V_H gene usage by family members affected with chronic lymphocytic leukaemia

Abstract

Summary. The excess risk of chronic lymphocytic leukaemia (CLL) in the ®rst-degree relatives of affected patients suggests that familial CLL might constitute a useful model to study the pathogenesis of this disease, as has been demonstrated in numerous other neoplastic disorders. Previous studies have shown non-random utilization of immunoglobulin genes in CLL, some germline in sequence and others containing numerous somatic mutations. To investigate whether familial cases of CLL exhibit similarities in the composition of the B-cell receptor repertoire to the pattern expressed by CLL patients as a whole, we have studied 25 CLL patients belonging to 12 different families (four French and eight Italian), each of which contained at least two affected members. Among familial cases, V H gene segment utilization proved non-random and diverged from the frequencies previously reported among unrelated patients with CLL. Speci®cally, although the 4-34 and 5-51 gene segments were found repeatedly, the 1-69 and 4-39 gene segments were used sparingly and the 3-23 gene segment presented with increased frequency. Following the pattern detected in studies of unrelated patients, the single 1-69 expressing CLL contained an unmutated H chain sequence and included a long HCDR3 interval. In contrast, 3-23 containing H chains all used J H 4, retained at most 93% homology with germline sequence, and included only short HCDR3 intervals. The vast majority of the CLL variable domains contained a high degree of somatic mutation and exhibited an excess of replacement mutations in the CDR intervals. These ®ndings suggest that familial CLL cases may preferentially derive from B-cell progenitors that have responded to antigen.

Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936

“…44 The most frequently used VH gene segments in normal and malignant B cells belong to the VH3 family (30-50%), VH4 family (20-30%), and VH1 family (10-20%), together covering 75-95% of VH usage (Table 9). [45][46][47] However, in precursor B-ALL also VH6 gene segments are used relatively frequent. 48 The VH segments contain three framework (FR) and two complementarity-determining regions (CDRs) (Figure 4b).…”

Genetic susceptibility to chronic lymphocytic leukemia

“…To formally assess the significance, the observed distribution is compared with the random distribution predicted on the basis of the observed prevalence of the mutated phenotype. Whilst the distribution of phenotypes in the families reported study by Pritsch et al 43 is not significantly different from that expected, the distribution in the families reported by Sakai et al 44 shows a clear deviation. Combining data from the two studies, the concordance is significant within families ( 2 = 11.2, 1 df, P Ͻ 0.001).…”

“…One intriguing feature seen in the expression of CLL in many of the families reported is anticipation, the phenomenon of earlier onset and more severe phenotype in successive generations. [10][11][12][13][14] This phenomenon is observed in other Mendelian diseases, where it is known to have a specific molecular basis. Anticipation in familial CLL may have a similar basis, although other possibilities exist, such as a cohort effect in relation to viral or other environmental exposures, which act as risk factors.…”

“…Genetic heterogeneity severely reduces the power of any linkage analysis to detect disease genes. Since subcategorization of a disease provides a strategy to mitigate the impact of heterogeneity on linkage, IgV 43,44 and BCL-6 45 status may achieve this for familial CLL.…”

“…41,42 Two investigations have assessed IgV status in familial CLL. 43,44 In 23 CLL families, 66% of 48 affected family members had IgV mutations. This frequency is significantly higher for familial CLL than sporadic CLL (assuming a mutation frequency of approximately 50%, significance levels are Ͻ0.001 in Pritsch et al 43 and 0.04 in Sakai et al 44 ).…”