Loss of SOX9 Expression Is Associated with PSA Recurrence in ERG-Positive and PTEN Deleted Prostate Cancers

Abstract

The transcription factor SOX9 plays a crucial role in normal prostate development and has been suggested to drive prostate carcinogenesis in concert with PTEN inactivation. To evaluate the clinical impact of SOX9 and its relationship with key genomic alterations in prostate cancer, SOX9 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers. Data on ERG status and deletions of PTEN, 3p13, 5q21 and 6q15 were available from earlier studies. SOX9 expression levels were comparable in luminal cells of normal prostate glands (50% SOX9 positive) and 3,671 cancers lacking TMPRSS2:ERG fusion (55% SOX9 positive), but was markedly increased in 3,116 ERG-fusion positive cancers (81% SOX9 positive, p<0.0001). While no unequivocal changes in the SOX9 expression levels were found in different stages of ERG-negative cancers, a gradual decrease of SOX9 paralleled progression to advanced stage, high Gleason grade, metastatic growth, and presence of PTEN deletions in ERG-positive cancers (p<0.0001 each). SOX9 levels were unrelated to deletions of 3p, 5q, and 6q. Down-regulation of SOX9 expression was particularly strongly associated with PSA recurrence in ERG-positive tumors harboring PTEN deletions (p=0.001), but had no significant effect in ERG-negative cancers or in tumors with normal PTEN copy numbers. In summary, the results of our study argue against a tumor-promoting role of SOX9 in prostate cancer, but demonstrate that loss of SOX9 expression characterizes a particularly aggressive subset of ERG positive cancers harboring PTEN deletions.

Fig 1. Representative pictures SOX9 immunostaining in prostate cancer.

(a) negative, (b) weak, (c) moderate, (d) strong.

Fig 2. Relationship of SOX9 expression with ERG status.

IHC = immunohistochemistry; FISH = fluorescence in-situ hybridization.

Fig 3. SOX9 expression versus PTEN, 3p13, 6q15 and 5q21 deletions probed by FISH analysis.

(a) all cancers, (b) in ERG-negative, c) ERG-positive subset.

Fig 4. Association of SOX9 expression with biochemical recurrence.

(a) ERG-positive (ERG⁺) cancers (n = 2,906), (b) ERG-negative (ERG^-) cancers (n = 3,407), (c) PTEN deleted (PTEN^del) cancers (n = 771), (d) PTEN non-deleted (PTEN^norm) cancers (n = 3,367), (e) ERG-positive and PTEN deleted cancers (n = 512), (f) ERG-negative and PTEN non-deleted cancers (n = 1,859), (g) ERG-positive and PTEN non-deleted cancers (1,391), (h) ERG-negative and PTEN deleted cancers (n = 238). A detailed list of the number of patients at risk is given for (a) and (b) in S3 Table.