Patients with DLBCL exhibit heterogeneous clinical characteristics, as well as variability in their responses to treatment and prognoses.15–16 Although survival can be estimated based on clinical parameters (age, LDH levels in serum, extranodal site involvement, disease stage, and immunophenotype B), as well as molecular abnormalities (p53, BCL-2, BCL6, MUM.1 and Ki67), controversy exists regarding their utility as prognostic and survival markers.17 As a result, it is of paramount importance to find new markers that could be incorporated to determine the prognosis of this disease.
We evaluated the clinic pathological relevance of NY-ESO-1 gene expression in patients with DLBCL at diagnosis who were admitted to the Hematology service of the Hospital General de México. We decided to examine the expression of the NY-ESO-1 gene in patients with lymphoma, as it is a CTA present in various types of cancer and is associated with clinical factors such as poor prognosis and lower survival.18–19 We confirmed that NY-ESO-1 gene expression is associated with the advanced stage of the disease, changes in the levels of LDH and the IPI, and survival rates. In DLBCL, there are no reports of an association between the expression of this gene and clinical parameters. Hudolinet al.20 analyzed the expression of the NY-ESO-1 gene in 24 samples of testicular tissue with DLBCL; expression was observed in 54.1% and was not correlated with clinical parameters or survival. Other reported molecular markers for DLBCL include p53, bcl-2,and ki67, but these markers were not associated with clinical parameters.17
We observed increases in the frequency of expression and the amount of NY-ESO-1 gene transcription with disease stage in patients with DLBCL, with increases of 3.5% in stages I-II and up to 42.8% in stages III-IV. These results are consistent with previous reports on melanoma in which a 3.34% increase in this gene in stage I and a 9.52% increase in stage II were observed, as was an increase of up to 45% in stage III.21 Similar results were reported in bladder and prostate cancer, where the frequency of expression increases with respect to the stage of the disease.22–23 Only 2 studies have measured the expression levels in metastatic esophageal squamous cell carcinoma and non-small cell lung cancer using qRT-PCR, and elevated transcription levels were associated with advanced disease stages.24–25 In the past, our group demonstrated an association between transcription of the MAGE-A3 gene and advanced stages in patients with DLBCL and leukemia.26–27
In some patients, the MAGE-A3 gene was co-expressed with the NY-ESO-1 gene, which may indicate an unfavorable prognosis. The increase in the level of NY-ESO-1 gene transcription in patients with DLBCL is a finding of great importance; It could be a prognostic marker for this disease. Additionally, the increase in advanced stages of the disease may explain its oncogenic role and the proliferative advantage it confers to tumor cells.
Global survival is lower in patients who express NY-ESO-1, and these results concur with those reported for lung cancer, demonstrating that the expression of NY-ESO-1 is significantly associated with an adverse prognosis.28 Similar data associating the expression of this gene with decreased disease-free survival have been reported for gastrointestinal and bladder cancer.29 Other reports have examined the associations between the expression of the p53, bcl-2, and ki67 genes and global survival in patients with DLBCL and did not observe an association.17 Rearrangements of the BCL-6 gene have been associated with 50% survival at 5 years in patients treated with R-CHOP, although the reported expression frequency was only 19%.30 We have reported that the MAGE-A3 gene is associated with a decrease in survival in patients with DLBCL.26 Thus, the expression of the MAGE-A3 and NY-ESO-1 genes may have great utility for predicting survival in patients with DLBCL.
Similar reports have examined the expression of the MAGE-A2 gene, which inhibits the function of p53 through the recruitment of histone deacetylases and confers resistance to etoposide 31. Another study has demonstrated that in patients with DLBCL who were treated with anthracyclines, chemoresistance was associated with high expression levels of the PRAME gene, which is another member of the CTA family, as well as with a lower global survival32.
NY-ESO-1 gene expression in patients with DLBCL may be helpful for identifying and stratifying risk groups, with other molecular marker of this disease that may benefit from new or intensified therapies.