Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Detection of Rare Germline Variants in the Genomes of B Cell Neoplasms

Version 1 : Received: 15 January 2021 / Approved: 18 January 2021 / Online: 18 January 2021 (12:14:32 CET)

A peer-reviewed article of this Preprint also exists.

Mosquera Orgueira, A.; Cid López, M.; Peleteiro Raíndo, A.; Díaz Arias, J.Á.; Antelo Rodríguez, B.; Bao Pérez, L.; Alonso Vence, N.; Bendaña López, Á.; Abuin Blanco, A.; Melero Valentín, P.; Ferreiro Ferro, R.; Aliste Santos, C.; Fraga Rodríguez, M.F.; González Pérez, M.S.; Pérez Encinas, M.M.; Bello López, J.L. Detection of Rare Germline Variants in the Genomes of Patients with B-Cell Neoplasms. Cancers 2021, 13, 1340. Mosquera Orgueira, A.; Cid López, M.; Peleteiro Raíndo, A.; Díaz Arias, J.Á.; Antelo Rodríguez, B.; Bao Pérez, L.; Alonso Vence, N.; Bendaña López, Á.; Abuin Blanco, A.; Melero Valentín, P.; Ferreiro Ferro, R.; Aliste Santos, C.; Fraga Rodríguez, M.F.; González Pérez, M.S.; Pérez Encinas, M.M.; Bello López, J.L. Detection of Rare Germline Variants in the Genomes of Patients with B-Cell Neoplasms. Cancers 2021, 13, 1340.

Journal reference: Cancers 2021, 13, 1340
DOI: 10.3390/cancers13061340

Abstract

Growing evidence has revealed the implication of germline variation in cancer predisposition and prognostication. Here, we describe an analysis of putatively disruptive rare variants across the genomes of 726 patients with B-cell lymphoid neoplasms. We discovered a significant enrichment of 26 genes in germline protein truncating variants (PTVs), affecting cell signaling (MET, JAK2, ANGPT2), energy metabolism (ACO1) and nucleic acid metabolism and repair pathways (NT5E, DCK). Interestingly, some of these variants were restricted to either chronic lymphocytic leukemia (CLL) (i.e., ANGPT2 and AKR1C3) or B-cell lymphoma cases (PNMT, TPT1 and IGHMBP2). Additionally, we detected 1,675 likely disrupting variants in genes associated with cancer, of which 44.75% were novel events and 7.88% were PTVs. Among these, the most frequently affected genes were ATM, BIRC6, CLTCL1A and TSC2. Homozygous or compound heterozygous variants were detected in 28 cases; and coexisting somatic events were observed in 17 patients, some of which affected key lymphoma drivers such as ATM, KMT2D and MYC. Finally, we observed that variants in the helicase gene WRN were independently associated with shorter survival in CLL. Our study results support an important role for rare germline variation in the pathogenesis, clinical presentation and disease outcome of B-cell lymphoid neoplasms.

Keywords

germline; rare variant; cancer; lymphoid; B-cell; lymphomal; CLL; driver; prognosis

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