Refining tumor-associated aneuploidy through ‘genomic recoding’ of recurrent DNA copy number aberrations in 150 canine non-Hodgkin lymphomas

Abstract

Identification of the genomic regions most intimately associated with non-Hodgkin's lymphoma (NHL) pathogenesis is confounded by the genetic heterogeneity of human populations. We hypothesize that the restricted genetic variation of purebred dogs, combined with the contrasting architecture of the human and canine karyotypes, will increase the penetrance of fundamental NHL-associated chromosomal aberrations in both species. We surveyed non-random aneuploidy in 150 canine NHL cases, revealing limited genomic instability compared to their human counterparts and no evidence for CDKN2A/B deletion in canine B-cell NHL. ‘Genomic recoding’ of canine NHL data into a ‘virtual human’ chromosome format showed remarkably few regions of copy number aberration (CNA) shared between both species; restricted to regions of dog chromosomes 13 and 31, and human chromosomes 8 and 21. Our data suggest that gene discovery in NHL may be enhanced through comparative studies exploiting the less complex association between CNAs and tumor pathogenesis in canine patients.

Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma

“…In dogs, the main aneuploidies observed in NHL include gains of chromosomes 13 and 31, which are analogous to the partial gains of human chromosomes 4 and 8 and a gain of chromosome 21. 33 Subchromosomal regions of CFA 13/HSA8 and CFA31/HSA21 harbor genes important in tumorigenesis such as c-myc, frequently involved in human B-cell lymphomas through aberrant fusion with immunoglobin genes. 34 Canine and human peripheral T-cell lymphomas also demonstrate some conservation of copy number aberrations with both having deletions in chromosomal regions leading to loss of CDKN2A/B and CDKN2A/p16-RB1 pathway activity.…”

Comparative oncology: what dogs and other species can teach us about humans with cancer

“…As discussed in §2, canine cancers share evolutionarily conserved genomic changes that are found in their human counterparts. Man's best friend is already providing scientists with an opportunity to generate data beneficial to both species [3,4,10,11,18,19].…”

Simultaneous Inactivation of the <i>p16, p15</i> and <i>p14</i> Genes Encoding Cyclin-Dependent Kinase Inhibitors in Canine T-Lymphoid Tumor Cells

“…Thomas et al [40] indicated the frequent DNA copy number losses in p15-p14-p16 locus of chromosome 11 in canine T-cell lymphomas but not in b-cell malignancies, using array-based comparative genomic hybridization. Although further studies are needed, deletion of p15-p14-p16 locus would be an important candidate to understand the tumorigenesis in a subtype (possibly high-grade T-cell lymphoma) of canine lymphoid tumors.…”

“…Partial loss of chromosome 11, on which these genes are located, has also been reported in canine lymphoid malignancies using fluorescent in situ hybridization analysis and comparative genomic hybridization [9,12,40]. based on these reports, the p16, p15 and p14 genes are speculated to be partially or completely deleted in canine lymphoid malignancies, similar to human lymphoid tumors.…”

“…They are clustered in a region on human chromosome 9 corresponding to mouse chromosome 4, and canine chromosome 11 [9,40]. The P16 and P15 proteins belong to the inhibitor of cyclin-dependent kinase 4 (INK4) family, and are known as INK4a (cyclin-dependent kinase inhibitor 2A [CDKN2A]) and INK4b (CDKN2b), respectively.…”