Key processes in the onset and evolution of chronic lymphocytic leukemia
(CLL) are thought to include chronic (antigenic) activation of mature B
cells through the B cell receptor (BcR), signals from the
microenvironment, and acquisition of genetic alterations. Here we
describe three families in which two or more siblings were affected by
CLL. We investigated whether there are immunogenetic similarities in the
leukemia-specific immunoglobulin heavy (IGH) and light (IGL/IGK) chain
gene rearrangements of the siblings in each family. Furthermore, we
performed array analysis to study if similarities in CLL-associated
chromosomal aberrations are present within each family and screened for
somatic mutations using paired tumor/normal whole-genome sequencing
(WGS). In two families a consistent IGHV gene mutational status (one
IGHV-unmutated, one IGHV-mutated) was observed. Intriguingly, the third
family with four affected siblings was characterized by usage of the
lambda IGLV3-21 gene, with the hallmark R110 mutation of the recently
described clinically aggressive IGLV3-21(R110) subset. In this family,
the CLL-specific rearrangements in two siblings could be assigned to
either stereotyped subset #2 or the immunogenetically related subset
#169, both of which belong to the broader IGLV3-21(R110) subgroup.
Consistent patterns of cytogenetic aberrations were encountered in all
three families. Furthermore, the CLL clones carried somatic mutations
previously associated with IGHV mutational status, cytogenetic
aberrations and stereotyped subsets, respectively. From these findings,
we conclude that similarities in immunogenetic characteristics in
familial CLL, in combination with genetic aberrations acquired, point
towards shared underlying mechanisms behind CLL development within each
family