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The transcription factor SOX2(3q26.3–q27) is a key regulator of foregut development and an embryonic stem cell factor cooperating during induction of pluripotency in terminally differentiated somatic cells. Recently, we found SOX2to be amplified in a subset of squamous cell lung and esophageal cancers. The aim of this study was to explore the prognostic role of SOX2in a large series of squamous cell carcinomas and adenocarcinomas of the lung. A total of 891 samples from two independent population-based cohorts were assessed by fluorescence in situhybridization and immunohistochemistry. Furthermore, we assessed for associations between SOX2amplification/upregulation and clinicopathological features. Similar results were found in the two cohorts. Within squamous cell carcinoma cases, 8% high-level as well as 68 and 65% low-level SOX2amplifications occurred in the two cohorts, respectively. In adenocarcinomas, no high-level amplification was found and low-level amplification occurred in 6% of the two cohorts. Within squamous cell carcinomas of one cohort, SOX2amplification was associated with lower tumor grade, while higher levels of SOX2 expression were related to younger age, smaller tumor size, and lower probability of angiolymphatic invasion and metastasis. High SOX2 expression levels proved to be a marker for prolonged overall survival among patients with squamous cell carcinomas. In conclusion, SOX2amplification and upregulation are frequent events in squamous cell carcinomas of the lung and are associated with indicators of favorable prognosis.

A majority of prostate cancers exhibit a recurrent gene rearrangement involving chromosome 21. In approximately 90% of cases, the rearrangement is characterized by fusion of the androgen-regulated gene TMPRSS2with the oncogene ERG. A recent study suggested that TMPRSS2–ERGgene fusion is lacking in cancers arising from the transition zone of the prostate. A dominant transition zone cancer was detected in 62/397 (16%) patients who underwent radical prostatectomy at our institution and were reviewed and mapped by a single pathologist. In 46/62 specimens, a secondary tumor was identified in the peripheral zone of the prostate. A tissue microarray containing both transition and peripheral zone tumors was constructed and evaluated for gene fusion analysis. TMPRSS2–ERGfusion status was determined using a multicolor interphase fluorescence in situhybridization assay for ERGbreak-apart. The median age of the patients was 59 years. Prostatectomy Gleason score was 6 in 21, 7 in 34, and ≥8 in 7 cases. Median tumor volume was 200 mm2. TMPRSS2–ERGgene fusion was present in 7/59 (12%) transition zone, and in 12/35 (34%) peripheral zone tumors. Transition zone fusion-positive cases were larger than their negative counterparts. No significant correlation was found between fusion status and Gleason score or pathologic stage. Gene fusion through deletion occurred in 4/7 transition zone and 7/12 peripheral zone tumors. Transition zone prostate cancers are considered biologically and genetically different from peripheral zone tumors. Although ERGrearrangement is more common in peripheral zone tumors, we have detected TMPRSS2–ERGfusion in a subset of transition zone cancers (12%). The lower frequency of gene fusion in transition zone prostate cancer may suggest distinct molecular alterations from peripheral zone tumors and the association with a high tumor volume may indicate a growth advantage for transition zone tumors harboring the gene fusion. Further studies are necessary to confirm this hypothesis.

Identification of specific somatic gene alterations is crucial for the insight into the development, progression, and clinical behavior of individual cancer types. The recently discovered recurrent ERGrearrangement in prostate cancer might represent a prostate cancer-specific alteration that has not been systematically assessed in tumors other than prostate cancer. Aim of this study was to assess, whether the ERGrearrangement and the distinct deletion site between TMPRSS2and ERG, both predominantly resulting in a TMPRSS2–ERGfusion, occur in tumors other than prostate cancer. We assessed 54 different tumor types (2942 samples in total) for their ERGrearrangement status by fluorescence in situhybridization (FISH). To calibrate, we analyzed 285 prostate cancer samples for the ERGrearrangement frequency. Additionally, we interrogated a high-resolution single nucleotide polymorphism (SNP) data set across 3131 cancer specimens (26 tumor types) for copy number alterations. None of the 54 different tumor types assessed by FISH harbored an ERGrearrangement, whereas the prostate cancer samples revealed an ERGrearrangement in 49.5% of cases. Furthermore, within the 26 tumor types assessed for copy number alterations by SNP, the distinct deletion site between TMPRSS2and ERG(21q22.2–3) was detectable exclusively in prostate cancer. Although Ewing's sarcoma and AML have known rearrangements rarely involving ERG, we hypothesize that the ERGrearrangement as well as the distinct deletion site on 21q22.2–3 between TMPRSS2and ERGare prostate-cancer-specific genomic alterations. These observations provide further insight into the oncogenesis of prostate cancer and might be critical for the development of ERGrearrangement assessment as a clinical tool.

The majority of prostate cancers harbor recurrent gene fusions between the hormone-regulated TMPRSS2and members of the ETS family of transcription factors, most commonly ERG. Prostate cancer with ERGrearrangements represent a distinct sub-class of tumor based on studies reporting associations with histomorphologic features, characteristic somatic copy number alterations, and gene expression signatures. This study describes the frequency of ERGrearrangement prostate cancer and three 5 prime (5′) gene fusion partners (ie, TMPRSS2, SLC45A3,and NDRG1) in a large prostatectomy cohort. ERGgene rearrangements and mechanism of rearrangement, as well as rearrangements of TMPRSS2, SLC45A3,and NDRG1,were assessed using fluorescence in situhybridization (FISH) on prostate cancer samples from 614 patients treated using radical prostatectomy. ERGrearrangement occurred in 53% of the 540 assessable cases. TMPRSS2and SLC45A3were the only 5′ partner in 78% and 6% of these ERGrearranged cases, respectively. Interestingly, 11% of the ERG rearranged cases showed concurrent TMPRSS2and SLC45A3rearrangements. TMPRSS2or SLC45A3rearrangements could not be identified for 5% of the ERGrearranged cases. From these remaining cases we identified one case with NDRG1rearrangement. We did not observe any associations with pathologic parameters or clinical outcome. This is the first study to describe the frequency of SLC45A3–ERGfusions in a large clinical cohort. Most studies have assumed that all ERGrearranged prostate cancers harbor TMPRSS2–ERGfusions. This is also the first study to report concurrent TMPRSS2and SLC45A3rearrangements in the same tumor focus, suggesting additional complexity that had not been previously appreciated. This study has important clinical implications for the development of diagnostic assays to detect ETS rearranged prostate cancer. Incorporation of these less common ERGrearranged prostate cancer fusion assays could further increase the sensitivity of the current PCR-based approaches.

Novel recurrent gene fusions between the androgen-regulated gene TMPRSS2and the ETSfamily members ERG, ETV1,or ETV4have been recently identified as a common molecular event in prostate cancer development. We comprehensively analyzed the frequency and risk of disease progression for the TMPRSS2and ETSfamily genes rearrangements in a cohort of 96 American men surgically treated for clinically localized prostate cancer. Using three break apart (TMPRSS2, ERG, ETV4) and one fusion (TMPRSS:ETV1) fluorescence in situhybridization (FISH) assays, we identified rearrangements in TMPRSS2, ERG, ETV1, and ETV4in 65, 55, 2, and 2% of cases, respectively. Overall, 54 and 2% of cases demonstrated TMPRSS2:ERGand TMPRSS2:ETV1fusions, respectively. As intronic loss of genomic DNA between TMPRSS2and ERGhas been identified as a mechanism of TMPRSS2:ERGfusion, our assays allowed us to detect deletion of the 3′ end of TMPRSS2and the 5′ end of ERGin 41 and 39% of cases rearranged for respective genes. Prostate cancers demonstrating TMPRSS2gene rearrangement were associated with high pathologic stage (P=0.04). Our results confirm that recurrent chromosomal aberrations in TMPRSS2and/or ETSfamily members are found in about 70% of prostate cancers. Importantly, we define a novel approach to study these gene fusions and identified cases where TMPRSS2was rearranged without rearrangement of ERG, ETV1or ETV4and cases with ETSfamily gene rearrangement without TMPRSS2rearrangement, suggesting that novel 5′ and 3′ partners may be involved in gene fusions in prostate cancer.