Tobin Gerard, Thunberg Ulf, Laurell Anna, Karlsson Karin, Aleskog Anna, Willander Kerstin, Söderberg Ola, Merup Mats, Vilpo Juhani, Hultdin Magnus, Sundström Christer, Roos Göran, Rosenquist Richard
Dept. of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Haematologica. 2005 Apr;90(4):465-9.
The immunoglobulin VH gene mutation status is a strong prognostic indicator in B-cell chronic lymphocytic leukemia (CLL), since unmutated VH genes are correlated with short survival. However, the traditional cut-off level dividing mutated and unmutated cases, i.e. more or less than 2% mutations, has been questioned and other cut-offs have been suggested. We investigated whether an alternative cut-off should be applied and the relation of mutational status to another prognostic marker, Binet staging.
VH gene mutation status was assessed in 332 CLL cases by polymerase chain reaction amplification and nucleotide sequencing and was further correlated with overall survival using different VH mutation cut-offs (1-7%) and Binet stage.
After testing different mutation borders, the 2% cut-off remained the best discriminative level for determining prognosis. Interestingly, prognostic stratification was improved by combining the information on VH gene mutation status with that of Binet stage: unmutated cases (all stages, n=151, mutated cases with stage A (n=77), and mutated cases with stage B or C (n=37) had a median survival of 82, 179 and 74 months, respectively.
CLL cases displaying mutated VH genes with Binet stage B or C had a survival similar to that of unmutated cases and significantly shorter than that of mutated stage A CLL. Our result reveals clinical heterogeneity within the VH mutated CLL group by inclusion of Binet stage data, a finding which is of importance when considering surrogate marker(s) for VH mutation status.
免疫球蛋白VH基因突变状态是B细胞慢性淋巴细胞白血病（CLL）的一个重要预后指标，因为未突变的VH基因与生存期短相关。然而，传统上区分突变和未突变病例的临界值，即突变率或多或少超过2%，受到了质疑，有人提出了其他临界值。我们研究了是否应采用替代临界值，以及突变状态与另一个预后标志物Binet分期之间的关系。
通过聚合酶链反应扩增和核苷酸测序对332例CLL病例的VH基因突变状态进行评估，并使用不同的VH突变临界值（1%-7%）和Binet分期进一步与总生存期相关联。
在测试了不同的突变边界后，2%的临界值仍然是判断预后的最佳区分水平。有趣的是，将VH基因突变状态信息与Binet分期信息相结合可改善预后分层：未突变病例（所有分期，n=151）、A期突变病例（n=77）和B期或C期突变病例（n=37）的中位生存期分别为82个月、179个月和74个月。
Binet分期为B或C期且VH基因发生突变的CLL病例的生存期与未突变病例相似，且显著短于A期突变的CLL病例。我们的结果通过纳入Binet分期数据揭示了VH基因突变的CLL组内的临床异质性，这一发现在考虑VH突变状态的替代标志物时具有重要意义。
