Abstract 5417: Genomic analysis of infant KMT2A-r acute lymphoblastic leukemia reveals weak association with underlying germline cancer predisposition
Authors: Saeed Azhar , Farooqi Midhat , Yoo Byunggil , Kostadinov Rumen , Farrow Emily , Miller Neil , Brown Patrick , Guest Erin 
Published: September 2020

Abstract
Introduction:KMT2A (MLL) rearranged (KMT2A-r) infant acute lymphoblastic leukemia (ALL) is a distinct leukemia with a poor prognosis, especially when compared to childhood ALL. Previous studies on KMT2A-r leukemia have demonstrated that KMT2A rearrangement can occur in utero with a short latency after birth. Infant ALL with KMT2A-r also demonstrates a low frequency of other somatic mutations. Given that germline mutations in cancer predisposition genes are found in 5-15% of children with cancer, we hypothesized that there might be distinct germline mutations in infants with this type of leukemia that could inform about leukemogenesis and biologic behavior of this entity. Methods: We performed whole genome sequencing (WGS) and whole exome sequencing (WES) on DNA isolated from 43 peripheral blood samples at the time of remission, on 3 cohorts of infants. The cohorts were comprised of infants with KMT2A-r ALL who were known to relapse (n=14) (Cohort A), infants with KMT2A-r ALL who to date have remained in remission (n=14) (Cohort B), and infants with KMT2A germline ALL (n=15) (Cohort C). Sequencing was performed using an Illumina Hiseq 4000 or 2500 to a minimum depth of 90Gb. Alignment and variant calling were performed using the Dragon Bio-IT platform (v 3.2.8, Illumina). We then looked for variants in 347 genes associated with cancer predisposition and bone marrow failure syndromes. Variants present in remission samples at a variant allele frequency of ~50%, and rare (minor allele frequency &lt;0.1%) in control population databases (gnomAD), were considered for analysis and interpreted using ACMG/AMP variant interpretation guidelines.Results:We found 64 germline variants in cohort A (63 variants of unknown significance (VUS) and 1 likely pathogenic (LP) variant), 39 of which are associated with cancer predisposition ( 15 autosomal dominant (AD), 11 autosomal recessive (AR) and 13 others) and 25 other variants associated with bone marrow failure (BMF). In cohort B, we found 67 germline variants (64 VUS and 3 LP), 42 of which are associated with cancer predisposition (12 AD, 14 AR, and 16 others) and 25 other variants associated with bone marrow failure (BMF). Cohort C had 67 germline variants (67 VUS), 50 of which are associated with cancer predisposition (21 AD, 15 AR, and 14 others) and 17 other variants associated with bone marrow failure (BMF).Conclusion:Overall, there were no significant differences across the 3 cohorts in terms of the number and types of variants identified. Although there were germline VUS present in cancer predisposition genes in KMT2A-r infant ALL, there were no distinct recurrent pathogenic variants seen to make a significant association with an underlying cancer predisposition syndrome.
Citation Format: Azhar Saeed, Midhat Farooqi, Byunggil Yoo, Rumen Kostadinov, Emily Farrow, Neil Miller, Patrick Brown, Erin Guest. Genomic analysis of infant KMT2A-r acute lymphoblastic leukemia reveals weak association with underlying germline cancer predisposition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5417.