Identifying a prognostic test in follicular lymphoma using a tissue microarray and immunohistochemistry
Foster, Cheryl June
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Follicular lymphoma (FL) is an attractive model for discovering biomarkers and elucidating mechanisms of tumour progression. We hypothesized that alterations in the expression of proteins with known roles in cancer biology and hematological cells might correlate with clinical outcome and thereby shed light on biological mechanisms. Sections from a tissue microarray (TMA) containing FL samples from 67 patients were immunostained for candidate biomarkers, including p53, p16INK4a, Bcl-2, Bcl-6, MUM1, PML, phospho-ERK, and p27Kip1. The Kaplan-Meier method and log-rank test were used to identify markers that correlate significantly (p<0.05) with overall survival (OS). The chi-squared or Fisher exact test were used to examine associations between histological markers and baseline clinical features, including the Follicular Lymphoma International Prognostic Index (FLIPI) score. Expression of p16INK4a or p53, or absent CD10 expression correlated with poor survival. Patients with p16INK4a-negative tumours had a median OS of 13.4 years compared to 8.3 years for those with p16INK4a-positive tumours (p=0.006). Expression of p16INK4a was significantly associated with low hemoglobin, elevated serum lactate dehydrogenase (LDH), high histological grade, high cell proliferation index, presence of associated diffuse large B-cell lymphoma (DLBCL) and high-risk FLIPI classification. Our observation of a positive association between p16INK4a expression and indicators of tumour aggressiveness is novel and perhaps surprising since loss of the INK4a tumour suppressor gene is one of the most frequently observed lesions in human cancers, including lymphoma. Expression of p16INK4a may be part of a cellular response to unidentified pro-mitotic mutations, such as deleterious mutations of the RB tumour suppressor gene, associated with more aggressive instances of FL. Immunostaining FL diagnostic biopsies for expression of p16INK4a may serve as an informative prognostic biomarker to aid clinicians managing FL patients.