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. 2021 Mar 16;13(6):1340.
doi: 10.3390/cancers13061340.

Detection of Rare Germline Variants in the Genomes of Patients with B-Cell Neoplasms

Adrián Mosquera Orgueira  1   2   3 , Miguel Cid López  1   2   3 , Andrés Peleteiro Raíndo  1   2   3 , José Ángel Díaz Arias  1   2 , Beatriz Antelo Rodríguez  1   3 , Laura Bao Pérez  2 , Natalia Alonso Vence  1   2 , Ángeles Bendaña López  1   2   3 , Aitor Abuin Blanco  2 , Paula Melero Valentín  2 , Roi Ferreiro Ferro  2 , Carlos Aliste Santos  3 , Máximo Francisco Fraga Rodríguez  1   3   4 , Marta Sonia González Pérez  1   2 , Manuel Mateo Pérez Encinas  1   2   3 , José Luis Bello López  1   2   4
Affiliations

Detection of Rare Germline Variants in the Genomes of Patients with B-Cell Neoplasms

Adrián Mosquera Orgueira et al. Cancers (Basel). .

Abstract

There is growing evidence indicating the implication of germline variation in cancer predisposition and prognostication. Here, we describe an analysis of likely disruptive rare variants across the genomes of 726 patients with B-cell lymphoid neoplasms. We discovered a significant enrichment for two genes in rare dysfunctional variants, both of which participate in the regulation of oxidative stress pathways (CHMP6 and GSTA4). Additionally, we detected 1675 likely disrupting variants in genes associated with cancer, of which 44.75% were novel events and 7.88% were protein-truncating variants. Among these, the most frequently affected genes were ATM, BIRC6, CLTCL1A, and TSC2. Homozygous or germline double-hit 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 six different genes were independently associated with shorter survival in CLL. Our study results support an important role for rare germline variation in the pathogenesis and prognosis of B-cell lymphoid neoplasms.

Keywords: B-cell; CLL; cancer; driver; germline; lymphoid; lymphoma; prognosis; rare variant.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) Lollipop plot of the rare and predictively disruptive germline variants detected in the ATM gene. (B) Representation of a 28 bp frameshift deletion present in one patient.
Figure 2
Figure 2
Kaplan–Meier plots representing the association of rare variants in WRN with time to first treatment (A) and overall survival (B) in chronic lymphocytic leukemia (CLL). Variants considered in this plot are represented in Table 4.
Figure 3
Figure 3
Frequency of highly dysfunctional variants within genes identified in the burden test.
See this image and copyright information in PMC

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