Circulating t(14;18)+ Cells As Predictive Markers Of Follicular Lymphoma Development

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 the relationship with progression to disease remains unclear. A key gap in our understanding is whether such t(14;18)⁺ cells in healthy individuals constitute committed FL precursors, and if high t(14;18) frequencies in blood represent a suitable predictive biomarker of FL development.

Among 520,000 healthy participants enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we identified 100 subjects who developed FL 2-161 months after enrolment. Blinded Prediagnostic blood from these and 218 controls were screened for t(14;18) by sensitive PCR-based assays. Results were subsequently validated on an independent cohort (65 cases, 128 controls). Clonal relationships between t(14;18) cells and FL biopsy were also assessed by molecular backtracking of paired prediagnostic/tumor samples.

Clonal analysis of t(14;18) junctions in paired prediagnostic blood vs. tumor demonstrated that progression to FL occurred from t(14;18)⁺ committed precursors. Furthermore, we show that the prevalence of t(14;18) was significantly higher in individuals that subsequently develop FL compared to the controls (56% vs. 28.9%, p<10^-3). Using a ROC curve analysis, we estimated that an optimal frequency value for predicting FL development was 10^-4. Findings from the discovery cohort were fully validated in an independent cohort and when combined, we confirmed the optimal frequency value of 10^-4. Overall, the combined analysis reports a 23-fold higher risk of subsequent FL associated with the 10-4 threshold (OR: 23.17; 95% CI, 9.98-67.31; P=7.7x10^-9). Remarkably, stratified analyses on time to diagnosis revealed that risk estimates remained high and significant up to 15 years before diagnosis.

We demonstrated that high t(14;18) frequencies in blood from healthy individuals discriminates commitment to FL development up to 15 years before diagnosis and define the first predictive biomarker for FL. Providing they represent bona fide precursors, this molecular blood-based biomarker could therefore be of great value in identifying groups of at-risk individuals and their detailed geno-phenotypic characterization should provide important insights into the factors and kinetics of events driving early FL progression.

No relevant conflicts of interest to declare.