Two independent exome sequencing studies have identified new genetic subtypes of prostate cancer. Presenting its findings in Nature, a University of Michigan Medical School-led team identified CHD1 mutations in 8% of heavily pretreated lethal metastatic castration-resistant prostate cancers (CRPCs). Notably, CHD1 mutations were almost always found in tumors that didn’t display ETS gene family fusions. Reporting in Nature Genetics, a Weill Cornell Medical College group identified substrate-binding SPOP mutations in up to 15% of treatment-naive prostate adenocarcinomas. Again, SPOP mutations were found exclusively in tumors that lacked ETS family gene rearrangements.
Scott A. Tomlins, Ph.D., and colleagues at the University of Michigan sequenced the exomes of 50 lethal, heavily pretreated metastatic CRPCs obtained at rapid autopsy. They evaluated the resulting data in combination with that obtained from three prostate cancer array comparative genome hybridization (aCGH) studies and nine expression profiling studies, totalling 835 additional cancers.
Topping the results list was the finding that focal deletions or mutations in CHD1 (CHD1-) occurred in about 8% of pretreated metastatic CRPCs, and was almost always associated with ETS gene family fusion-negative (ETS-) status, suggestive of a new CHD1-ETS- molecular subtype of prostate cancer, the researchers note. The sequencing data also demonstrated recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (which was mutated in 8.6% of prostate cancers), and mutations in the androgen receptor-collaborating factor FOXA1, which was mutated in 3.4% of prostate cancers, including both untreated localized prostate cancer and CRPC.
Notably, immunoprecipitation and RNA interference experiments indicated that interaction of the MLL complex with androgen receptor (AR) is required for AR-mediated signaling, and that mutated FOXA1 represses androgen signaling and increases tumor growth. Drs. Tomlins et al report their findings in a paper titled “The mutational landscape of lethal castration-resistant prostate cancer.”
Levi Garraway, Ph.D., and colleagues at Weill Cornell Medical College sequenced the exomes of 112 prostate tumors and their matched normal tissue. They focused specifically on treatment-naive radical prostatectomy specimens from patients with a range of tumor grades, stages and risks of recurrence. The most frequently mutated gene was SPOP, alterations in which were found in 13% of tumors. SPOP mutations have previously been reported in prostate cancer, but not at high frequency in any malignancy, they note. Interestingly, and in concurrence with the Michigan team’s findings, the Weill Cornell researchers also found nonsilent FOXA1 mutations in 4 of 111 exomes, and another 4 of 41 independent RNA-seq samples.
Because the prevalence and functional importance of SPOP mutations hasn’t yet been determined, the team went on to sequence the SPOP gene in other cohorts including 300 primary and metastatic tumors. The analyses identified recurrent heterozygous SPOP substitutions in 6–13% of primary prostate adenocarcinomas and 14.5% of metastatic tumors, but not in any benign prostate tissue sample or prostate cancer cell line. All the mutations affected conserved residues in the structurally defined substrate-binding cleft.
Further in vitro studies to evaluate the effects of mutant SPOP expression or knockdown demonstrated that lack of normal SPOP was linked with increased invasiveness, although not changes in cell growth or viability.
Importantly, all the SPOP mutated exomes lacked the TMPRSS2-ERG fusion, or other ETS family gene rearrangements that are found in up to 50% of prostate cancers. This observation is similar to that reported for the CHDI mutations found in the lethal CRPC tumors by Drs. Tomlins et al. “Thus, SPOP mutation and ETS family gene fusions may represent early and divergent driver events in prostate carcinogenesis,” the Nature Genetics authors write.
TP53 mutations were also generally absent in SPOP-mutated tumors, despite the fact that the tumor suppressor is regularly absent or mutated in prostate cancer. In contrast, SPOP mutations were associated with an increased likelihood of recurrent somatic deletions in at 5q21 at 6q21. Interestingly, in light of the Michigan team’s findings reported in Nature, 5q21 harbors the CHD1 gene, and 6q21 harbors FOXO3, a FOXA1 homolog that has previously been identified in prostate carcinogenesis and progression.
Drs. Garraway et al report their findings in a paper titled “Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer.” While there is still a need for increased discovery, it does appear that the overall genetic landscape of prostate cancer is taking shape, and better understanding of the biology and possible therapeutic avenues linked to these alterations has become a very high priority,” Dr. Garraway concludes.