Abstract 4869: Whole genome sequence analysis of MLL rearranged infant acute lymphoblastic leukemias reveals remarkably few somatic mutations: A Report From the St Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project (2012)

Abstract Infant acute lymphoblastic leukemia (ALL) is characterized by MLL rearrangements (MLLr) and poor prognosis. To determine the complement of somatic mutations in this high risk leukemia, we performed whole genome sequencing (WGS) on 22 infants with MLL rearranged ALL. An analysis of the structure of the MLLr revealed that over half had complex rearrangements involving either three or more chromosomes, carried cryptic rearrangements, or contained at the breakpoints deletions, amplifications, insertions, or inversion of sequences. In three cases, genetic rearrangements were predicted to generate in addition to the MLL-partner gene fusion, novel in-frame fusions including KRAS-MLL; RAD51B-MLL / AFF1-RAD51B, AFF1-RAD51B-MLL; MLLT10-ATP5L-YPEL4 / ATP5L-YPEL4. An analysis of the number of non-silent mutations revealed infant ALL to have the lowest frequency of somatic mutations of any cancer sequenced to date. After removal of SVs and CNAs associated with the MLLr, a mean of only 3.5 SVs and 2.2 SNVs affecting the coding region of annotated genes or regulatory RNAs were detected per case. Despite the paucity of mutations several pathways were recurrently targeted including PI3K/RAS pathway in 45% (KRAS (n=4), NRAS (n=2), and non-recurrent mutations in NF1, PTPN11, PIK3R1, and ARHGAP32 (p200Rho/GAP)), B cell differentiation in 23% as a result of mono-allelic deletion or gains of PAX5, 14% with deletions of the CDKN2A/B, and 2 cases with focal deletions of the non-coding RNA genes DLEU1/2. WGS of two infant ALL relapse samples and comparison with their matched diagnostic samples revealed a marked increase in the number of mutations at relapse. Moreover, an analysis of the allelic ratios of mutated genes revealed clonal heterogeneity at diagnosis with relapse appearing to arise from a minor diagnostic clone. Because of the exceedingly low number of mutations detected in infant ALL, we used exome sequencing to determine the frequency of non-silent SNVs in 20 MLLr leukemias (9 ALLs, 10 AMLs and 1 AUL) in older children (7-19 yrs). This analysis revealed that non-infant pediatric MLL leukemias harbor a significantly higher number of non-silent somatic SNVs than infant ALL (mean 7.4/case in older patients vs 2.2/case in infants, p&amp;lt;0.001). Although the higher frequency of mutations may be a reflection of age, the low number of cooperating mutations in infants raises the possibility that the target cell of transformation differs between infants and older children, with the cells present during early development requiring fewer cooperating mutations to induce leukemia. In summary our data demonstrated an exceedingly small number of mutations in infant leukemia. The number of detected somatic mutations may represent the lower limit required to transform a normal human cell into cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4869. doi:1538-7445.AM2012-4869