4824

NKX3-1

NK3 homeobox 1;NKX3-1;NK3 homeobox 1

NK homeobox, family 3, A|NK3 transcription factor homolog A|NK3 transcription factor related, locus 1|homeobox protein NK-3 homolog A|homeobox protein Nkx-3.1

8p21.2

protein-coding

NKX3.1 is a prostatic tumor suppressor gene located on chromosome 8p. Although most studies have shown that staining for NKX3.1 protein is positive in the majority of primary prostatic adenocarcinomas, it has been shown to be downregulated in many high-grade prostate cancers, and completely lost in the majority of metastatic prostate cancers (eg, in 65% to 78% of lesions). A recent study showed that NKX3.1 staining with a novel antibody was highly sensitive and specific for high-grade prostatic adenocarcinoma when compared with high-grade urothelial carcinoma. This raised the question that this antibody may perform better than earlier used antibodies in metastatic prostate tumors. However, the sensitivity and specificity for prostate carcinomas for this antibody in metastatic lesions was not determined. Although prostate-specific antigen (PSA) and prostatic-specific acid phosphatase (PSAP) are excellent tissue markers of prostate cancer, at times they may be expressed at low levels, focally, or not at all in poorly differentiated primary and metastatic prostatic adenocarcinomas. The purpose of this study was to determine the performance of NKX3.1 as a marker of metastatic adenocarcinoma of prostatic origin. Immunohistochemical staining against NKX3.1, PSA, and PSAP was carried out on a tissue microarray (TMA) (0.6-mm tissue cores) of hormone naive metastatic prostate adenocarcinoma specimens from lymph nodes, bone, and soft tissue. To determine the specificity of NKX3.1 for prostatic adenocarcinoma, we used TMAs that contained cancers from various sites including the urinary bladder, breast, colon, salivary gland, stomach, pancreas, thyroid, and central nervous system, and standard paraffin sections of cancers from other sites including the adrenal cortex, kidney, liver, lung, and testis. Overall 349 nonprostatic tumors were evaluated. Any nuclear staining for NKX3.1 was considered positive and the percentage of cells with nuclear staining and their mean intensity level were assessed visually. Sensitivity was calculated by considering a case positive if any TMA core was positive. The sensitivity for identifying metastatic prostatic adenocarcinomas overall was 98.6% (68/69 cases positive) for NKX3.1, 94.2% (65/69 cores positive) for PSA, and 98.6% (68/69 cores positive) for PSAP. The specificity of NKX3.1 was 99.7% (1/349 nonprostatic tumors positive). The sole positive nonprostatic cancer case was an invasive lobular carcinoma of the breast. NKX3.1 seems to be a highly sensitive and specific tissue marker of metastatic prostatic adenocarcinoma. In the appropriate clinical setting, the addition of IHC staining for NKX3.1, along with other prostate-restricted markers, may prove to be a valuable adjunct to definitively determine prostatic origin in poorly differentiated metastatic carcinomas.

The prognosis of oral squamous cell carcinoma (OSCC) is significantly dependent on the existence of cervical lymph node metastasis (LNM), with the overall survival rate being much lower in patients with LNM. Primary causes and molecular mechanisms of LNM are still largely unclear. We hypothesized that factors related with cancer progress and/or prognosis in OSCC are revealed by genome-wide investigation of DNA copy number aberrations (CNAs). In order to find biomarkers for occult LNM of OSCC, we comprehensively investigated genomic DNAs from 60 OSCC patients using Affymetrix mapping arrays and statistically analyzed correlations between CNAs of genes and the presence of occult LNM in the patients. The genome-wide CNA study indicated significant correlations between the presence of occult LNM and CNAs of certain genes. Through a literature survey, we narrowed down the candidates and focused on loss of NKX3-1, which is a homeodomain-containing transcription factor. NKX3-1 is known as a tumor suppressor gene in prostate cancer but has never been reported in OSCC. Quantitative RT-PCR and immunohistochemistry (IHC) analyses also showed significantly lower expression of NKX3-1 in the cases with occult LNM, which was further validated by IHC analysis in independent cases. The survival analyses indicated that NKX3-1 loss is a significant risk factor to decrease the disease-free survival (DFS) and the overall survival (OS) rates. This is the first time that the significant association of NKX3-1 loss and occult LNM was indicated in OSCC. The present results suggest that loss of NKX3-1 may be a potential biomarker for occult LNM of OSCC.

BACKGROUND: Radical prostatectomy (RP) is not curative if patients have undetected metastatic prostate cancer. Markers that indicate the presence of metastatic disease would identify men who may benefit from systemic adjuvant therapy. Our approach was to analyze the primary tumors of men with metastatic disease versus organ-confined disease to identify molecular changes that distinguish between these groups. METHODS: Patients were identified based on long-term follow-up of serum prostate specific antigen (PSA) levels following RP. We compared the tumors of African American (AA) men with undetectable serum PSA for >9 year after RP (good outcome) versus those of AA men with a rising PSA and recurrence after radiation or androgen ablation or both (poor outcome). We used real-time quantitative PCR to assay gene copy number alterations in tumor DNA relative to patient-matched non-tumor DNA isolated from paraffin-embedded tissue. We assayed several genes located in the specific regions of chromosome 8p and 8q that frequently undergo loss and/or gain, respectively, in prostate cancer, and the androgen receptor gene at Xq12. RESULTS: Gain of the MIR151 gene at 8q24.3 (in 33% of poor outcome vs. 6% of good outcome tumors) and/or loss of the NKX3-1 gene at 8p21.2 (in 39% of poor outcome vs. 11% of good outcome tumors) affected 67% of poor outcome tumors, compared to only 17% of good outcome tumors. CONCLUSIONS: copy number gain of the MIR151 gene and/or loss of the NKX3-1 gene in the primary tumor may indicate the presence of metastatic disease.