t(14;18) Translocation: A Predictive Blood Biomarker for Follicular Lymphoma

Abstract

Purpose The (14;18) translocation constitutes both a genetic hallmark and critical early event in the natural history of follicular lymphoma (FL). However, t(14;18) is also detectable in the blood of otherwise healthy persons, and its relationship with progression to disease remains unclear. Here we sought to determine whether t(14;18)-positive cells in healthy individuals represent tumor precursors and whether their detection could be used as an early predictor for FL. Participants and Methods Among 520,000 healthy participants enrolled onto the EPIC (European Prospective Investigation Into Cancer and Nutrition) cohort, we identified 100 who developed FL 2 to 161 months after enrollment. Prediagnostic blood from these and 218 controls were screened for t(14;18) using sensitive polymerase chain reaction–based assays. Results were subsequently validated in an independent cohort (65 case participants; 128 controls). Clonal relationships between t(14;18) cells and FL were also assessed by molecular backtracking of paired prediagnostic blood and tumor samples. Results Clonal analysis of t(14;18) junctions in paired prediagnostic blood versus tumor samples demonstrated that progression to FL occurred from t(14;18)-positive committed precursors. Furthermore, healthy participants at enrollment who developed FL up to 15 years later showed a markedly higher t(14;18) prevalence and frequency than controls (P < .001). Altogether, we estimated a 23-fold higher risk of subsequent FL in blood samples associated with a frequency > 10 −4 (odds ratio, 23.17; 95% CI, 9.98 to 67.31; P < .001). Remarkably, risk estimates remained high and significant up to 15 years before diagnosis. Conclusion High t(14;18) frequency in blood from healthy individuals defines the first predictive biomarker for FL, effective years before diagnosis.

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Affiliated Institutions

• Academy of Athens GR
• Centre Hospitalier Universitaire de Tours FR
• Inserm FR
• Istituto per lo Studio e la Prevenzione Oncologica IT
• Directorate of Health IS
• Université Paris-Sud FR
• Aix-Marseille Université FR
• Fondazione IRCCS Istituto Nazionale dei Tumori IT
• Centre international de recherche sur le cancer FR
• Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública ES
• Imperial College London GB
• Universidad de Murcia ES
• University of Freiburg DE
• Danish Cancer Society DK
• Azienda Usl 8 Arezzo IT
• Centre National pour la Recherche Scientifique et Technique (CNRST) MA
• German Institute of Human Nutrition DE
• Lund University SE
• Regional Health US
• Institut Català d'Oncologia ES
• National and Kapodistrian University of Athens GR

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