Researchers have investigated the relationship between spontaneous mutations present in blood cells and why certain cancer therapies can lead to a secondary blood cancer years later.
Dr Kelly Bolton and colleagues at Memorial Sloan Kettering Cancer Center, New York, USA, looked at the potential triggers for therapy-related acute myeloid leukaemia or myelodysplastic syndrome.
Historically, it had been believed that these conditions were caused by chemotherapy or radiotherapy used to treat a primary cancer. However, researchers have recently discovered that spontaneous mutations may contribute to these conditions, independent of cancer therapy – a phenomenon called clonal haematopoiesis.
The researchers set out to understand the relationship between this clonal haematopoiesis and therapy-related blood cancers. To do this, they sequenced the DNA present in blood cells from samples taken from 24,000 patients with a wide range of primary cancers. They found that clonal haematopoiesis was present in a third of patients.
Further analysis showed certain patterns of clonal haematopoiesis caused by radiation therapy, platinum chemotherapies, or topoisomerase II inhibitors. They found that clonal haematopoiesis mutations after cancer treatment occurred most frequently in the genes whose protein products protect the genome from damage, including TP53, the so-called ‘guardian of the genome’.
Their findings suggest that certain clonal haematopoiesis mutations could indicate which cancer patients are at the highest risk of developing therapy-related blood cancers.
Co-senior author Dr Elli Papaemmanuil says that the findings, published in the journal Nature Genetics, “provide a direct link between mutation type, specific therapies, and how these cells progress towards becoming a blood cancer.”
She adds: “Our hope is that this research will help us to understand the implications of having clonal haematopoiesis, and to begin to develop models that predict who with clonal haematopoiesis is at higher risk for developing a blood cancer.”
Co-senior author Dr Ahmet Zehir comments: “We are now routinely screening our patients for the presence of clonal haematopoiesis mutations. As we continue to study more patients in the clinic, we expect to learn more about how to use these findings to find ways to detect treatment-related blood cancers early when they may be more treatable.”
Bolton KL, Ptashkin RN, Gao T, Braunstein L, Devlin SM, Kelly D, Patel M, Berthon A, Syed A, Yabe M, Coombs CC, Caltabellotta NM, Walsh M, Offit K, Stadler Z, Mandelker D, Schulman J, Patel A, Philip J, Bernard E, Gundem G, Ossa JEA, Levine M, Martinez JSM, Farnoud N, Glodzik D, Li S, Robson ME, Lee C, Pharoah PDP, Stopsack KH, Spitzer B, Mantha S, Fagin J, Boucai L, Gibson CJ, Ebert BL, Young AL, Druley T, Takahashi K, Gillis N, Ball M, Padron E, Hyman DM, Baselga J, Norton L, Gardos S, Klimek VM, Scher H, Bajorin D, Paraiso E, Benayed R, Arcila ME, Ladanyi M, Solit DB, Berger MF, Tallman M, Garcia-Closas M, Chatterjee N, Diaz LA Jr, Levine RL, Morton LM, Zehir A, Papaemmanuil E. (2020) “Cancer therapy shapes the fitness landscape of clonal hematopoiesis.” Nature Genetics, doi: 10.1038/s41588-020-00710-0
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