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What causes therapy-related malignancies in childhood cancer survivors? Dissecting the etiology of second cancers

Periodic Reporting for period 2 - SecondCANCERinKIDS (What causes therapy-related malignancies in childhood cancer survivors? Dissecting the etiology of second cancers)

Período documentado: 2021-10-01 hasta 2023-03-31

The survival of children with cancer has increased tremendously during the last decades. For example, the 15 years survival rate of children with acute lymphoblastic leukemia (ALL), which is the most common type of cancer in children, has increased from less than 10% in the 1960s to more than 90% now. This success in childhood cancer survival can be attributed to increasingly higher doses of chemo- and/or radiotherapy. Although high-intensity therapy more efficiently eradicates tumor cells, it can also be genotoxic to normal, that is noncancerous, cells. Indeed, because of their life-saving therapy, childhood cancer survivors are confronted with a variety of chronic health conditions later in life, including an increased risk for developing a novel (second) malignancy unrelated to the initial cancer. Compared to the general population, childhood cancer survivors not only show a higher incidence in novel malignancies, but also develop the disease earlier in life. In fact, second malignancies are one of the major causes for long-term mortality among survivors of childhood cancer. Importantly, the incidence of second malignancies is expected to rise in parallel with the increase of cancer survivors worldwide. Ideally, therapeutic strategies should be developed, which are aimed at preventing carcinogenesis in patients at risk for second malignancies.

Our overall aim is to determine the mechanisms and rate-limiting steps underlying the genesis of second malignancies in childhood cancer survivors. For this, we will study mutation accumulation at the single cell level in longitudinally collected blood samples of children who developed a therapy-related hematopoietic malignancy. Instead of focusing on identifying cancer driver mutations, we will utilize the entire set of (mostly passenger) mutations in these cells to i) track down the cellular origin of second malignancies by retrospective lineage tracing, ii) identify the mechanisms causing second malignancies by in-depth mutational analyses, and iii) study phenotypic effects of cancer treatment on population dynamics of blood.
We have generated a large collection of bone marrow aspirates and/or peripheral blood samples of childhood cancer survivors, who developed a therapy-related myeloid neoplasm (t-MN) after successful treatment of their first cancer. In total, we included samples of 20 patients from our in-house biobank. In addition, we requested additional samples from different European countries through the international BFM study group and obtained material of another 42 patients.

So far, we have analyzed by whole genome sequencing (WGS) the mutational landscapes of the t-MN of 47 of these patients. In addition, for 19 patients we have also analyzed nonmalignant normal hematopoietic stem and progenitor cells (HSPCs). Most t-MNs are driven by structural variation. Posttreatment HSPCs had an average mutation burden increase comparable to what treatment-naïve cells accumulate during 16 years of life independent of the patient’s age, with excesses up to 80 years. These additional mutations were mostly induced by clock-like processes, which are also active during healthy aging. Using phylogenetic inference, we demonstrate that most t-MN in children originate after the start of treatment and that leukemic clones become dominant during or directly after chemotherapy exposure. This work has been published in the scientific journal Cancer Discovery.

We also identified novel mutational signatures of unknown etiology in children that received hematopoietic stem cell transplantation (HSCT) as part of their treatment. Therefore, we tested if HSCT is associated with increased mutagenesis. We analyzed by WGS HSPCs before and after transplantation of 9 children who received the treatment. The majority of transplanted HSPCs did not display altered mutation accumulation; however, treatment of viral reactivation because of the transplantation procedure increased mutation burden. Using a newly developed genotoxicity assay, we could attribute this increase to a mutational signature caused by the antiviral drug ganciclovir. We detected this signature in cancer genomes of multiple patients who received HSCT or solid organ transplantation earlier in life. Antiviral treatment with nucleoside analogs can cause enhanced mutagenicity in transplant recipients, which may ultimately contribute to therapy-related carcinogenesis. This work was published in the scientific journal Cell Stem Cell. We filed a patent for the genotoxicity assay.
We have found that some chemotherapeutic drugs are mutagenic, whereas others are not. The clearest example is the antiviral drug ganciclovir, which is widely used in patients but extremely mutagenic. This compound is also capable of generating cancer driving mutations, amongst others in the RAS genes that are strong oncogenes. Using our genotoxicity assay, we have found compounds that are not mutagenic, but have the same antiviral efficacy. We are currently screening and characterizing the mutagenic action of >15 approved antiviral drugs to identify the most save drugs to use in human patients.

We continue to characterize the mutational landscape and clonal history of t-MN in childhood cancer survivors. So far, half of the cohort has been analyzed. We are currently analyzing how each individual chemotherapeutic drug the children receive affects the outgrow of leukemic clones. Our aim is to identify markers that allow us identify children at risk for t-MN at the time of treating the first cancer (i.e. before the t-MN develops). In addition, we also included patients with genetic predisposition for cancer to assess for genotype and chemotherapeutic exposure relationship. Especially in these patients, substituting certain mutagenic agents will likely be beneficial for preventing the development of a second malignancy.