Sequencing thousands of tumours has revealed patterns of somatic changes across sub-types, however, the impact of germline variations is poorly understood. There is a growing body of evidence that many childhood cancers carry an unrecognised milieu of rare germline alleles that may contribute to tumourigenesis and drug responses. This gap in knowledge could be an impediment to fulfilling the promise of precision medicine, which in oncology often involves therapy targeting specific mutations. We hypothesised that infant cancers express pathogenic germline and somatic alleles and due to the short latency of disease there will be limited accrual of confounding lesions compared to adult cancer.
Histone-lysine N-methyltransferase 2A translocations (KMT2A-R) occur in 80% of infant acute lymphoblastic leukemia, however they are insufficient to initiate leukaemogenesis [1]. We therefore investigated the genetic landscape of KMT2A-R infant leukemia, cataloguing the complement of expressed somatic mutations and germline variations in 40 patients using RNA-sequencing and genome/exome sequencing for 24 cases. 53,105 unrelated adults were used as controls. Enrichment of rare/predicted deleterious germline KEAP1 alleles was observed in patients. Five/six patient KEAP1 alleles coincide with somatic mutations in adult lung cancer patients. In adult lung cancer patients, KEAP1 loss-of-function promotes cancer progression, cooperates with RAS-activation and induces sensitivity to specific drugs [2-4]. We have been investigating the effects of Keap1 loss in lymphoid cells focusing on metabolism, redox control, cell growth and response to small molecule inhibitors. In addition, at the protein-protein interaction gene-network level, we observe rare/predicted deleterious variants in four cancer gene modules comprising: (1) the RAS-pathway, (2) DNA-damage response, (3) chromatin regulation and (4) leukaemia-associated genes. In vitro studies suggest that enforced expression of a novel germline KRAS-V160M allele promotes survival of lymphoid cells and induces sensitivity to small molecule inhibitors of the mitogen-activated protein kinase pathway. Taken together, these results suggest that germline DNA sequence variations in infant leukaemia patients may alter disease progression and induce novel therapeutic vulnerabilities.