Predictive Biomarkers and Personalized Medicine Inactivation of the CDKN2A Tumor-Suppressor Gene by Deletion or Methylation Is Common at Diagnosis in Follicular Lymphoma and Associated with Poor Clinical Outcome

Purpose: Follicular lymphoma, the most common indolent lymphoma, is clinically heterogeneous. CDKN2A encodes the tumor suppressors p16 and p14 and frequently suffers deleterious alterations in cancer. We investigated the hypothesis that deletion or hypermethylation of CDKN2A might identify follicular lymphoma cases with distinct clinical or pathologic features potentially amenable to tailored clinical management. Experimental Design: Deletion of CDKN2A was detected in pretreatment biopsy specimens using a single nucleotide polymorphism–based approach or endpoint PCR, and methylation of CpG elements in CDKN2Awasquantifiedbymethylation-specific PCR.Correlations betweenCDKN2A status andpathologic or clinical characteristics, including overall survival (OS), were investigated in 106 cases using standard statistical methods. Results:Deletion of CDKN2Awas detected in 9 of 111 samples (8%) andmethylation was detectable in 22 of 113 (19%). CDKN2A was either deleted or methylated in 29 of 106 cases (27%) and this status was associatedwith inferiorOS especially among patients treatedwith rituximab (P1⁄4 0.004).CDKN2Adeletion ormethylation was associated withmore advanced age (P1⁄4 0.012) and normal hemoglobin (P1⁄4 0.05) but not with sex, FLIPI score, ECOG stage, LDH, performance status, number of involved nodal sites, B symptoms, histologic grade, the presence of a component of diffuse large B-cell lymphoma, proliferation index, or other pathologic factors. Conclusions: Our results show that deletion or methylation of CDKN2A is relatively common in pretreatment follicular lymphoma biopsy specimens and defines a group of cases associated with reduced survival in the rituximab era presumably on the basis of more aggressive disease biology. Clin Cancer Res; 20(6); 1676–86. 2014 AACR.