possible bony disease that had been missed on the original

report. The types of missed lesions included three patients with

humeral lesions, three with thoracic spine pedicle loss, three

lumbar spine angular end plate depressions, two femoral

lesions, one pelvic lesion (Fig 1) and two potential fracture

risks. In a further four patients, lytic lesions had been reported

that were not felt to be genuine/significant. As a result of these

findings, the diagnosis was changed from asymptomatic to

symptomatic myeloma requiring treatment in two cases, and

recommendations for orthopaedic intervention or additional

radiotherapy treatment were made in a further five patients.

This data confirm the value of specialist radiological review

at Myeloma MDT meetings with respect to patient manage-

ment and ensuring the accurate staging and treatment of bony

lesions. Interestingly, we observed both false-positive and false-

negative reports compared with the original skeletal survey. A

previous audit between 2001 and 2003 revealed a similar

incidence of missed lesions, emphasising the need for expert

musculoskeletal radiological review for new patients because,

despite on-going training, some lesions may be difficult to

identify by general radiologists. At present, the MDT does not

formally discuss patients with suspected monoclonal gamm-

opathy of undetermined significance who have low-level

plasma cell infiltrates and negative skeletal surveys. Ideally,

these patients should also be reviewed in case lesions are being

missed that would alter the diagnosis, although this would

have a major resource implication.

Jas Singh,1

K. Julia Fairbairn,1

Catherine Williams,2

Emma P. Das-Gupta,2

Nigel H. Russell2

and Jennifer L. Byrne2

1Department of Radiology, Nottingham, University Hospitals Trust, City

Campus, Hucknall Road, Nottingham, and 2Department of

Haematology, Nottingham University Hospitals Trust, City Campus,

Hucknall Road, Nottingham, UK

E-mail: jenny.byrne@nottingham.ac.uk

References

Lecouvet, F., Molgham, J., Micjaux, L., Ferrant, A., Michaux, J.C. &

Vande Berg, B.L. (1999) Skeletal survey in advanced multiple

myeloma: radiographic versus MR imaging survey. British Journal of

Haematology, 106, 35–39.

National Institute of Clinical Excellence (2003) Guidance on Cancer

Services – Improving Outcomes in Haematological Cancers – The

manual. http://www.nice.org.uk/pdf/NICE_HAEMATOLOGICAL_

CSG.pdf; [accessed 2003].

Keywords: multiple myeloma, multi-disciplinary teams, skel-

etal survey.

doi:10.1111/j.1365-2141.2007.06536.x

No association of ARLTS1 polymorphisms and risk for familialchronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is the most prevalent

form of adult leukaemia in western countries. A subset of CLL

is due to genetic susceptibility. Familial CLL is rare and most

likely represents a genetically heterogeneous disease (Sellick

et al, 2005; Ng et al, 2006). Population and family studies

show a sevenfold increased risk of CLL among first degree

relatives of patients with CLL (Goldin et al, 2004). Deletion of

13q14 is frequently detected in solid tumours, sporadic CLL,

and other lymphoproliferative diseases (Liu et al, 1995). ADP-

ribosylation factor-like tumour-suppressor gene 1 (ARLTS1)

spans a 790 kb segment within a minimal deleted chromosome

region at 13q14Æ3 (Calin et al, 2005). ARLTS1 mediates

apoptosis in lung-cancer transplantation experiments in im-

munodeficient mice (Calin et al, 2005). A non-sense poly-

morphism G446A (Trp149Stop) in ARLTS1 has been reported

to be more frequent (odds ratio 5Æ7, P ¼ 0Æ02) among patients

with a family history of cancer or multiple cancers in

comparison with healthy controls (Calin et al, 2005). In that

previous study, two of seventeen familial CLL cases were

positive for the Trp149Stop polymorphism (Calin et al, 2005).

In the present study, we screened DNA from 31 probands

(males ¼ 17, females ¼ 14, median age at diagnosis ¼ 55,

ethnicity ¼ 100% Caucasian) from the National Cancer Insti-

tute CLL family registry to determine if ARLTS1 variants are

associated with the risk of developing CLL. Coding exons and

splice junctions of ARLTS1 were screened for sequence

variants. Sequence data were compared with the published

ARLTS1 sequence (GenBank reference # NM_138450) using

Sequencher 4Æ5 software (Gene Codes Corp., Ann Arbor, MI,

USA). We also screened DNA from 100 unrelated individuals

on the Centre d’Etude du Polymorphisme Humain (CEPH)

database for ARLTS1 sequence variants. Prior pharmacogenetic

studies comparing allele frequencies of CEPH individuals to

healthy volunteers from Tennessee found that CEPH individ-

uals are representative of the European American population.

Polymorphism frequencies in CLL families and CEPH controls

Journal Compilation ª 2007 Blackwell Publishing LtdNo claim to original US government works, British Journal of Haematology, 137, 170–175 173

Correspondence

were compared. All cases and controls were in Hardy–

Weinberg equilibrium.

DNA sequencing identified the Trp149Stop polymorphism

in two of thirty-one familial CLL cases (Table I). The

ARLTS1 Trp149Stop variant did not cosegregate with CLL

affection status or lymphoproliferative disease in these two

families. Family one (Fig S1a) is a three-generation family of

French/German descent affected with lymphoproliferative

disorders [CLL, non-Hodgkin lymphoma (NHL), monoclonal

gammopathy of unknown significance (MGUS), Walden-

strom macroglobulinemia (WM)]. Sequence analysis revealed

the Trp149Stop polymorphism in the proband with CLL (ID

no. 2006) and his sister with NHL (ID no. 2003), but not in

his sister with CLL (ID no. 2005), brother with MGUS (ID

no. 2002) or his niece (ID no. 1001) diagnosed with WM.

Family two (Fig S1b) is of Greek descent with four siblings

and their father with CLL. The Trp149Stop polymorphism

was detected in only two of four CLL affected siblings (ID no.

1005, 1008).

The ARLTS1 Trp149Stop polymorphism did not show

a statistically significantly higher frequency among 31 families

with CLL compared with CEPH controls. Our findings are

consistent with a recent study showing no evidence of

association between ARLTS1 polymorphisms and CLL risk

among individuals with sporadic and familial CLL (Sellick

et al, 2006). These results are in contrast to a previous report

of an association between Trp149Stop with familial CLL

(Calin et al, 2005). The Ser22Leu, Glu164Lys (Calin et al,

2005) and Lys132Lys (Sellick et al, 2006) were not present in

our study population. We identified three previously reported

ARLTS1 variants (Cys148Arg, Pro131Leu, Ser99Ser) (Calin

et al, 2005; Sellick et al, 2006) in the CLL group. In addition,

we identified a new missense variant (Lys194Gln) among two

CEPH controls (Table I). In conclusion, we found no

association of ARLTS1 polymorphisms and risk for familial

CLL.

Acknowledgements

This research was supported [in part] by the Intramural

Research Program of the NIH, National Cancer Institute,

Division of Cancer Epidemiology and Genetics and Center for

Cancer Research. This study could not have been done without

the generosity of the families and their long term involvement

in our research program.

David Ng1

Ousmane Toure1

Laura Fontaine2

Mary L. McMaster1

Lynn R. Goldin1

Neil Caporaso1

Jorge R. Toro1

1Genetic Epidemiology Branch, Division of Cancer Epidemiology and

Genetics, National Cancer Institute, NIH, DHHS, and2Westat Research Inc., Rockville, MD, USA.

E-mail: toroj@mail.nih.gov

References

Calin, G.A., Trapasso, F., Shimizu, M., Dumitru, C.D., Yendamuri, S.,

Godwin, A.K., Ferracin, M., Bernardi, G., Chatterjee, D., Baldassarre,

G., Rattan, S., Alder, H., Mabuchi, H., Shiraishi, T., Hansen, L.L.,

Overgaard, J., Herlea, V., Mauro, F.R., Dighiero, G., Movsas, B.,

Rassenti, L., Kipps, T., Baffa, R., Fusco, A., Mori, M., Russo, G., Liu,

G.G., Neuberg, D., Bullrich, F., Negrini, M. & Croce, C.M. (2005)

Familial cancer associated with a polymorphism in ARLTS1. New

England Journal of Medicine, 352, 1667–1676.

Goldin, L.R., Pfeiffer, R.M., Li, X. & Hemminki, K. (2004) Familial risk

of lymphoproliferative tumors in families of patients with chronic

lymphocytic leukemia: results from the Swedish Family-Cancer

Database. Blood, 104, 1850–1854.

Liu, Y., Hermanson, M., Grander, D., Merup, M., Wu, X., Heyman, M.,

Rasool, O., Juliusson, G., Gahrton, G., Detlofsson, R., Nikiforova, N.,

Buys, C., Soderhall, S., Yankovsky, N., Zabarovsky, E. & Einhorn, S.

(1995) 13q deletions in lymphoid malignancies. Blood, 86, 1911–1915.

Ng, D., Marti, G.E., Fontaine, L., Toro, J.R., Caporaso, N. & Goldin,

L.R. (2006) High density mapping and follow-up studies on

chromosomal regions 1, 3, 6, 12, 13 and 17 in 28 families with

chronic lymphocytic leukaemia. British Journal of Haematology,

133, 59–61.

Sellick, G.S., Webb, E.L., Allinson, R., Matutes, E., Dyer, M.J.S.,

Jonsson, V., Langerak, A.W., Mauro, F.R., Fuller, S., Wiley, J., Lyt-

telton, M., Callea, V., Yuille, M., Cartovsky, D. & Houlston, R.S.

Table I. Frequency of ARLTS1 polymorphisms found in 31 familial CLL cases and 100 CEPH controls.

Nucleotide

variant

Amino acid

change

Case [CLL patients] n ¼ 31

no./total no. (%)

Control [unrelated CEPH]

n ¼ 100 no./total no. (%) Fishers P OR (95%)

c.65C>T Ser22Leu 0/31 0/100

c.297G>A Ser99Ser 1/31 (0Æ03) 9/100 (0Æ09) 0Æ45 0Æ34 (0Æ04–2Æ77)

c.392C>T Pro131Leu 4/31 (0Æ13) 5/100 (0Æ05) 0Æ21 2Æ81 (0Æ71–11Æ22)

c.396G>C Lys132Lys 0/31 0/100

c.442T>C Cys148Arg 18/31 (0Æ58) 67/100 (0Æ67) 0Æ39 0Æ68 (0Æ3–1Æ56)

c.446G>A Trp149Stop 2/31 (0Æ06) 1/100 (0Æ01) 0Æ14 6Æ83 (0Æ6–78)

c.490G>A Glu164Lys 0/31 0/100

c.580A>C Lys194Gln 0/31 (0Æ0) 2/100 (0Æ02) 1Æ0

CLL, chronic lymphocytic leukaemia; CEPH, Centre d’Etude du Polymorphisme Humain; OR, odds ratio.

Journal Compilation ª 2007 Blackwell Publishing Ltd174 No claim to original US government works, British Journal of Haematology, 137, 170–175

Correspondence

(2005) A high-density SNP genomewide linkage scan for chronic

lymphocytic leukemia-susceptibility loci. American Journal of Hu-

man Genetics, 77, 420–429.

Sellick, G.S., Catovsky, D. & Houlston, R.S. (2006) Relationship be-

tween ARLTS1 polymorphisms and risk of chronic lymphocytic

leukemia. Leukemia Research, 30, 1573–1576.

Keywords: familial chronic lymphocytic leukaemia, ARLTS1

mutation analysis.

Supplementary material

The following supplementary material is available for this

article:

Fig S1. Two CLL families with the Trp149Stop polymorphism.

This material is available as part of the online article from:

http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2141.

2007-06544.x

Please note: Blackwell Publishing are not responsible for the

content or functioning of any supplementary materials

supplied by the authors. Any queries (other than missing

material) should be directed to the corresponding author for

the article.

Journal Compilation ª 2007 Blackwell Publishing LtdNo claim to original US government works, British Journal of Haematology, 137, 170–175 175

Correspondence