FOXA1 expression is a strong independent predictor of early PSA recurrence in ERG negative prostate cancers treated by radical prostatectomy.

FOXA1 (Fork-head box protein A1, HNF-3a) is a transcription factor involved in androgen signaling with relevance for lineage-specific gene expression of the prostate. The expression was analyzed by immunohistochemistry on a tissue microarray containing 11152 prostate cancer specimens. Results were compared with tumor phenotype, biochemical recurrence, androgen receptor expression, ETS-related gene (ERG) status and other recurrent genomic alterations. FOXA1 expression was detectable in 97.6% of 8227 interpretable cancers and considered strong in 28.5%, moderate in 46.2% and weak in 22.9% of cases. High FOXA1 expression was associated with TMPRSS2:ERG rearrangement and ERG expression (P < 0.0001). High FOXA1 expression was linked to high Gleason grade, advanced pathological tumor (pT) stage and early PSA recurrence in ERG negative cancers (P < 0.0001), while these associations were either weak or absent in ERG positive cancers. In ERG negative cancers, the prognostic role of FOXA1 expression was independent of Gleason grade, pathological tumor stage, lymph node stage, surgical margin status and preoperative PSA. Independent prognostic value became even more evident if the analysis was limited to preoperatively available features such as biopsy Gleason grade, preoperative PSA, cT stage and FOXA1 expression (P < 0.0001). Within ERG negative cancers, FOXA1 expression was also strongly associated with PTEN and 5q21 deletions (P < 0.0001). High expression of FOXA1 is an independent prognostic parameter in ERG negative prostate cancer. Thus, FOXA1 measurement might provide clinically useful information in prostate cancer.

Family with sequence similarity 13C (FAM13C) overexpression is an independent prognostic marker in prostate cancer.

FAM13C, a gene with unknown function is included in several mRNA signatures for prostate cancer aggressiveness. To understand the impact of FAM13C on prognosis and its relationship to molecularly defined subsets, we analyzed FAM13C expression by immunohistochemistry on a tissue microarray containing 12,400 prostate cancer specimens. Results were compared to phenotype, ERG status, genomic deletions of 3p, 5q, 6q and PTEN, and biochemical recurrence. FAM13C was detectable in cell nuclei of cancerous and non-neoplastic prostate cells. 67.5% of 9,633 interpretable cancers showed FAM13C expression: strong in 28.3%, moderate in 24.6% and weak in 14.6%. Strong FAM13C expression was linked to advanced pT stage, high Gleason grade, positive lymph node status, and early biochemical recurrence (p < 0.0001 each). FAM13C expression was associated with TMPRSS2:ERG fusions. It was present in 85% of ERG positive but in only 54% of ERG negative cancers (p < 0.0001), and in 91.1% of PTEN deleted but in only 69.2% of PTEN non-deleted cancers (p < 0.0001). The prognostic role of FAM13C expression was independent of classical and quantitative Gleason grade, pT stage, pN stage, surgical margin status and preoperative PSA. In conclusion, the results of our study demonstrate that expression of FAM13C is an independent prognostic marker in prostate cancer. Finding FAM13C also in non-neoplastic prostate tissues highlights the importance of properly selecting cancer-rich areas for RNA-based FAM13C expression analysis.

VEGFR-1 overexpression identifies a small subgroup of aggressive prostate cancers in patients treated by prostatectomy.

The VEGFR-1 is suggested to promote tumor progression. In the current study we analyzed prevalence and prognostic impact of the VEGFR-1 by immunohistochemistry on a tissue microarray containing more than 3000 prostate cancer specimens. Results were compared to tumor phenotype, ETS-related gene (ERG) status, and biochemical recurrence. Membranous VEGFR-1 expression was detectable in 32.6% of 2669 interpretable cancers and considered strong in 1.7%, moderate in 6.7% and weak in 24.2% of cases. Strong VEGFR-1 expression was associated with TMPRSS2:ERG fusion status as determined by fluorescence in situ hybridization (FISH) and immunohistochemistry (p < 0.0001 each). Elevated VEGFR-1 expression was linked to high Gleason grade and advanced pT stage in TMPRSS2:ERG negative cancers (p = 0.0008 and p = 0.001), while these associations were absent in TMPRSS2:ERG positive cancers. VEGFR-1 expression was also linked to phosphatase and tensin homolog (PTEN) deletions. A comparison with prostate specific antigen (PSA) recurrence revealed that the 1.7% of prostate cancers with the highest VEGFR-1 levels had a strikingly unfavorable prognosis. This could be seen in all cancers, in the subsets of TMPRSS2:ERG positive or negative, PTEN deleted or undeleted carcinomas (p < 0.0001 each). High level VEGFR-1 expression is infrequent in prostate cancer, but identifies a subgroup of aggressive cancers, which may be candidates for anti-VEGFR-1 targeted therapy.

ßIII-tubulin overexpression is an independent predictor of prostate cancer progression tightly linked to ERG fusion status and PTEN deletion.

Evidence suggests that class III ß-tubulin (ßIII-tubulin) may represent a prognostic and predictive molecular marker in prostate cancer. ßIII-Tubulin expression was determined by IHC in 8179 prostate cancer specimens in a TMA format. Results were compared with tumor phenotype, biochemical recurrence, v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) status, and deletions on PTEN, 3p13, 5q21, and 6q15. ßIII-Tubulin expression was detectable in 25.6% of 8179 interpretable cancers. High ßIII-tubulin expression was strongly associated with both TMPRSS2:ERG rearrangement and ERG expression (P < 0.0001 each). High ßIII-tubulin expression was tightly linked to high Gleason grade, advanced pT stage, and early prostate-specific antigen (PSA) recurrence in all cancers (P < 0.0001 each), but also in the subgroups of ERG-negative and ERG-positive cancers. When all tumors were analyzed, the prognostic role of ßIII-tubulin expression was independent of Gleason grade, pT stage, pN stage, surgical margin status, and preoperative PSA. Independent prognostic value became even more evident if the analysis was limited to preoperatively available features, such as biopsy specimen Gleason grade, preoperative PSA, cT stage, and ßIII-tubulin expression (P < 0.0001 each). ßIII-Tubulin expression was associated with PTEN (P < 0.0001) when all tumors were analyzed, but also in the subgroups of ERG-negative and ERG-positive cancers. ßIII-Tubulin expression is an independent prognostic parameter. The significant associations with key genomic alterations of prostate cancer, such as TMPRSS2:ERG fusions and PTEN deletions, suggest interactions with several pivotal pathways involved in prostate cancer.

SPINK1 expression is tightly linked to 6q15- and 5q21-deleted ERG-fusion negative prostate cancers but unrelated to PSA recurrence.

BACKGROUND: The serine peptidase inhibitor, Kazal type 1 (SPINK1) has been suggested to define an aggressive molecular subtype of ERG-fusion negative prostate cancer. It was the aim of this study to further study the clinical relevance of SPINK1 expression and its relationship with other key genomic alterations of prostate cancer. METHODS: A tissue microarray containing more than 10,000 prostate cancers with clinical follow-up was used for immunohistochemical SPINK1 analysis. Data on ERG status as well as PTEN, 6q, 5q, and 3p deletions were available for comparison. RESULTS: SPINK1 expression was absent in benign prostate glands and detectable in 5.9% of 9,503 interpretable prostate cancers. Presence of SPINK1 expression was markedly more frequent in ERG negative (10.4%) than in ERG positive cancers (0.3%; P < 0.0001). However, SPINK1 expression was unrelated to tumor phenotype and biochemical recurrence in all cancers and in the subgroup of ERG negative cancers. Further subgroup analyses revealed, however, that--within ERG negative cancers--SPINK1 expression was significantly linked to deletions at 6q15 (P < 0.0001) and 5q21 (P = 0.0042). CONCLUSIONS: Our results exclude SPINK1 as a relevant prognostic prostate cancer biomarker. However, the data demonstrate that SPINK1 overexpression is tightly linked to the small subsets of 6q15- and 5q21-deleted ERG negative prostate cancers. These findings support the concept of molecularly defined subtypes of prostate cancers.