Genetic Variants of Ataxia Telangiectasia Mutated (ATM) and Susceptibility for Childhood T-Lineage Acute Lymphoblastic Leukemia.

ATM was identified as the gene mutated in Ataxia Telangiectasia (AT), a degenerative neurological disorder that is characterized by, amongst others, an increased risk to develop a hematomalignancy at young age. Striking is the high incidence of T cell derived lymphoid malignancies amongst AT patients. As sporadic T-lineage Acute Lymphoblastic Leukemia (T-ALL) is particularly found in childhood, we have investigated the occurrence and frequency of mutations in 62 coding exons of the ATM gene in 41 children with T-ALL at initial diagnosis and their relation to susceptibility for T-ALL. Moreover, as ATM is implicated in cellular signaling events in response to DNA damaging agents, we have also investigated whether genetic variants of ATM are possibly related to cellular resistance to drugs and clinical outcome in childhood T-ALL. We have identified 18 different ATM alterations, of which 9 were not previously reported, in 68% of T-ALL patients. None of the alterations co-segregated with loss of heterozygosity of the ATM gene. The simultaneous presence of more than one genetic variant was observed in 32% of T-ALL patients compared to only 12% of healthy controls (P = 0.006). An increased frequency of ATM alterations was of no influence on the level of ATM mRNA and did not associate with cellular resistance to daunorubicin, prednisolone, vincristine and L-asparaginase nor with age at diagnosis, white blood cell count or long-term clinical outcome. However, the presence of specific genetic variants, i.e. S707P, F858L, T896A, P1054R and L1472W was related to an age younger than 10 years (P = 0.034) and an increased relapse-risk (P = 0.025). In addition, an increased frequency of carriers of these genetic variants was observed amongst T-ALL children (29%) compared to controls (11%) (P = 0.028). We conclude that ATM gene alterations might pre-dispose carriers to develop T-ALL in childhood, in particular involving specific genetic variants of ATM as their occurrence is significantly associated with a young age.