• a Hematology and Oncology, Clinic for Internal Medicine C, University of Greifswald , Greifswald , Germany.
• b Division of Cancer Epidemiology and Genetics, National Cancer Institute , Bethesda , MD , USA.
• c Division of Cancer Prevention, National Cancer Institute , Bethesda , MD , USA.
• d Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA.

Many adults have circulating lymphocytes with the BCL2 gene translocation characteristic of follicular lymphoma. We therefore conducted a nested case-control study of incident lymphomas with peripheral blood obtained a median 4.9 years pre-diagnosis from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Overall, 13 of 26 cases of lymphoma and 14 of 47 controls had BCL2 major breakpoint region (MBR) translocations in pre-diagnosis blood (odds ratio [OR] = 2.8). Nine cases had BCL2-MBR-positive tumors; eight of these nine had BCL2-MBR translocations in paired blood versus five of the 17 with BCL2-MBR-negative tumors (p = 0.01). Comparing both tumor types to controls, blood BCL2-MBR translocations had a strong, statistically significant association with BCL2-MBR-positive tumors (OR = 26), but not with BCL2-MBR-negative tumors (OR = 0.9). All eight BCL2-MBR-positive tumors with pre-diagnosis BCL2 translocations were clonally related to these circulating cells, based on similarity of recombination sequences. These data indicate that blood BCL2-MBR translocations represent lymphoma precursor clones with malignant potential.