Loss of Heterozygosity (LOH) of PTPRJ in Non-Hodgkin`s Lymphoma (NHL)

Abstract 5231

The identification of Tumor Suppressor Genes (TSGs) in tumor tissue lacking of its normal germ-line counterpart has been limited due to the absence of proper statistical approaches that allow inferring the specific germ-line heterozygous status of a patient. Nonetheless, the implementation of Hidden Markov model (HMM) or cohort heterozygosity comparisons (CHC) approaches in the analysis of SNP array data from un-paired tumor DNA samples have permitted the detection of LOH regions and possible TSGs that might be implicated in the origin and development of cancer. Non-Hodgkin's Lymphoma (NHL) is the most common type of lymphoma. Nevertheless, its aetiology and pathogenesis remain unclear because of heterogeneity in biology, genetics and chemoresponse.

Here, we employed high-density SNP array analysis of tumors from two of the most frequent subtypes of NHL, Follicular Lymphoma (FL) and Diffuse Large B-cell Lymphoma (DLBCL). This revealed a high frequency of LOH over the chromosomal region of 11p11.2, containing the gene encoding the receptor-type protein tyrosine phosphatase, PTPRJ. LOH of this gene has been previously described in colorectal, lung, thyroid and breast cancer and the gene product regulates key survival pathways in B-cells, such as MAPK, PLCγ1, Scr and BCR signalling.

We validated LOH of the PTPRJ region by microsatellite analysis of an extended cohort of NHL tumors and found significantly increased rates of homozygosity compared to a patient-matched control population. Furthermore, sequencing of NHL cases revealed a strong association between LOH and the presence of a non-synonymous SNP in the PTPRJ coding region. Together, these results show the utility of LOH screening in identifying novel tumor suppressor genes, and implicate LOH of the PTPRJ gene as a potential lymphomagenic mechanism.