Allelotyping in Mycosis Fungoides and Sézary Syndrome: Common Regions of Allelic Loss Identified on 9p, 10q, and 17p
2001; Elsevier BV; Volume: 117; Issue: 3 Linguagem: Inglês
10.1046/j.0022-202x.2001.01460.x
ISSN1523-1747
AutoresJulia Scarisbrick, Alison J.‐A. Woolford, R. Russell‐Jones, Sean Whittaker,
Tópico(s)T-cell and Retrovirus Studies
ResumoAllelotyping studies have been extensively used in a wide variety of malignancies to define chromosomal regions of allelic loss and sites of putative tumor suppressor genes; however, until now this technique has not been used in cutaneous lymphoma. We have analyzed 51 samples from patients with mycosis fungoides and 15 with Sézary syndrome using methods to detect loss of heterozygosity. Micro satellite markers were selected on 15 chromosomal arms because of their proximity to either known tumor suppressor genes or chromosomal abnormalities identified in previous cytogenetic studies in cutaneous lymphoma. Allelic loss was present in 45% of patients with mycosis fungoides and 67% with Sézary syndrome. Loss of heterozygosity was found in over 10% of patients with mycosis fungoides on 9p, 10q, 1p, and 17p and was present in 37% with early stage (T1 and T2) and 57% with advanced disease (T3 and T4). Allelic loss on 1p and 9p were found in all stages of mycosis fungoides, whereas losses on 17p and 10q were limited to advanced disease. In Sézary syndrome high rates of loss of heterozygosity were detected on 9p (46%) and 17p (42%) with lower rates on 2p (12%), 6q (7%), and 10q (12%). There was no significant difference in the age at diagnosis or number of treatments received by those with loss of heterozygosity and those without, suggesting that increasing age and multiple treatments do not predispose to allelic loss. These results provide the basis for further studies defining more accurately chromosomal regions of deletions and candidate tumor suppressor genes involved in mycosis fungoides and Sézary syndrome. Allelotyping studies have been extensively used in a wide variety of malignancies to define chromosomal regions of allelic loss and sites of putative tumor suppressor genes; however, until now this technique has not been used in cutaneous lymphoma. We have analyzed 51 samples from patients with mycosis fungoides and 15 with Sézary syndrome using methods to detect loss of heterozygosity. Micro satellite markers were selected on 15 chromosomal arms because of their proximity to either known tumor suppressor genes or chromosomal abnormalities identified in previous cytogenetic studies in cutaneous lymphoma. Allelic loss was present in 45% of patients with mycosis fungoides and 67% with Sézary syndrome. Loss of heterozygosity was found in over 10% of patients with mycosis fungoides on 9p, 10q, 1p, and 17p and was present in 37% with early stage (T1 and T2) and 57% with advanced disease (T3 and T4). Allelic loss on 1p and 9p were found in all stages of mycosis fungoides, whereas losses on 17p and 10q were limited to advanced disease. In Sézary syndrome high rates of loss of heterozygosity were detected on 9p (46%) and 17p (42%) with lower rates on 2p (12%), 6q (7%), and 10q (12%). There was no significant difference in the age at diagnosis or number of treatments received by those with loss of heterozygosity and those without, suggesting that increasing age and multiple treatments do not predispose to allelic loss. These results provide the basis for further studies defining more accurately chromosomal regions of deletions and candidate tumor suppressor genes involved in mycosis fungoides and Sézary syndrome. Mycosis fungoides is the most common form of primary cutaneous T cell lymphoma (CTCL) with an incidence of 0.36 per 105 person-years (Weinstock and Gardstein, 1999Weinstock M.A. Gardstein B. Twenty-year trends in the reported incidence of mycosis fungoides and associated mortality.Am J Public Health. 1999; 89: 1240-1244Crossref PubMed Scopus (167) Google Scholar). It is generally a low-grade lymphoma, which typically presents with cutaneous patches and plaques; however some patients develop progressive disease with cutaneous tumors, erythroderma, or visceral spread. Sézary syndrome is a leukemic form of CTCL with an aggressive clinical course; it is rarer than mycosis fungoides accounting for 2–10% of new cases of CTCL (Willemze et al., 1997Willemze R. Kerl H. Sterry W. et al.EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer.Blood. 1997; 90: 354-371PubMed Google Scholar;Zackheim et al., 1999Zackheim H.S. Amin S. Kashani-Sabet M. McMillan A. Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients.J Am Acad Dermatol. 1999; 40: 418-425Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar). It typically presents with lymphomatous involvement of more than 90% of the skin (erythroderma), intense pruritus, peripheral lymphadenopathy, atypical lymphocytes with convoluted nuclei in the peripheral circulation (Sézary cells), and a peripheral blood T cell clone as demonstrated by T cell receptor (TCR) gene analysis studies (Russell-Jones and Whittaker, 1999Russell-Jones R. Whittaker S. TCR gene analysis in the diagnosis of Sézary syndrome.J Am Acad Dermatol. 1999; 41: 254-259Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). Little is known about the molecular pathogenesis of mycosis fungoides and unlike nodal lymphomas specific chromosomal abnormalities have not been identified. Cytogenetic studies in nodal lymphomas and leukemia have been very rewarding and have identified several disease-specific abnormalities (Weiss et al., 1987Weiss L.M. Warnke R.A. Sklar J. Cleary M.L. Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas.N Engl J Med. 1987; 317: 1185-1189Crossref PubMed Scopus (572) Google Scholar;Kurzrock et al., 1988Kurzrock R. Gutterman J.U. Topless M. The molecular genetics of Philadelphia chromosome-positive leukaemias.N Engl J Med. 1988; 319: 990-998Crossref PubMed Scopus (697) Google Scholar;Chiou et al., 1994Chiou S. Rao L. White E. Bcl-2 blocks p53 dependent apoptosis.Mol Cell Biol. 1994; 14: 2556-2563Crossref PubMed Scopus (352) Google Scholar;Argatoff et al., 1997Argatoff L.H. Connors J.M. Klasa R.J. Horsman D.E. Gascoyne R.D. Mantle cell lymphomas: a clinicopathological study of 80 cases.Blood. 1997; 89: 2067-2078PubMed Google Scholar;Beylot-Barry et al., 1998Beylot-Barry M. Groppi A. Vergier B. Pulford K. Merlio J.P. Characterization of t(2;5) reciprocal transcripts and genomic break points in CD30+ve cutaneous lymphoproliferations.Blood. 1998; 91: 4668-4676PubMed Google Scholar). Attempts to identify these well-defined chromosomal abnormalities in primary cutaneous lymphoma have not been fruitful. The t(14; 18) that characterizes nodal follicular center cell lymphoma was found in only one of 14 cases of primary cutaneous follicular center cell (Cerroni et al., 1994Cerroni L. Volkenandt M. Reiger E. Soyer P. Kerl H. Bcl-2 protein expression and correlation with the inter-chromosomal 14; 18 translocation in cutaneous lymphoma and pseudolymphoma.J Invest Dermatol. 1994; 102: 231-235Abstract Full Text PDF PubMed Google Scholar). Similarly, the t(2;5) characteristic of nodal CD30+ large cell anaplastic lymphoma was not found in 14 cases of primary cutaneous CD30+ large cell anaplastic lymphoma (DeCoteau et al., 1996DeCoteau J. Butmarc J. Kinney M. Kadin M.E. The t(2;5) chromosomal translocation is not a common feature of primary cutaneous CD30+ lymphoproliferative disorders: comparison with anaplastic large-cell lymphoma of nodal origin.Blood. 1996; 87: 3437-3441PubMed Google Scholar). These findings suggest that primary cutaneous lymphomas have a different pathogenesis from their nodal counterparts despite similar morphologic features. Peripheral blood cytogenetic studies in CTCL have been ongoing since 1968 (Spiers et al, 1968). Clonal chromosomal abnormalities have been identified in 20–100% of patients with Sézary syndrome and in the peripheral blood of some patients with advanced stages of mycosis fungoides. Several cytogenetic studies in patients with advanced CTCL have identified multiple clonal chromosomal abnormalities, most commonly involving structural rearrangements of chromosomes 1, 2, 6, 9, 14, and 16 and numerical abnormalities of 6, 8, 10, 11, 13, 17, and 21. A recent study of 11 patients with CTCL identified chromosomal loss between 1p22 and 1p36 in five patients and rearrangements of chromosome 2 in four patients (Thangavelu et al., 1997Thangavelu M. Finn W.G. Yelavarthi K.K. et al.Recurring structural chromosomal abnormalities in peripheral blood lymphocytes of patients with mycosis fungoides/Sézary syndrome.Blood. 1997; 89: 3371-3377PubMed Google Scholar). Rearrangements involving 2p were also detected in two of six patients byBerger et al., 1988Berger R. Baranger L. Bernheimm A. Valensi F. Flandrin G. Cytogenetics of T-cell malignant lymphoma: Report of 17 cases and review of the chromosomal breakpoints.Cancer Genet Cytogenet. 1988; 36: 123-130Abstract Full Text PDF PubMed Scopus (34) Google Scholar who reviewed the literature to identify two common breakpoints on 2p; one clustering around 2p11–14 and the other around 2p23–25. Complete or partial monosomy of chromosomes 8p, 17p, and isochromosome 17q have been identified in CTCL (Nowell et al., 1982Nowell P.C. Finan J.B. Vonderheid E.C. Clonal characteristics of cutaneous T-cell lymphomas: cytogenetic evidence from blood, lymph nodes and skin.J Invest Dermatol. 1982; 78: 69-75Crossref PubMed Scopus (74) Google Scholar;Berger et al., 1988Berger R. Baranger L. Bernheimm A. Valensi F. Flandrin G. Cytogenetics of T-cell malignant lymphoma: Report of 17 cases and review of the chromosomal breakpoints.Cancer Genet Cytogenet. 1988; 36: 123-130Abstract Full Text PDF PubMed Scopus (34) Google Scholar;Thangavelu et al., 1997Thangavelu M. Finn W.G. Yelavarthi K.K. et al.Recurring structural chromosomal abnormalities in peripheral blood lymphocytes of patients with mycosis fungoides/Sézary syndrome.Blood. 1997; 89: 3371-3377PubMed Google Scholar). Deletions of 6q have also been identified in several studies (Thangavelu et al., 1997Thangavelu M. Finn W.G. Yelavarthi K.K. et al.Recurring structural chromosomal abnormalities in peripheral blood lymphocytes of patients with mycosis fungoides/Sézary syndrome.Blood. 1997; 89: 3371-3377PubMed Google Scholar;Nowell et al., 1982Nowell P.C. Finan J.B. Vonderheid E.C. Clonal characteristics of cutaneous T-cell lymphomas: cytogenetic evidence from blood, lymph nodes and skin.J Invest Dermatol. 1982; 78: 69-75Crossref PubMed Scopus (74) Google Scholar;Shapiro et al., 1987Shapiro P.E. Warburton D. Berger C.L. Edelson R.L. Clonal chromosomal abnormalities in cutaneous T-cell lymphoma.Cancer Genet Cytogenet. 1987; 28: 267-276Abstract Full Text PDF PubMed Scopus (30) Google Scholar). Rearrangements involving 9p were identified in three of six patients with CTCL byBerger et al., 1988Berger R. Baranger L. Bernheimm A. Valensi F. Flandrin G. Cytogenetics of T-cell malignant lymphoma: Report of 17 cases and review of the chromosomal breakpoints.Cancer Genet Cytogenet. 1988; 36: 123-130Abstract Full Text PDF PubMed Scopus (34) Google Scholar in addition one patient had a rearrangement involving 14q32. This locus was also involved in a translocation in two of 23 patients with CTCL in a previous study byNowell et al., 1986Nowell P.C. Vonderheid E.C. Besa E. Hoxie J.A. Moreau L. Finan J.B. The most common chromosome change in 86 chronic B cell or T cell tumours: a 14q32 translocation.Cancer Genet Cytogenet. 1986; 19: 219-227Abstract Full Text PDF PubMed Scopus (65) Google Scholar. Studies of Sézary syndrome have identified frequent abnormalities also involving 1p, 2p, 6q, 9, 10q, 13q, 17p, and 21 (Johnson et al., 1985Johnson G.A. Dewald G.W. Strand W.R. Winkelmann R.K. Chromosome studies in 17 patients with Sézary syndrome.Cancer. 1985; 55: 2426-2433Crossref PubMed Scopus (45) Google Scholar;Sole et al., 1988Sole F. Woessner S. Vallespi T. et al.Cytogenetic studies in 5 patients with Sézary syndrome.Cancer Genet Cytogenet. 1988; 36: 123-130Abstract Full Text PDF PubMed Scopus (26) Google Scholar;Limon et al., 1995Limon J. Nedoszytko B. Brozek I. Hellmann A. Zajaczek S. Lubinski J. Mrozek K. Chromosome aberrations, spontaneous SCE and growth kinetics in PHA-stimulated lymphocytes in 5 cases of Sézary syndrome.Cancer Genet Cytogenet. 1995; 83: 75-81Abstract Full Text PDF PubMed Scopus (35) Google Scholar;Brito-Babpulle et al., 1997Brito-Babpulle V. Maljaie S.H. Matutes E. Hedges M. Yuille M. Catovsky D. Relationship of T leukaemias with cerebriform nuclei to T-prolymphocytic leukaemia: a cytogenetic analysis with in situ hybridization.Br J Haematol. 1997; 96: 724-732Crossref PubMed Scopus (29) Google Scholar). Most cytogenetic studies have been based on analysis of metaphases from peripheral blood lymphocyte cultures even though morphologic abnormalities are seldom present in the peripheral blood of patients with MF. These multiple chromosomal abnormalities have mainly been found in patients with advanced stages of mycosis fungoides and are associated with a poor prognosis (Thangavelu et al., 1997Thangavelu M. Finn W.G. Yelavarthi K.K. et al.Recurring structural chromosomal abnormalities in peripheral blood lymphocytes of patients with mycosis fungoides/Sézary syndrome.Blood. 1997; 89: 3371-3377PubMed Google Scholar;Whang-Peng et al., 1979Whang-Peng J. Bunn P. Knutsen T. Schechter G.P. Gazdar A.F. Mathews M.J. Minna J.D. Cytogenetic abnormalities in patients with cutaneous T-cell lymphoma.Cancer Treat Rep. 1979; 63: 575-580PubMed Google Scholar;Shapiro et al., 1987Shapiro P.E. Warburton D. Berger C.L. Edelson R.L. Clonal chromosomal abnormalities in cutaneous T-cell lymphoma.Cancer Genet Cytogenet. 1987; 28: 267-276Abstract Full Text PDF PubMed Scopus (30) Google Scholar). Studies of skin biopsy material from patients with mycosis fungoides have generally not been successful for a variety of biologic and technical reasons. The growth of tumor cells from solid tissues in culture is often poor because of a low mitotic index. Cultures may be contaminated with keratinocytes, fibroblasts, or reactive lymphocytes and preparations of good quality metaphases from solid tumor can be difficult. Although rearrangements of specific oncogenes have rarely been found in CTCL, studies of tumor suppressor genes have been more rewarding. Inactivation of P53 has been found in advanced mycosis fungoides and Sézary syndrome (McGregor et al., 1995McGregor J. Dublin E. Levison D. MacDonald D.M. Smith N.P. Whittaker S. p53 immunoreactivity is uncommon in primary cutaneous lymphoma.Br J Dermatol. 1995; 132: 353-358Crossref PubMed Scopus (29) Google Scholar,McGregor et al., 1999McGregor J.M. Crook T. Fraser-Andrews E.A. Rozycka M. Crossland S. Whittaker S.J. Spectrum of p53 gene mutations suggests a possible role for ultraviolet radiation in the pathogenesis of advanced cutaneous lymphomas.J Invest Dermatol. 1999; 112: 317-321https://doi.org/10.1046/j.1523-1747.1999.00507.xCrossref PubMed Scopus (71) Google Scholar;Lauritzen et al., 1995Lauritzen A. Vejlsgaard G. Hou-Jensen K. Ralfkier E. p53 protein expression in cutaneous T-cell lymphomas.Br J Dermatol. 1995; 133: 32-36Crossref PubMed Scopus (33) Google Scholar;Marks et al., 1996Marks D. Vonderheid E. Kurz B. et al.Analysis of p53 and mdm-2 expression in 18 patients with Sézary syndrome.Br J Haematol. 1996; 92: 890-899Crossref PubMed Scopus (37) Google Scholar;Marrogi et al., 1999Marrogi A.J. Khan M.A. Vonderheid E.C. Wood G.S. McBurney E. p53 tumour suppressor gene mutations in transformed cutaneous T-cell lymphoma: a study of 12 cases.J Cut Pathol. 1999; 26: 369-378Crossref PubMed Scopus (32) Google Scholar), which is similar to findings in nodal non-Hodgkin's lymphoma and suggests that P53 gene mutations are associated with disease progression in lymphoma (Gaidano et al., 1991Gaidano G. Ballerini P. Gong J.Z. et al.p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukaemia.Proc Natl Acad Sci USA. 1991; 88: 5413-5417Crossref PubMed Scopus (824) Google Scholar). Abnormalities of the P16 gene were detected in seven of nine patients with mycosis fungoides in both early and advanced stages of disease (Navas et al., 2000Navas I.C. Oritz-Romero P.L. Villuendas R. et al.p16 gene alterations are frequent in lesions of mycosis fungoides.Am J Pathol. 2000; 156: 1565-1572Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). In addition a further study found absent expression of the P16 gene in five of 20 patients with early stages of mycosis fungoides (Peris et al., 1999Peris K. Stanta G. Fargnoli C. Bonin S. Felli A. Amantea A. Chimenti S. Reduced expression of CDKN2a/p16 in mycosis fungoides.Arch Dermatol Res. 1999; 291: 207-211https://doi.org/10.1007/s004030050395Crossref PubMed Scopus (21) Google Scholar). Germline mutations of P15 and P16 genes are found in some cases of familial melanoma (Hussussian et al., 1994Hussussian C.J. Struewing J.P. Goldstein A.M. et al.Germline p16 mutations in familial melanoma.Nat Genet. 1994; 8: 15-21Crossref PubMed Scopus (1100) Google Scholar) and inactivation of these genes has also been found in non-Hodgkin's lymphoma (Gombart et al., 1995Gombart A.F. Morosetti R. Miller C.W. Said J.W. Koeffler H.P. Deletions of the cyclin-dependant inhibitor genes p16 and p15 in non-Hodgkin's lymphoma.Blood. 1995; 86: 1534-1539PubMed Google Scholar;Heyman et al., 1996Heyman M. Rasool O. Borgonov-Brandter L. et al.Prognostic importance of p15INK4B and p16INK4 gene inactivation in childhood acute lymphocytic leukemia.J Clin Oncol. 1996; 14: 1512-1520PubMed Google Scholar). We have performed an extensive allelotyping in order to identify patterns of loss of heterozygosity (LOH) in both early and advanced cutaneous stages of mycosis fungoides and Sézary syndrome. Allelic loss is a common mechanism of tumor suppressor gene inactivation and provides information on the likely involvement of such genes in the pathogenesis of mycosis fungoides and Sézary syndrome. Tumour DNA from lesional skin and normal control DNA from the patients' peripheral blood mononuclear cells or lymph nodes, was extracted according to standard procedures by proteinase K digestion and phenol/chloroform extraction, from individual patients with mycosis fungoides. All tumor samples were chosen because, either southern blot or single strand conformational polymorphism–polymerase chain reaction (PCR) based TCR gene analysis (Whittaker et al., 1991Whittaker S.J. Smith N.P. Russell-Jones R. Luzzatto L. Analysis of beta, gamma and delta TCR genes in mycosis fungoides and Sézary syndrome.Cancer. 1991; 68: 1572-1582Crossref PubMed Scopus (83) Google Scholar; Fraser-Andrews et al, 2000) had previously demonstrated a clonal population in lesional skin, which was absent from the peripheral blood or lymph node. Furthermore, only those samples with a large dominant clone were selected for this study: a large dominant clone was determined by measuring the signal intensity of the discrete band, using Image Master Scanning Densitometer (Amersham Pharmacia, Piscataway, NJ) with Image Master Softwear (Amersham Pharmacia) and only samples with a signal intensity of more than 50% in the discrete band compared with the background smear were considered to contain a large dominant clone. These samples consisted of 51 patients with mycosis fungoides with different cutaneous stages of disease: T1 = 14, T2 = 16, T3 = 17, and T4 = 4, which included IA = 14, IB = 13, IIA = 3, IIB = 11, III = 1, and IVA = 9 (Lamberg et al., 1984Lamberg S.I. Green S.B. Byar D.P. et al.Clinical staging for cutaneous T-cell lymphoma.Ann Intern Med. 1984; 100: 187-192Crossref PubMed Scopus (95) Google Scholar) and 15 patients with Sézary syndrome (III = 8 and IVA = 7). Microsatellite analysis requires comparison between tumor and normal DNA from individual patients. In most patients with mycosis fungoides tumor DNA was extracted from lesional skin and normal control DNA from either peripheral blood lymphocytes or lymph nodes. All 15 cases with Sézary syndrome had a large dominant T cell clone in peripheral blood. In three cases DNA from lymph nodes did not demonstrate a T cell clone and these samples were used as a normal control. In the other 12 cases with Sézary syndrome and three patients with tumor stage mycosis fungoides T cell clones were detected in skin, blood, lymph nodes, and bone marrow aspirates. In these patients no DNA was available without a T cell clone and normal DNA was obtained by isolating CD8+ cells from peripheral blood lymphocytes as described below. Prior to isolation of CD8+ cells, formalin-fixed paraffin-embedded histologic sections from lesional skin were immunostained using CD4 and CD8 monoclonal antibodies (Vector Laboratories, Burlingame, CA) to confirm that the tumor cells had a typical CD4+ CD8‒ phenotype (Willemze et al., 1997Willemze R. Kerl H. Sterry W. et al.EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer.Blood. 1997; 90: 354-371PubMed Google Scholar). First, lymphocytes were separated from whole blood using Lymphoprep (N Fiemed, Norway) and centrifuged at 1400 r.p.m. for 25 min with gentle acceleration and deceleration. The lymphocytes were then removed and washed using phosphate-buffered saline (Sigma, Poole, U.K.) with centrifugation at 1400 r.p.m. for a further 10 min. The lymphocyte pellet was then resuspended in phosphate-buffered saline with 2% fetal bovine serum (Helena Technologies, Barnsley, U.K.). Viable lymphocytes were counted using a Neubaeu hemocytometer with trypan blue dye exclusion. This manual counting method includes all lymphocytes (both T cells (CD3+, including CD4+ and CD8+ lymphocytes) and B cells (CD20+). A more accurate estimate of the number of CD8+ lymphocytes was then calculated using the percentage CD3 count and CD4/8 ratio for each sample. Cells were stored in liquid nitrogen for future isolation of the CD8+ lymphocytes. CD8 Dynabeads (Dynal AS, Norway) were used to isolate CD8+ cells following the manufacturers' instructions. DNA extraction was then performed using Genomic Prep Cells and Tissues DNA isolation kit (Amersham Pharmacia) in accordance with manufacturers' instructions. DNA was precipitated by ethanol and resuspended in 50 µl of water. Tumor and normal DNA samples from patients with mycosis fungoides were analyzed for allelic loss using oligonucleotide primers for 25 microsatellite markers from 15 chromosomal arms. In Sézary syndrome 17 microsatellite markers on eight chromosomal arms were analyzed. This more limited analysis was performed due to the limited amount of normal DNA available for comparison in LOH studies. Microsatellite markers were chosen with high rates of heterozygosity (> 0.8) and were either close to chromosomal regions found to be deleted in previous cytogenetic studies of CTCL or known tumor suppressor genes Table I. These included 21 dinucleotide markers: Primer sequences were taken from the Genethon Human Linkage Map (Gyapay et al., 1994Gyapay G. Morissette J. Vignal A. et al.The 1993–4 Genethon Human Genetic Linkage Map.Nat Genet. 1994; 7: 246-249Crossref PubMed Scopus (1958) Google Scholar), excluding U09579, RH70320, L11910 (EMBL, Meyerhofstr, Germany), IFNA, p15, p16 (Heyman et al., 1996Heyman M. Rasool O. Borgonov-Brandter L. et al.Prognostic importance of p15INK4B and p16INK4 gene inactivation in childhood acute lymphocytic leukemia.J Clin Oncol. 1996; 14: 1512-1520PubMed Google Scholar), p53 (Futreal et al., 1991Futreal P.A. Barrett J.C. Wiseman R.W. An Alu polymorphism intragenic to the TP53 gene.Nucleic Acids Res. 1991; 19: 6977Crossref PubMed Scopus (119) Google Scholar), and four mononucleotide repeats: BAT 26, BAT RII, BAT 34C4 (Zhou et al., 1997Zhou X.P. Hoang J.M. Cottu P. Thomas G. Hamelin R. Allelic profiles of mononucleotide repeat microsatellites in control individuals and in colorectal tumours with and without replication errors.Oncogene. 1997; 15: 1713-1718Crossref PubMed Scopus (115) Google Scholar), and the G8 tract of the BAX gene (Molenaar et al., 1998Molenaar J.J. Gerard B. Chambon-Pautas C. Cave H. Duval M. Vilmer E. Grandchamp B. Microsatellite instability and frameshift mutations in BAX and transforming growth factor-beta RII genes are very uncommon in acute lymphoblastic leukemia in vivo but not in cell lines.Blood. 1998; 92: 230-233PubMed Google Scholar).Table ISummary of chromosomal locations analyzed with reference to previous cytogenetic findings and candidate tumor suppressor genesChromosomal regionRegions of allelic loss in CTCLCandidate TSGMicrosatellite markers1p22–3611Berger et al (1988).,2Limon et al (1995)., 1p22–363Thangavelu et al (1997).P7316Kawano et al (1999)., P1817Hatta et al (1997)., TAL-118Janssen et al (1993).D1S201, D1S2472p16–212p14–251Berger et al (1988)., 2p114Van Vloten et al (1980)., 2p215Sole et al (1988).hMSH2,hMSH619Lowsky et al (1997).,20Indraccolo et al (1999).BAT26, D2S1233p22TGF-beta receptor 221Lagneaux et al (1997).BAT-RII5q13,21–22,5q35P2122Villuendas et al (1997).,APC23Baeg et al (1995).U09579, D5S346, D5S6776q16.3–21,21–23.36q3Thangavelu et al (1997).,4Van Vloten et al (1980).,5Sole et al (1988).,6Shapiro et al (1987).,7Nowell et al (1982). and 8Whang-Peng et al (1982)., 6q21–239Johnson et al (1985).D6S283, D6S2619p2194Van Vloten et al (1980).,8Whang-Peng et al (1982)., 9p1Berger et al (1988).P15,P1624Gombart et al (1995).,25Heyman et al (1996).IFNA, p15,1610q23–24103Thangavelu et al (1997).,5Sole et al (1988).,8Whang-Peng et al (1982)., 10q22–262Limon et al (1995).,10Edelson et al (1979).,11Karenko et al (1997). and 12Karenko et al (1999).PTEN26Nakahara et al (1998)., FAS27Komada et al (1997).D10S215, D10S541, D10S20911q23111Berger et al (1988).,10Edelson et al (1979).ATM47D11S134712p12.31210Edelson et al (1979).,13Barbieri et al (1986)., 12p11–132Limon et al (1995).LRP629Baens et al (1999).T6811513q14.2–2213q5Sole et al (1988).,8Whang-Peng et al (1982).,13q21–2210Edelson et al (1979).,11Karenko et al (1997).Rb30Pescarmona et al (1999)L11910, D13S16014q3214q13Barbieri et al (1986)., 14q321Berger et al (1988).,14Nowell et al (1986).D14S105417q11.2–12Iso17q4Van Vloten et al (1980).,7Nowell et al (1982).,9Johnson et al (1985).BRCA131Beckmann et al (1996)., NF132Bollag et al (1996).D17S25017p13.117p2Limon et al (1995).,3Thangavelu et al (1997)., 17p1315Brito-Babpulle et al (1997).P5333McGregor et al (1995).,34Lauritzen et al (1995).,35McGregor et al (1999). and 36Marks et al (1996).BAT34C, p5319qBAX37Molenaar et al (1998).BAX(G8tract)21q22.1214Van Vloten et al (1980).,10Edelson et al (1979).TIAM-138Chen et al (1995).D21S26328 Takeuchi et al., 1998Takeuchi S. 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