Rafael Fonseca, M.D., is the interim director of Mayo Clinic Cancer Center. As principal investigator of the Multiple Myeloma Laboratory, he concentrates on the genetic and cytogenetic nature of the clonal cells of plasma cell disorders.
To achieve this, Dr. Fonseca's lab uses a variety of tools, including next-generation sequencing, single-cell analysis molecular genetics, fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), gene expression profiling, array-based comparative genomic hybridization (aCGH) and others. The laboratory is currently composed of five full-time technologists and three postdoctoral fellows.
- Origin of the monoclonal gammopathy of undetermined significance (MGUS) and myeloma clone. Dr. Fonseca and his colleagues have begun a systematic evaluation of MGUS plasma cells by molecular and cytogenetic methods. Ultimately, they want to understand the nature of the clone, clinical and biologic significance of the abnormalities, and order of acquisition of abnormalities. They are also interested in the factors permissive for the significant genomic instability observed in the plasma cell neoplasms.
Dr. Fonseca's laboratory was the first to describe that the two main pathways in myeloma pathogenesis, hyperdiploid versus non-hyperdiploid, are dictated by the presence of IgH translocations. Further, his lab was the first to show that this dichotomy is existent since MGUS, and was among the first to describe the presence of the same genetic abnormalities in MGUS as are seen in myeloma, including the high-risk genetic features.
- Progression from MGUS to myeloma. Dr. Fonseca and his team want to better understand why some MGUS patients progress to multiple myeloma and why some never do, and which abnormalities are acquired and thus important for disease progression. In the context of a funded Specialized Program of Research Excellence (SPORE) grant, Dr. Fonseca's lab is doing a detailed genetic characterization of the risk of progression in MGUS according to cytogenetic status.
The lab has also described the presence of these IgH translocations in MGUS cells, even those associated with an aggressive clinical behavior in myeloma. Most recently, the lab is studying how the acquisition of other genetic factors may lead to progression, including the newly described aberrations resulting in NF-kB activation.
- Clinical significance of chromosomal abnormalities in myeloma. Dr. Fonseca is studying the clinical, biologic and prognostic implications of specific chromosomal and genetic abnormalities for patients with myeloma. Ultimately, Dr. Fonseca and his colleagues believe that the accurate knowledge of the abnormalities underlying myeloma will allow for better management and treatment of patients. For instance, they have described the negative impact on prognosis of some genetic aberrations and better outcome with others.
Further, Dr. Fonseca's lab has shown different pathology and clinical features of myeloma based on this genetic characterization. His lab was the first to show the clinical implications of the high-risk genetic translocations, including the t(4;14) and t(14;16). This information is now included in what the myeloma community calls high-risk myeloma. Many medical centers do not proceed to autologous stem cell transplants for patients with high-risk myeloma. Dr. Fonseca's studies have been converted into a clinical test available from Mayo Medical Laboratories. His lab was the first, in conjunction with Leif Bergsagel, M.D., to show the genetic basis of NF-kB upregulation in myeloma.
- Molecular studies of genetic abnormalities in clonal cells of light-chain amyloidosis. Ultimately, Dr. Fonseca and his collaborators want to understand the nature of the clone and its relation to the protein abnormality. They are also interested in the features of the light chains that make them amyloidogenic.
- Molecular studies of genetic abnormalities in clonal cells of lymphoid malignancies, including chronic lymphocytic leukemia, lymphoma and Waldenstrom macroglobulinemia. Dr. Fonseca's studies have focused on the genetic abnormalities of clonal cells of patients with macroglobulinemia and their relation to other B-cell malignancies. His lab described the presence of losses in chromosome 6 in nearly half of patients with Waldenstrom macroglobulinemia.
The lab also showed that these cells lack chromosome translocations and never have the t(9;14), resulting in PAX5 upregulation. Dr. Fonseca and his team also have other major efforts in collaboration with the Lymphoma SPORE to understand genetic variation in lymphoma cells, and were the first to describe NF-kB mutations in lymphoplasmacytic lymphomas based on data generated via aCGH.
Significance to patient care
Dr. Fonseca's research is of importance in the clinic because it's now better understood what the subtypes of myeloma are and how that relates to outcomes. Myeloma is said to be a chronic disease, but that is only true if patients do not have any of the high-risk markers. If a person has high-risk markers, clinicians need to be more cautious and intensive on treatment.