t(14;18) Translocation: A predictive blood biomarker for follicular lymphoma.
Roulland S., Kelly RS., Morgado E., Sungalee S., Solal-Celigny P., Colombat P., Jouve N., Palli D., Pala V., Tumino R., Panico S., Sacerdote C., Quirós JR., Gonzáles CA., Sánchez M-J., Dorronsoro M., Navarro C., Barricarte A., Tjønneland A., Olsen A., Overvad K., Canzian F., Kaaks R., Boeing H., Drogan D., Nieters A., Clavel-Chapelon F., Trichopoulou A., Trichopoulos D., Lagiou P., Bueno-de-Mesquita HB., Peeters PHM., Vermeulen R., Hallmans G., Melin B., Borgquist S., Carlson J., Lund E., Weiderpass E., Khaw K-T., Wareham N., Key TJ., Travis RC., Ferrari P., Romieu I., Riboli E., Salles G., Vineis P., Nadel B.
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.