ASH 2010 abstract 43 summarizes a collaboration between 16 different laboratories in which a total of 7596 patients with CLL who had had their V genes sequenced were compared, looking for evidence of stereotypy. They have assembled three times as many cases as ever published before (around a thousand of them came from my old lab). Stereotypy was found in 2308 (30.4%) cases. 218 sequences were placed in the V3-21 cluster, the first one to be recognized and the most common. The second most common with 184 sequences, was different in that it was not confined to a single V gene type. This is typical of an immune response; what is important is that the antibody combining site or B cell receptor (BCR) is configured to combine with an antigen.. This cluster utilizes different IGHV genes of Clan I (ie IGHV1-2, 1-3, 1-8, 1-18, 5-a, 7-4-1) but the same three amino acids (glutamine-tryptophan-leucine) at a vital point of the CDR3 (positions 108-110) which constitutes the BCR.
As more sequences have been studied, more stereotypes have been recognized. In some cases there are only two members of a cluster – but then there should be no cases with identical sequences for the antibody combining site unless something bizarre was going on, so even two with the same sequence is suspicious.
The question then has to be asked whether if enough cases were sequenced, would every CLL belong to one cluster of stereotypes or another. To that, the answer is no. As more cases are sequenced the rate of increase in stereotypes found diminishes and the authors think it won’t exceed more than 1 in 3 cases. Do stereotyped and non-stereotyped cases differ qualitatively? Probably not. Most stereotyped cases are unmutated and it will probably possible to recognize patterns of behaviour for these and even to devise targeted treatments. Most of the mutated subtypes are not stereotyped and most will not require targeted treatment.