Signature SBS7a in pediatric BCP-ALL

Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer in the Netherlands, with an incidence of around 115 new cases per year. Although the survival rates have reached 90%, the underlying mutational mechanisms are still not fully understood. Multiple genetic subtypes have been identified, with large differences in prognosis. While patients with ALL typically have a very low tumor mutation burden (TMB), some patients show the presence of an active mutational process which can increase the TMB1–3 . To gain insight into which mutational processes play a role in the carcinogenesis and drug resistance of ALL, we extracted mutational signatures from whole genome sequencing data. Strikingly, we have identified 14 patients with ALL across multiple cohorts who show a mutational profile similar to single base substitution signature 7a (SBS7a), which is typically seen in melanomas and has been associated with damage by ultraviolet (UV) light. Here, we aim to study the etiology of mutational signature SBS7a in ALL by analyzing common features between SBS7a-positive ALL samples and comparing them with those found in melanomas. Major copy number alterations (CNAs) were often found in chromosome 21. Additionally, copy number analysis showed that the presence of signature SBS7a is enriched within the group of ALL patients with intrachromosomal amplifications of chromosome 21 (iAMP21). While amplifications of chromosome 21 were found to be neither sufficient nor necessary for the development of signature SBS7a, CNAs were always present prior to SBS7a mutations. Next, we compared SBS7a-postive ALL patients to patients with melanomas, in which SBS7a is known to be caused by UV light, to investigate a possible role for UV light in the mutagenesis of ALL. While some characteristics of SBS7a in melanomas could also be found in ALL, such as an overrepresentation of SNVs on the untranscribed strand of the deoxyribonucleic acid (DNA), no replication bias was found. All patients with signature SBS7a also showed the presence of doublet base substitution signature 1 (DBS1), which can be caused by UV light. The presence of insertion and deletion signature 13 (indel/ID13), however, could not be identified in patients with ALL, as opposed to most melanoma cases. Patients who had developed relapses provided information about the timing of SBS7a, showing that no new SBS7a mutations were gained after the initial diagnosis in 3 out of 5 patients. In the other 2 patients, however, new SBS7a mutations were present in the first relapse. Lastly, our data shows that SBS7a can influence disease progression through the inactivation of glucocorticoid-related genes, potentially leading to prednisolone resistance. Although UV light is unlikely to play a role in the development of ALL, our results show the presence of a similar type of damage in ALL for which the underlying mutational process has not yet been identified.