Genetic studies of follicular and mantle cell lymphoma

Abstract

Non-Hodgkin lymphoma is a malignancy derived from lymphoid tissues. In Sweden, non-Hodgkin lymphoma constituted 3% of all cancers recorded in 2003. Follicular and mantle cell lymphoma are the two types of non-Hodgkin lymphomas studied in this thesis.

The treatment modalities of these lymphomas vary, and the reasons why some patients have a good response to therapy while other fail to respond are largely unknown. To address this problem we compared the gene expression of follicular lymphomas that had good response to therapy with follicular lymphomas that did not respond. The investigated treatment was combination chemotherapy with CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone). With high-density oligonucleotide arrays we could show that 14 genes involved in the G2/M transition of the cell cycle were up-regulated in the responders compared with the non-responders. Six out of these 14 genes were correlated with survival in a cohort of 57 patients with follicular lymphoma. Furthermore, one of these genes was also investigated with immunohistochemistry and there was a good correlation between mRNA expression and protein expression of this gene (Paper I).

The gene expression measured with high-density oligonucleotide arrays was correlated with survival in two independent cohorts of follicular lymphoma. A total of 21 genes were associated with a prolonged survival in both cohorts. This association was independent of the international prognostic index. Genes of particular interest in this study were ERCC1, PTAFR, C4A, RPL23A, BCLAF and ABCC5 (Paper II).

The gene expression in mantle cell lymphoma was also studied with high-density oligonucleotide arrays. Differences in genetic profiles were shown between tumors with a high and a low proliferation rate and also between primary and relapsed tumors (Paper III).

In mantle cell lymphoma the prevalence of mutated V H-genes was investigated. In a cohort of 110, 17% of the tumors had somatic mutations. This implies that a subgroup of mantle cell lymphomas has a post germinal center origin. It was further demonstrated that there was a preferential V H3-21 usage in 19% of the tumors, and that patients with tumor usage of this V H-gene had a longer survival compared with the rest of the patients (Paper IV) .