Abstract 01: Genetic variation within genes related to telomere maintenance and DNA repair in a cohort of pediatric acute myeloid leukemia (AML) subjects
Authors: Gramatges Maria , Oak Ninad , Wheeler David , Ritter Deborah , Muzny Donna , Plon Sharon 
Published: May 2015

Abstract
Introduction: Short telomeres characterize a spectrum of disorders related to defects in telomere maintenance. The prototypic telomere biology disorder is dyskeratosis congenita (DC), a syndrome associated with specific mucocutaneous features in combination with a markedly increased risk for bone marrow failure, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML), among other cancers. Germline defects in a subset of telomere maintenance genes have been observed in cohorts of subjects with various hematologic malignancies, including AML. In the setting of defects in DNA repair, critical telomere shortening may result in genomic instability and subsequent malignant transformation. However, a more extensive evaluation of telomere biology and DNA repair genes in childhood AML has not been performed. We hypothesized that variants resulting in premature truncation or rare missense mutations would be identified in a pediatric AML cohort.
Methods: Our patient population included 82 subjects diagnosed with AML or MDS at the Texas Children's Cancer Center, all between the ages of 0 and 18. DNA samples included 61 that were from initial AML diagnosis, 18 that were in AML remission, and 3 from individuals with MDS. The specimens were analyzed using a custom Ampliseq Ion Torrent platform comprised of 43 genes related to telomere maintenance and DNA repair.
Results: Our preliminary analysis focused on 13 genes with the strongest association to a DC or AML/MDS clinical phenotype, including the nine genes currently recognized as DC-associated genes. In addition, for the purposes of this initial analysis we included only variants categorized as stoploss/stopgain mutations or frameshift insertions/deletions. After excluding variants found in HapMap controls, those with a MAF ≥ 1% as reported in dbSNP or ARIC, and those with unacceptably low coverage or quality reads, 87 variants remained of which 33 were unique. Sequence reads for all 87 underwent two distinct and independent reviews for verification, using Integrated Genomics Viewer (IGV), with discordant variants undergoing re-review. After eliminating those variants with consensus from both reviewers to be false positives, 33 samples from all three patient subpopulations demonstrated a total of 14 unique variants resulting in a stoploss/stopgain or frameshift mutation in the following genes: CTC1, RTEL1, RUNX1, TEP1, TERC, TERT, TINF2, and WRAP53. Three of the variants were described in dbSNP and the remaining 11 variants were novel. None of the variants were previously associated with DC-spectrum, AML, or MDS phenotype.
Conclusions: Preliminary analysis indicates that a proportion of this pediatric AML/MDS cohort demonstrates rare and potentially deleterious stoploss/stopgain or frameshift mutations within a set of genes related to telomere maintenance and DNA repair. Further analysis of this data, including variants resulting in missense changes, may provide additional evidence supporting the utility of this platform in better understanding factors contributing to the development of AML and MDS.
Citation Format: Maria Gramatges, Ninad Oak, David Wheeler, Deborah Ritter, Donna Muzny, Sharon Plon. Genetic variation within genes related to telomere maintenance and DNA repair in a cohort of pediatric acute myeloid leukemia (AML) subjects. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 01. doi:10.1158/1538-7445.CANSUSC14-01