The mutational landscape of lethal castration-resistant prostate cancer

• Published in: Nature (London) Vol. 487; no. 7406; pp. 239 - 243
• Main Authors: Grasso, Catherine S., Wu, Yi-Mi, Robinson, Dan R., Cao, Xuhong, Dhanasekaran, Saravana M., Khan, Amjad P., Quist, Michael J., Jing, Xiaojun, Lonigro, Robert J., Brenner, J. Chad, Asangani, Irfan A., Ateeq, Bushra, Chun, Sang Y., Siddiqui, Javed, Sam, Lee, Anstett, Matt, Mehra, Rohit, Prensner, John R., Palanisamy, Nallasivam, Ryslik, Gregory A., Vandin, Fabio, Raphael, Benjamin J., Kunju, Lakshmi P., Rhodes, Daniel R., Pienta, Kenneth J., Chinnaiyan, Arul M., Tomlins, Scott A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-07-2012; Nature Publishing Group
• Subjects: 631/208/737; 631/67/69; 631/80/86; 692/699/67/589/466; Biological and medical sciences; Cell Proliferation; Cells, Cultured; Deoxyribonucleic acid; Development and progression; DNA; Gene mutations; Genetic aspects; Genetics; Genomics; Gynecology. Andrology. Obstetrics; Health aspects; Hepatocyte Nuclear Factor 3-alpha - genetics; Humanities and Social Sciences; Humans; Kinases; letter; Male; Male genital diseases; Medical sciences; Molecular Sequence Data; multidisciplinary; Mutation; Nephrology. Urinary tract diseases; Orchiectomy; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Receptors, Androgen - metabolism; Science; Science (multidisciplinary); Sequence Alignment; Signal Transduction; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; United States; Human; Nephrology; Treatment resistance; Urinary system disease; Prostate disease; Transcription factor Ets2; Malignant tumor; Urology; Cancerology; Castration; Deletion; Genetics; Mutation; Male genital diseases; Prostate cancer; Cancer
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11125

Exome sequencing is used to investigate the role of mutations and copy number aberrations in metastatic castration-resistant prostate cancer, revealing recurrent mutations in multiple chromatin/histone modifying genes, as well as genes involved in androgen signalling.
Mutations in aggressive prostate cancer
Great strides have been made in the treatment of localized prostate cancer, but the metastatic disease and its progression to castration-resistant prostate cancer (CRPC) are commonly lethal. This study uses whole-exome sequencing of 132 samples comprising tumour and matched germ line from 50 patients with heavily treated CRPC, and 11 untreated high-grade localized prostate cancers. Although the overall mutation rate is low, the authors find recurrent mutations in multiple chromatin/histone-modifying genes, as well as in the gene encoding the androgen receptor. They identify a diverse series of potentially driving mutations and copy-number alterations in both known and novel genes and pathways, including
FOXA1
.
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)
1
. However, less is known about the role of mutations
2
,
3
,
4
. 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.