC
Brenner
Irfan A
IA
Asangani
Bushra
B
Ateeq
Sang Y
SY
Chun
Javed
J
Siddiqui
Lee
L
Sam
Matt
M
Anstett
Rohit
R
Mehra
John R
JR
Prensner
Nallasivam
N
Palanisamy
Gregory A
GA
Ryslik
Fabio
F
Vandin
Benjamin J
BJ
Raphael
Lakshmi P
LP
Kunju
Daniel R
DR
Rhodes
Kenneth J
KJ
Pienta
Arul M
AM
Chinnaiyan
Scott A
SA
Tomlins
D049109:Cell Proliferation; D002478:Cells, Cultured; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction
C410798:AR protein, human; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D011944:Receptors, Androgen