Allelic Forms Of PRDM9 Associated With High Hyperdiploid Childhood Acute Lymphoblastic Leukaemia

Whilst a great deal is known about acquired somatic aberrations associated with the diagnosis and prognosis of acute leukaemias, relatively little is known about the effects of germline variation. A recent study reported a link between germline variations in the zinc finger (ZnF) binding domain array of the PR domain-containing 9 (PRDM9) gene, regulator of meiotic recombination, with the development of acute lymphoblastic leukaemia (ALL) in children. An excess of rare PRDM9 alleles that affect meiotic recombination events were seen in parents of children affected with B-cell precursor ALL (pre-B-ALL), and in an independent cohort of children with pre-B-ALL; in particular in aneuploid and infant ALL. In the present study, we carried out Sanger sequencing to investigate variation of PRDM9 alleles in a cohort of parents (n=59) with children diagnosed with high hyperdiploid ALL (HeH; 51-67 chromosomes) (n=31) and a control cohort of individuals (n=66) from the south of Sweden. Whereas similar numbers of rare PRDM9 alleles were observed in both groups, a larger number of rare alleles that affect recombination events were observed in the parents from the family cohort with children diagnosed with HeH ALL compared to individuals of the population control cohort (15.3% vs. 4.5%, P=0.0414). Two-thirds of the parents transmitted the rare allele to their affected children. A previously unreported ZnF repeat was also detected in two individuals of the control cohort but it was not detected in the family cohort. A statistically significant difference in frequency of rare alleles affecting recombination events between the two groups indicates a true association between PRDM9 allelic forms and HeH ALL in an independent cohort. Thus, our results confirm the previous findings that PRDM9 may play a role in the development of childhood ALL.