Abstracts of 4^th Annual UKMF Scientific Meeting on 07-Feb-2003

Patterns of somatic mutations in VH genes reveal pathways of clonal transformation from MGUS to multiple myeloma

Niklas Zojer^1,2, Heinz Ludwig², Freda K. Stevenson¹ and Surinder S. Sahota¹

¹Molecular Immunology Group, Tenovus Laboratory, Cancer Sciences Division, Southampton University Hospitals UK;
²1st Department of Internal Medicine and Medical Oncology, Wilhelminenspital, Vienna, Austria.

Functionally rearranged immunoglobulin variable (V) region genes are retained in the genome of B-cell tumours following tumourigenic arrest. They are readily identified on the basis of signature motifs, and their analysis can reveal the clonal history of the cell of origin. Most significantly, tumour V gene analysis can reveal if the cell of origin has encountered somatic hypermutation, likely to have occurred in the germinal centre (GC). V genes analysis can identify origins from a cell which enters the GC and continues to be be exposed to somatic mutation. Such a cell is likely to be sIg^+ve, to mediate signals for hypermutation. Tumour cells in this site reveal intraclonal variation in V gene sequences. In contrast, tumour origins may be from a cell which has traversed the GC and has exited. These tumours display homogeneity of clonal sequence patterns in V genes.

Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell proliferation which can transform to multiple myeloma (MM). Mutated VH genes in myeloma reveal sequence homogeneity, consistent with a post-follicular origin. Previously, some MGUS cases revealed mutated VH genes with intraclonal variation, indicating an earlier stage of arrest compared to myeloma. Here, we investigated the nature of progression from MGUS to MM in 4 individuals. The same tumor VH genes were identified at both stages, confirming clonal evolution. In 1/4 MGUS cases, intraclonal heterogeneity in tumor sequences was evident. In this case, transformation to myeloma occurred rapidly and led to silencing of somatic mutation with apparent homogeneity in the emergent clone. However, residual MGUS-derived sequences could also be detected at this time. Heterogeneity in MGUS clearly does not associate with benign disease. It delineates origins from a tumorigenic cell, most likely sIg^+ve, undergoing somatic mutation, which can differentiate further. The remaining 3/4 cases displayed intraclonal homogeneity at the MGUS stage, and this may be more common. Conceivably, these MGUS may result from a self-cloning outgrowth from MGUS with heterogeneity. Transformation can clearly occur at either MGUS stage but it involves a single cell in which somatic mutation is then silent.

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