Clonal Evolution of a Tumor in Two Separate Hosts

On Weigert et al., 2012  in Cancer Discovery

Follicular lymphoma is the tumor of Follicle Center B-cells. Although Bcl2-IGH rearrangement is the main hallmark of this disease, additional genetic events are required for the tumor formation. The studies on the  molecular evolution and the time-course of these genetic events had been missing because of the indolent nature of the disease and because of the scarcity of patient specimens. Weigert et al., in the recent issue of Cancer Discovery present a rare and interesting case which demonstrates clonal evolution in follicular lymphoma.

In 2000, a 41-year old female chronic myelogenous leukemia (CML) patient had started receiving bone marrow transplantation and leukocyte infusions from her HLA-matched sister. This myeloablative therapy combined with cytokine and Gleevec therapies had resulted in complete molecular remission of her CML. 9 years after the first transplant and 7 years after the last leukocyte infusion, the donor sister was diagnosed with grade II follicular lymphoma. Interestingly, in 6 months, recipient sister was also diagnosed with the same grade follicular lymphoma. Molecular genetic analyses showed that the lymphomas originated from the tumorigenic cells of the donor sister which were dormant at the time of infusions.

This kind of donor-derived malignancies after hematopoietic transfer is rare but has been reported in the literature. What makes this study unique is that the authors had access to the DNA samples from the leukocyte infusions as well as to the tumor DNA samples from the patients. By deep sequencing the gene-coding regions, they were able to observe clonal evolution of the genetic changes in two separate hosts.

With deep sequencing they detected 12 non-synonymous mutations and 2 coding insertions/deteletions common to both patients. All but one of these changes were present in the leukocyte infusion thus they were acquired before the transplantation. The authors also detected 3 mutations unique to the donor's lymphoma and 4 mutations unique to the recipient's, suggesting divergent evolution after the delivery of last leukocyte infusion.

One of the mutations unique to the recipient caused a premature stop codon in ARID1A gene and loss of the protein product. Intriguingly, although the donor did not have this mutation, she also had reduced ARID1A protein. Further analyses shown that the donor had copy-number loss at this locus (deletion) in at least a fraction of the tumor cells. In this way, the authors reported convergent evolution of a tumor in two hosts by showing the loss of the same protein via different routes.

Another implication of the study is the development of the tumors with surprisingly similar latency. 7 years after the transplant, the donor presented with the tumor.The time lag was only 6 months for the other patient to develop the disease despite the immunosuppression associated with the initial CML treatment.

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• Oliver Weigert, 
• Nadja Kopp, 
• Andrew A. Lane, 
• Akinori Yoda, 
• Suzanne E. Dahlberg,
• Donna Neuberg, 
• Anita Y. Bahar, 
• Bjoern Chapuy, 
• Jeffery L. Kutok,
• Janina A. Longtine, 
• Frank C. Kuo, 
• Terry Haley, 
• Maura Salois, 
• Timothy J. Sullivan,
• David C. Fisher, 
• Edward A. Fox, 
• Scott J. Rodig, 
• Joseph H. Antin,
• and David M. Weinstock

Molecular Ontogeny of Donor-Derived Follicular Lymphomas Occurring after Hematopoietic Cell Transplantation

Cancer Discovery; 2(1); 47–55