Stockholm, Sweden: Geneticists have discovered that a gene involved in the modification of ribonucleic acid (RNA) is mutated in a significant proportion of people with a collection of blood cancers called myelodysplastic syndromes (MDS). The researchers found that mutations in the SF3B1 gene tended to be associated with a better prognosis, raising the possibility that patients could be screened for the mutation and their treatment tailored accordingly.
Dr Elli Papaemmanuil told the 2011 European Multidisciplinary Cancer Congress  that she and her colleagues found mutations of the SF3B1 gene in 20.3% of MDS patients and that it was closely associated with a particular feature of MDS called ring sideroblasts, which are found in bone marrow. “This is the first time that a close relationship between a mutated gene in MDS and specific feature of the disease has been detected. Mutations were found in about two-thirds (64.6%) of patients whose disease was defined by the presence of ring sideroblasts,” said Dr Papaemmanuil, who is a postdoctoral research fellow working at the Cancer Genome Project at the Wellcome Trust Genome Centre (Cambridge, UK) under the leadership of Dr Peter Campbell.
“Further analysis showed that patients with the SF3B1 mutation had significantly better overall survival and leukaemia-free survival compared to those without the mutation. This suggests that the SF3B1 mutations drive a benign form of MDS. As these mutations can be detected easily in blood samples taken from patients, it may be feasible to identify a group of MDS patients with a benign prognosis who could receive less aggressive treatment – without recourse to an invasive bone marrow biopsy to look for the presence of ring sideroblasts.”
Dr Papaemmanuil’s presentation to the congress coincides with the simultaneous publication of a paper about the research in the New England Journal of Medicine. 
MDS are a diverse group of chronic malignancies of the blood. MDS patients often develop severe anaemia and require frequent blood transfusions. Their blood cell counts can fall due to progressive bone marrow failure, and, for a subset of patients with MDS, their disease can progress into acute myelogenous leukaemia (AML). MDS occur mostly in people aged 60 and over, and, as more people live longer, these syndromes have become the most prevalent myeloid cancer, with an incidence of around 20 cases per 100,000 of the population in the over-70s. Although several genes have been identified as mutated in MDS, all but one are mutated in only 5-15% of cases, and usually at a lower rate in the more benign subtypes of the disease.
Dr Papaemmanuil and her colleagues used high throughput sequencing technology, also dubbed “massively parallel sequencing”, to scan the genomes of nine MDS patients. Massively parallel sequencing enables researchers to work out the sequence order of the components of DNA (four nucleotides: A, C, G and T) in genetic material from the tumour. The purpose of this is to identify any somatically acquired mutations – alterations in the DNA that have occurred after birth in the cancer cells that may be responsible for driving the malignancy.
They identified mutations in SF3B1, a gene that encodes a core component of RNA splicing machinery. RNA splicing is an important editing mechanism that controls the final sequence content of transcribed genetic material. To define the prevalence of the mutation, the researchers undertook targeted sequencing of the gene in 2,087 samples from patients with a range of myeloid and other common cancers (the samples were from blood, bone marrow or primary tumour cells). Somatic mutations of SF3B1 were found in 20.3% of patients with MDS, 5.3% of patients with AML and 2.9% in patients with myeloproliferative neoplasms (a related group of blood disorders). Interestingly, mutations in the same gene were also found in 1-5% of a range of other common cancers such as breast cancer, multiple myeloma and kidney cancer.
Dr Papaemmanuil found a close relationship between the mutated gene and the presence of ring sideroblasts in the bone marrow; significant numbers of ring sideroblasts are found in over a quarter of MDS patients. Ringed sideroblasts are abnormal precursors to mature red blood cells, with a partial or complete ring of iron-laden mitochondria (energy generators) surrounding the nucleus of the cell. Their presence causes anaemia because the body has iron available but is unable to incorporate it into haemoglobin, which red blood cells need to transport oxygen efficiently. Anaemia is one of the symptoms of MDS.
“The close association between SF3B1 mutation and ring sideroblasts that we saw in these MDS patients is consistent with a causal relationship, and makes this the first gene to be strongly associated with a specific feature of MDS,” said Dr Papaemmanuil.
Data on how the patients fared were available for 123 of the MDS patients, of whom 34 had the SF3B1 mutation. The researchers found that patients with the mutation had a milder form of the disease, had significantly better overall survival and were less likely to survive without the disease transforming into leukaemia, compared with patients without the mutation.
Dr Papaemmanuil concluded: “MDS diagnosis and accurate classification still remains challenging. The identification of SF3B1 and the continuous characterisation of the underlying molecular mechanisms of this disease will provide useful insights that can directly inform both the understanding and clinical management of this disease. Our next step is to study a larger cohort of patients with MDS for the presence of known mutations such as the ones we identified in SF3B1, but also to continue to search for additional novel genes that may be mutated in this disease. A larger study population will also prove to be an invaluable resource in helping us quantify the clinical correlates of each mutation or group of mutations with clinical course and outcome.”
Abstract no: 11 LBA, Presidential session IV, 09.00 hrs (CEST), Tuesday 27 September, Hall A1.
 The 2011 European Multidisciplinary Cancer Congress is the 16th congress of the European CanCer Organisation (ECCO), the 36th congress of the European Society for Medical Oncology (ESMO) and the 30th congress of European Society for Therapeutic Radiology and Oncology (ESTRO).
 New England Journal of Medicine. volume 365, issue 15. doi: 10.1056/nejmoa1103283.
 This study is a project for the International Cancer Genome Consortium – a forum for collaboration amongst leading cancer researchers worldwide.