SF3B1 Mutations Linked to Improved Prognosis in MDS

Roxanne Nelson

September 29, 2011

September 29, 2011 (Stockholm, Sweden) — Mutations in the SF3B1 gene might indicate a more favorable prognosis in myelodysplastic syndromes (MDS).

The SF3B1 gene is involved in the modification of RNA. In a recent study, it was observed in 20% of MDS patients; there was a particularly high frequency in patients whose disease was characterized by ring sideroblasts (65%).

Importantly, patients with SF3B1 mutations had fewer episodes of cytopenia and enjoyed longer event-free survival than patients without these mutations.

The study results were published online September 26 in the New England Journal of Medicine to coincide with their presentation here at the 2011 European Multidisciplinary Cancer Congress.

Dr. Elli Papaemmanuil

"Genomic studies give new insight into the causes of MDS, and can complement standard analyses," said lead author Elli Papaemmanuil, PhD, a postdoctoral research fellow working at the Cancer Genome Project, the Wellcome Trust Genome Centre, Cambridge, United Kingdom. "Using SF3B1 could improve and accelerate diagnosis and can identify high-risk patients, and understanding the molecular mechanisms will help stratify therapy and search for drug targets.

Genetic Mutations Unclear

MDS are a heterogeneous group of hematologic cancers that are characterized by low blood counts, most commonly anemia, explained Dr. Papaemmanuil. Patients face a risk for progression to acute myeloid leukemia (AML).

More than a quarter of all patients with MDS present with large numbers of ring sideroblasts in the bone marrow. These are abnormal precursors of mature red blood cells, and have a distinctive partial or complete ring of iron-laden mitochondria that surrounds the cell nucleus. Several genetic lesions related to inherited sideroblastic anemias have been identified, but the pathogenesis of ring sideroblasts in MDS remains unclear.

Improved Diagnostics Needed

Patients often present with symptoms of unexplained anemia, bleeding, bruising, and frequent infections. "But the diagnostic course in the clinic is not always very straightforward," she said. "It will take multiple blood tests, most of which will be abnormal, and the exclusion of other common infections before the hematologist will decide to subject the patient to a bone marrow examination."

Bone marrow exams are invasive, painful, expensive, and time consuming, but are often needed to confirm a diagnosis of MDS, Dr. Papaemmanuil explained. "This process can take anywhere from a few months to 2 years; during that time, the patient is living with MDS."

"What is most important about this is that for every patient who is diagnosed with MDS, it is estimated that there is another patient with MDS who never gets diagnosed," she emphasized. "The key point is that there is a large proportion of MDS patients."

Receiving an MDS diagnosis is not the end point, she continued. About 20% will progress to AML and require different treatment.

Quite often, a patient cannot be assigned to any of the disease subtypes. This makes it difficult to decide on an appropriate treatment regimen, Dr. Papaemmanuil explained.

Although there are a number of mutations in MDS, none of them really explain the different subtypes or the different responses seen in patients. "We believe that there are mutations that can not only explain every MDS subtype, but can directly inform us of the likely response of the patient and clinical course," she said.

Mutation in SF3B1 Identified

Dr. Papaemmanuil and colleagues sought to identify recurrently mutated cancer genes in patients with low-grade MDS, which could prove useful in diagnosing these disorders and provide insight into the molecular pathogenesis.

Using massively parallel sequencing technology of all protein-coding exons, the researchers identified mutations in the genome of 9 patients with low-grade MDS. In 6 of these patients, recurrent somatic mutations in the SF3B1 gene, which encodes a core component of the RNA splicing machinery, were identified. Overall, 64 point mutations were identified in the 9 patients.

The gene was then resequenced in 2087 specimens from patients with MDS, primary cancers, and core cancer cell lines. The researchers detected somatic mutations of SF3B1 in 28.1% of patients with MDS, 19.3% of patients with MDS or myeloproliferative neoplasm, and 5.3% of patients with AML.

Mutations of the gene were also observed in 1% to 5% of other common tumor types, including breast cancer, multiple myeloma, and renal cancer. In patients with myeloid neoplasms, there was also a close relation between mutant SF3B1 and the presence of ring sideroblasts (P < .001). In multivariable analysis, SF3B1 mutations were independently associated with better overall survival (hazard ratio [HR], 0.18; P = .028) and a lower risk for leukemic evolution (HR, 0.32; P = .048).

A "Seminal Discovery"

Acting as a discussant of the study, Carlos Caldas, MD, from the Cambridge Research Institute, United Kingdom, asserted that "we now have to look at all of these genes as candidate cancer genes in all tumor types."

"Not just point mutations but amplifications also," he emphasized." I think we are in the face of a seminal discovery, and we have to broaden our understanding of cancer."

"There is a lot of positive potential here for prognostication and for therapeutic strategies," he concluded.

The study was funded by the Wellcome Trust, the Kay Kendall Leukaemia Fund, Leukemia Lymphoma Research, the Adenoid Cystic Carcinoma Research Foundation, the Medical Research Council, the Oxford National Institutes for Health Research Biomedical Research Centre, the Swedish Cancer Society, the International Human Frontier Science Program Organization, the Department of Veterans Affairs, the National Institutes of Health, the Association for International Cancer Research, the Leukemia Lymphoma Society, Associazione Italiana per la Ricerca sul Cancro, and Fondazione Cariplo. Dr. Papaemmanuil has disclosed no relevant financial relationships. Several coauthors disclosed financial relationships with pharmaceutical and biotechnology companies.

N Engl J Med. Published online September 26, 2011. Abstract

2011 European Multidisciplinary Cancer Congress (EMCC): Abstract LBA 11. Presented September 27, 2011.

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