Blood, 1 March 2001, Vol. 97, No. 5, pp. 1517-1518
CORRESPONDENCE
To the editor:
Recurrent ATM mutations in T-PLL on diverse
haplotypes: no support for their germline origin
The ATM gene has been found to be mutated or deleted
in the majority of cases of T cell prolymphocytic leukemia
(T-PLL),1-5 and missense mutations were shown to
cluster in the highly conserved gene region encoding the ATM kinase
domain.1 Recently, Vanasse et al reported that as many as
half of the individuals without ataxia-telangiectasia (A-T) who
develop sporadic T-PLL are heterozygous carriers of mutations in the
ATM gene.6 In a response, Stoppa-Lyonnet et al
argued that there was no evidence in the literature for this assertion
and provided a valuable set of data supporting a somatic origin of
ATM mutations in this sporadic leukemia.5 Because nontumor DNA in T-PLL cases was largely unavailable in previous
studies, it is unknown to what extent, if any, A-T heterozygosity is
associated with a detectable risk of sporadic T-PLL. In addition, the
majority of identified ATM mutations in T-PLL were different from those observed in A-T families.1,2
If the ATM mutation in sporadic T-PLL is identical to a
previously detected A-T patient allele, haplotype analysis of tumor DNA
may be a useful way, in the absence of germline material, to
distinguish between a somatic and germline origin of the mutation. Evidence of the same ancestral chromosome shared by a T-PLL and an A-T
family would support a germline alteration, whereas an identical
mutation in a different haplotype background argues for a recurrent
mutation. Our previous analysis of 37 cases with T-PLL, largely from
the United Kingdom, identified 3 tumors carrying the same mutations as
previously found in the germline of A-T patients.1 Single
strand polymorphism (SSCP) analysis and nucleotide sequencing
identified only a single mutation in each of the 3 tumors and failed to
detect the presence of a normal allele.1 The first tumor
(1d5) carried a 9 base pair (bp) deletion (7636del9), the most common
A-T allele reported so far, found in 15 apparently unrelated
families.7-13 The second tumor (1c10) carried a 7271T>G transversion (V2424G), previously identified only in the British Isles,8 while the third tumor (BJ01) carried a nonsense
transition 9139C>T (R3047X) found in different
populations.8,9,14-16
The ATM mutations have been confirmed in all 3 tumors
independently. A series of highly polymorphic markers at and flanking the ATM gene and covering a physical distance of about 5.4 megabase (Mb) was used for the haplotype analysis of these
T-PLLs together with control DNA from A-T patients carrying the same
ATM mutation (Figure 1). Tumor
samples 1d5 and BJ01 were shown to be homozygous/hemizygous for markers
in the region of ATM. This is consistent with loss of
heterozygosity across the ATM region and
identification of only a single ATM mutation in each
case.1 T-PLL 1c10 also showed homozygosity for most
markers although some appeared to be heterozygous. Haplotypes were not
the same, however, between the tumor sample and the A-T patient for
each of these mutations (Figure 1).
View larger version (17K):
[in this window]
[in a new window]
| Figure 1.
Haplotype analysis of T-PLL tumors and A-T patients carrying the same
ATM mutation.
aHaplotype associated with mutation 7636del9 in 8 United
Kingdom families. bHaplotype associated with mutation
7271T>G in 3 United Kingdom families. cNot known which
haplotype is associated with 9139C>T mutation in this family.
dHaplotype associated with mutation 9139C>T in this
family.
|
|
In sample 1d5, the allele 5 at D11S2179 (within the
ATM gene between exons 62 and 63) was identical to that
found on the haplotype invariably carrying the 7636del9 mutation in 13 A-T patients in 8 families.8 But this is the most common
allele for D11S2179 (36% in normal chromosomes not carrying
an ATM mutation in the United Kingdom population), and in
the majority of the remaining marker loci, the observed alleles
differed. Although tumor 1c10 had allele 6 at D11S2179
identical to 6 A-T patients in 3 families with the same 7271T>G
mutation, this was the second most common allele for this locus in
United Kingdom families (26%). But alleles at and distal to
D11S1778 and at and proximal of the D11S1819 locus were different in T-PLL DNA compared with the founder haplotype in the A-T patients carrying the 7271T>G mutation. Finally, tumor BJ01, which was found to contain a truncating mutation 9139C>T, 1 also showed a haplotype distinct from the 2 different
haplotypes observed in 2 A-T families carrying the same 9139C>T
mutation (Figure 1).
Although a marker locus mutation can explain occasional variant alleles
in short tandem repeats (in particular in those differing by a single
repeat unit), this mechanism is unlikely to explain the multiple
allelic diversity observed between the A-T haplotypes and haplotypes of
T-PLL tumors. In A-T patients founder haplotypes are conserved over the
same range of markers as used here to analyze sporadic T-PLL
tumors.8 It is unlikely, therefore, that the distance over
which the markers are spread will allow changes from germline resulting
in such allelic diversity. We conclude that the haplotypes in the
region analyzed around the ATM locus are not the same as
those carrying the same mutation in the germline. Therefore, our
results are not consistent with the germline origin of reported changes
in T-PLL tumors, although they ultimately cannot exclude it. In their
response to the letter of Stoppa-Lyonnet et al,5 Vanasse
and colleagues17 argue that the recurrence of
ATM mutations previously found in T-PLL1,2 does
not fit well with their strictly somatic origin. Our present data
illustrate that recurrent mutations in tumor DNA are compatible with
their somatic origin. At present, we believe that there are no data to
support a tacit acceptance of the hypothesis of the germline origin of
ATM mutations in sporadic T-PLL. This, of course, can now be
tested prospectively using matched normal and tumor DNA from a larger
number of T-PLL cases with ATM mutations.
Tatjana Stankovic and A. Malcolm R. Taylor
CRC Institute for Cancer Studies The University of
Birmingham Birmingham, United Kingdom
Martin R. Yuille
Academic Department of Haematology and Cytogenetics Institute
of Cancer Research Sutton, Surrey, United Kingdom
Igor Vorechovsky
Karolinska Institute Department of Biosciences at
NOVUM Huddinge, Sweden
Acknowledgments
We thank the Leukaemia Research Fund, the
Cancer Research Campaign, the European Community (QLRT 1999-786), and
the Kay Kendall Leukaemia Fund for continued support and Tina
Bedenham for technical assistance.
References
1.
Vorechovsky I, Luo L, Dyer MJ, et al.
Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia.
Nat Genet.
1997;17:96-99[CrossRef][Medline]
[Order article via Infotrieve].
2.
Stoppa-Lyonnet D, Soulier J, Lauge A, et al.
Inactivation of the ATM gene in T-cell prolymphocytic leukemias.
Blood.
1998;91:3920-3926[Abstract/Free Full Text].
3.
Stilgenbauer S, Schaffner C, Litterst A, et al.
Biallelic mutations in the ATM gene in T-prolymphocytic leukemia.
Nat Med.
1997;3:1155-1159[CrossRef][Medline]
[Order article via Infotrieve].
4.
Yuille MA, Coignet LJ, Abraham SM, et al.
ATM is usually rearranged in T-cell prolymphocytic leukaemia.
Oncogene.
1998;16:789-796[CrossRef][Medline]
[Order article via Infotrieve].
5.
Stoppa-Lyonnet D, Lauge A, Sigaux F, Stern M-H.
No germline ATM mutation in a series of 16 T-cell prolymphocytic leukemias.
Blood.
2000;96:374-376[Free Full Text].
6.
Vanasse GJ, Concannon P, Willerford DM.
Regulated genomic instability and neoplasma in the lymphoid lineage.
Blood.
1999;94:3997-4010[Free Full Text].
7.
Byrd PJ, McConville CM, Cooper P, et al.
Mutations revealed by sequencing the 5' half of the gene for ataxia telangiectasia.
Hum Mol Genet.
1996;5:145-149[Abstract/Free Full Text].
8.
Stankovic T, Kidd AM, Sutcliffe A, et al.
ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer.
Am J Hum Genet.
1998;62:334-345[CrossRef][Medline]
[Order article via Infotrieve].
9.
Lakin ND, Weber P, Stankovic T, et al.
Analysis of the ATM protein in wild-type and ataxia telangiectasia cells.
Oncogene.
1996;13:2707-2716[Medline]
[Order article via Infotrieve].
10.
Gilad S, Khosravi R, Shkedy D, et al.
Predominance of null mutations in ataxia-telangiectasia.
Hum Mol Genet.
1996;5:433-439[Abstract/Free Full Text].
11.
Savitsky K, Bar-Shira A, Gilad S, et al.
A single ataxia telangiectasia gene with a product similar to PI-3 kinase.
Science.
1995;268:1749-1753[Abstract/Free Full Text].
12.
Wright J, Teraoka S, Onengut S, et al.
A high frequency of distinct ATM gene mutations in ataxia-telangiectasia.
Am J Hum Genet.
1996;59:839-846[Medline]
[Order article via Infotrieve].
13.
Watters D, Khanna KK, Beamish H, et al.
Cellular localisation of the ataxia-telangiectasia (ATM) gene product and discrimination between mutated and normal forms.
Oncogene.
1997;14:1911-1921[CrossRef][Medline]
[Order article via Infotrieve].
14.
Izatt L, Greenman J, Hodgson S, et al.
Identification of germline missense mutations and rare allelic variants in the ATM gene in early-onset breast cancer.
Genes Chrom Cancer.
1999;26:286-294[CrossRef][Medline]
[Order article via Infotrieve].
15.
Toyoshima M, Hara T, Zhang H, et al.
Ataxia-telangiectasia without immunodeficiency: novel point mutations within and adjacent to the phosphatidylinositol 3-kinase-like domain.
Am J Med Genet.
1998;75:141-144[CrossRef][Medline]
[Order article via Infotrieve].
16.
Gilad S, Chessa L, Khosravi R, et al.
Genotype-phenotype relationships in ataxia-telangiectasia and variants.
Am J Hum Genet.
1998;62:551-561[CrossRef][Medline]
[Order article via Infotrieve].
17.
Vanasse GJ, Concannon P, Willerford DM.
Somatic versus germline origin of ATM mutations in T-PLL [letter].
Blood.
2000;96:376.
