Breakpoints in the ataxia telangiectasia gene arise at the RGYW somatic hypermutation motif.

The mature sporadic T-cell malignancy, T-cell prolymphocytic leukemia (T-PLL) is remarkable for frequently harbouring somatic mutations of the Ataxia Telangiectasia (A-T) gene, ATM. Because some data suggest ATM is frequently rearranged in T-PLL, it was decided to investigate such rearrangements in detail by cloning breakpoints. Among 17 T-PLL tumour samples, three rearrangements were detected by Southern blotting. Two cases harboured a unique type of intragenic duplication in which breakpoints arose at the consensus sequence RGYW/WRCY. The third case harboured a large deletion terminating within the ATM gene. Also, 13 T-cell acute lymphoblastic leukemia (T-ALL) samples were examined and one sample harboured a deletion- insertion with the RGYW motif at the breakpoint in ATM. This is the first known deleterious mutation detected in ATM in T-ALL. Interestingly, the RGYW motif is the signal for a cell-cycle regulated DNA double strand break (DSB) that initiates somatic hypermutation of immunoglobulin and, probably, T-cell receptor genes. The structures of the ATM duplications suggest they may arise from an error in somatic hypermutation. We suggest that aberrant components of somatic hypermutation may contribute to the defective DSB repair characteristic of cancer.

Analysis of the Fanconi anaemia complementation group A gene in acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults. Around 10-15% of individuals with recessively inherited Fanconi anaemia (FA) develop AML. FA is one of a group of recessive syndromes characterized by excessive spontaneous chromosomal breakage in which heterozygote carriers appear to display an increased risk of cancer and there is some indirect evidence that FA carriers may also be at increased risk of AML. This suggests that FA genes may play a role in the development of AML in the wider context. To examine this proposition, further, we have screened samples from 79 AML patients for mutations in the major FA gene, FANCA. No truncating FANCA mutations were detected. One missense mutation previously designated as pathogenic and five novel missense mutations causing non-conservative amino acid substitutions were detected. The data suggests that while FANCA mutations are rare, FANCA mutations may contribute to the development of the disease in a subset of AML.

Instability of CAG-trinucleotide repeats in chronic lymphocytic leukemia.

Anticipation--earlier onset and more severe disease in the offspring generation--is a well documented feature of familial chronic lymphocytic leukaemia (CLL). In a number of Mendelian diseases, anticipation is caused by expansion of contiguous triplets of nucleotides. The severity of disease expression and penetrance is related to the extent of the triplet expansion. To investigate whether repeat nucleotide repeat expansion is a feature of CLL, the repeat expansion detection (RED) technique was applied to samples from 17 patients with familial disease and 32 patients with early-onset CLL disease. No potentially pathological CAG expansions were detected. We conclude that unstable CAG repeat expansion is not a feature of CLL and that other processes are likely to be involved in generating anticipation in familial forms of the disease.

ATM mutations are rare in familial chronic lymphocytic leukemia.

It is now recognized that a subset of B-cell chronic lymphocytic leukemia (CLL) is familial. The genetic basis of familial CLL is poorly understood, but recently germ line mutations in the Ataxia Telangiectasia (ATM) gene have been proposed to confer susceptibility to CLL. The evidence for this notion is, however, not unequivocal. To examine this proposition further we have screened the ATM gene for mutations in CLLs from 61 individuals in 29 families. Truncating ATM mutations, including a known ATM mutation, were detected in 2 affected individuals, but the mutations did not cosegregate with CLL in the families. In addition, 3 novel ATM missense mutations were detected. Common ATM missense mutations were not overrepresented. The data support previous observations that ATM mutation is associated with B-CLL. However, ATM mutations do not account for familial clustering of the disease.

Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion.

Monoclonal chronic lymphocytic leukemia (CLL)-phenotype cells are detectable in 3.5% of otherwise healthy persons using flow cytometric analysis of CD5/CD20/CD79b expression on CD19-gated B cells. To determine whether detection of such CLL-phenotype cells is indicative of an inherited predisposition, we examined 59 healthy, first-degree relatives of patients from 21 families with CLL. CLL-phenotype cells were detected in 8 of 59 (13.5%) relatives, representing a highly significant increase in risk (P =.00002). CLL-phenotype cell levels were stable with time and had the characteristics of indolent CLL. Indolent and aggressive clinical forms were found in family members, suggesting that initiation and proliferation involves distinct factors. The detection of CLL-phenotype cells provides a surrogate marker of carrier status, potentially facilitating gene identification through mapping in families and direct analysis of isolated CLL-phenotype cells.