Abstract 1753: Genomic and transcriptomic characterization of congenital trisomy reveal possible role for RB1 and MET
Authors: Bainazar Maryam A. , Maharry Sophia E. , Walker Christopher J. , Genutis Luke K. , Chapelle Albert de la , Eisfeld Ann-Kathrin 
Published: August 2019

Abstract
Introduction: The vast majority of solid tumors and half of leukemias and lymphomas possess an abnormal number of chromosomes. Individuals with congenital trisomy 21 have an increased risk of developing leukemia and respond differently to treatment when compared to leukemic individuals without congenital aneuploidies. Curiously, the chromosomes that most frequently undergo non-disjunction in malignancy are similar to the chromosomes that occur as trisomies in utero. We aimed to characterize the molecular landscapes of individuals with congenital trisomies to elucidate what changes may lead to an increased risk of cancer development in these individuals.
Methods: We extracted DNA and RNA from fibroblasts of 14 individuals with congenital trisomies, including trisomy 8, 9, 13, 18 and 21 (obtained from Coriell Biorepository). DNA and RNA sequencing were performed with AmpliSeq for Illumina Comprehensive Panel v3. Variants were detected in the DNA using VarScan and annotated with SnpEff, while Kallisto was used for mRNA expression analysis. We applied mRNA context mapping methodology developed by the Computational Cancer Analysis Lab (University of California, San Diego). We used quantitative PCR and Western blotting to validate RB1 and MET expression.
Results: Identification of transcripts highly expressed in multiple trisomies was performed. AXL was the only transcript that was highly expressed in all five trisomy groups, while ACBD5 and CCDC6 were each highly expressed in four. Interestingly, the number of unique highly expressed transcripts differed drastically by trisomy, ranging from n=0 for trisomy 9 to n= 111 for trisomy 13. We then generated a context map of the samples and observed that they cluster together by trisomy, with the exception of two samples. RB1 and MET were up-regulated in eleven samples, and down-regulated in the remaining three samples. We were able to validate these findings at the mRNA and protein level. Finally, we are in the process of identifying rare genetic variants that are unique to or enriched in this population.
Conclusion: Our data indicate that several genes with well-described roles in cancer might also be differentially expressed in individuals with trisomies. RB1 is a tumor suppressor and previous studies have shown that pRB loss leads to centromere dysfunction and chromosomal instability, which could imply dysregulated RB1 plays a role in trisomy acquisition. MET is a proto-oncogene and is implicated as the major driver of oncogenesis in papillary renal carcinomas with chromosomal gain. Further studies that compare congenital trisomy with malignancy-associated trisomy may improve our understanding of non-disjunction and mechanisms of oncogenesis that occur in congenital trisomy patients.
Citation Format: Maryam A. Bainazar, Sophia E. Maharry, Christopher J. Walker, Luke K. Genutis, Albert de la Chapelle, Ann-Kathrin Eisfeld. Genomic and transcriptomic characterization of congenital trisomy reveal possible role for RB1 and MET [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1753.