They performed paired-end, massively parallel sequencing on tumor and matched normal genomic DNA obtained from seven patients with ‘high-risk’ primary prostate cancer. All patients harbored tumors of stage T2c or greater, and Gleason grade 7 or higher. Serum prostate-specific antigen levels ranged from 2.1 to 10.2 ng ml.
Regarding mutations, they found two genes (SPTA1 and SPOP) harbored mutations in two out of seven tumors. SPTA1 encodes a scaffold protein involved in erythroid cell shape specification, while SPOP encodes a modulator of Daxx-mediated ubiquitination and transcriptional regulation. The chromatin modifiers CHD1, CHD5 and HDAC9 were mutated in 3 out of 7 prostate cancers. These genes regulate embryonic stem cell pluripotency, gene regulation, and tumor suppression. Members of the HSP-1 stress response complex (HSPA2, HSPA5 and HSP90AB1) were also mutated in three out of seven tumors. The corresponding proteins form a chaperone complex targeted by several anticancer drugs in development. Other known cancer genes were mutated in single tumors, including PRKCI and DICER.
Regarding gene fusions, there were 90 rearrangements per genome. This distribution of rearrangements was similar to that previously described for breast cancer. Three genes disrupted by rearrangements also harbored non-synonymous mutations in another sample: ZNF407, CHD1 and PTEN. These rearrangements predict truncated proteins, raising the possibility that dysregulated CHD1 may contribute to a block in differentiation in some prostate cancer precursor cells.
Regarding complex translocations, they found breakpoint pairs at TBK1 or NF-kB-activating kinase TP53, MAP2K4 (a kinase that induces anchorage-independent growth), and ABL1 (a proto-oncogene). Complex translocations may dysregulate multiple genes to drive prostate tumorigenesis. TMPRSS2, ERG, CSMD3, and CADM2 had rearrangements in 3 out of seven tumors with a high frequency (adjusted for gene size). CADM2 encodes a nectin-like member of the immunoglobulin-like cell adhesion molecules. Several members exhibited tumor suppressor properties. Aberrations were found in 6 out of 90 prostate tumor samples using the FISH assay.
Analysis of rearrangements disrupting PTEN and MAGI2 identified four out of seven tumors harboring rearrangements predicted to inactivate PTEN or MAGI2. MAGI2 encodes a Pten-interacting protein, PTEN rearrangements involve chromosomal copy loss, and MAGI2 rearrangements are balanced events.
In summary, this is the first whole genome sequencing analysis of human prostate cancer. Genome sequencing data indicates that complex rearrangements may enact gain- and loss-of-function driver events in primary prostate carcinogenesis. Complete genome sequencing, as opposed to approaches focused on exons or gene fusions, may be needed to elaborate the spectrum of mechanisms directing prostate cancer genesis and progression. A combination of ERG dysregulation, PTEN loss, and MAGI2 rearrangements might improve prognostication.
Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskis K, Sivachenko AY, Sboner A, Esgueva R, Pflueger D, Sougnez C, Onofrio R, Carter SL, Park K, Habegger L, Ambrogio L, Fennell T, Parkin M, Saksena G, Voet D, Ramos AH, Pugh TJ, Wilkinson J, Fisher S, Winckler W, Mahan S, Ardlie K, Baldwin J, Simons JW, Kitabayashi N, Macdonald TY, Kantoff PW, Chin L, Gabriel SB, Gerstein MB, Golub TR, Meyerson M, Tewari A, Lander ES, Getz G, Rubin MA, Garraway LA
Nature. 2011 Feb 10;470(7333):214-20