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Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 2113-2117
Allelotype Analysis of Adult T-Cell Leukemia
By
Yoshihiro Hatta,
Yasuaki Yamada,
Masao Tomonaga,
Jonathan W. Said,
Isao Miyosi, and
H. Phillip Koeffler
From the Division of Hematology/Oncology, Cedars-Sinai Research
Institute, UCLA School of Medicine, Los Angeles, CA; the Deparment of
Laboratoy Medicine and the Department of Hematology, Nagasaki
University School of Medicine, Nagasaki, Japan; the Department of
Pathology, Center for the Health Science, UCLA School of Medicine, Los
Angeles, CA; and the Department of Medicine, Kochi Medical School,
Kochi, Japan.
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ABSTRACT |
Allelotype analysis of adult T-cell leukemia (ATL) was undertaken
for the first time to identify chromosomal loci relevant to the
development of acute/lymphomatous ATL. Loss of heterozygosity (LOH) was
screened using 94 highly polymorphic microsatellite markers,
distributed among all nonacrocentric, autosomal chromosomes. In each of
the 22 cases, DNA obtained from their leukemic cells in
acute/lymphomatous phase was compared with their constitutional DNA
from mononuclear cells in chronic or remission phase. Allelic losses of
at least on one chromosome arm occurred in 91% of the cases (20 individuals). Among 39 chromosome arms, allelic losses were observed on
31 arms at least for one sample. A high frequency of allelic loss
(>30%) was seen on chromosome arms 6q (41%) and 17p (48%). The
mean fractional allelic loss (FAL) was 0.109. These findings suggest
that a novel tumor suppressor gene on chromosome arm 6q, as well as the
p53 gene on chromosome arm 17p, probably have an important role in the
development of acute/lymphomatous ATL.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
INITIATION AND PROGRESSION of neoplasia
can include inactivation of one or several tumor suppressor genes. The
paradigm of alterations of a tumor suppressor gene is a mutation of one
allele and loss of the second allele.1 Such losses may
involve deletions too small to be detected by conventional
cytogenetics. This reduction to homozygosity can be detected by the
finding of loss of heterozygosity (LOH) of polymorphic sequences in
tumor DNA as compared with constitutional DNA from the same individual.
Several tumor suppressor genes, such as the DCC gene, have been cloned
from the hot spot of LOH analysis.2-5 Thus, LOH analysis is
an indirect method to search for a tumor suppressor gene. Allelotype
analysis is an extensive survey of allelic loss throughout the genome,
screening multiple loci for regions containing tumor suppressor genes
that are likely to be altered.5-15 This technique has
recently become extremely powerful with the use of microsatellite
markers, which are short tracts of (CA)n repeats with high
polymorphism that exists throughout the genome.16,17
Adult T-cell leukemia (ATL) is an aggressive, fatal malignancy of
mature CD4+ T lymphocytes.18,19 The human T-
cell lymphotropic virus type I (HTLV-I) has been recognized as the
etiologic agent of ATL.20-22 However, a long period of
clinical latency (mean, 55 years) precedes the developement of
ATL23 and only a small percentage of HTLV-I-infected
individuals develop this malignancy (one patient/1,000 to 2,000 carriers/year),24,25 indicating that additional genetic
events probably are required to develop ATL after viral infection of
the target T cells. Statistical analysis suggests that ATL arises
following five independent genetic events.26
Studies to date by ourselves and others have implicated deletions or
mutations of several tumor suppressor genes in the pathogeneisis of
ATL, including p53 in about 40% of acute/lymphomatous
ATL,26-28 and the p15INK4B,
p16INK4A, and Rb genes in approximately 30%, 35%, and 5%
of such cases, respectively.29-32 In addition, loss of
expression of p18INK4C was found in ATL cell
lines.33 To begin to define further genetic events leading
to the evolution of acute/lymphomatous ATL, we performed comprehensive
allelotype analysis of ATL using 94 microsatellite markers that covered
all autosomal chromosomes.
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MATERIALS AND METHODS |
Samples.
Patients with acute/lymphomatous ATL were investigated; 21 samples were
from Japanese patients and one was from an individual from Panama. The
percentage of contaminating normal cells in the acute/lymphomatous
phase samples was at most 30% and usually less than 10%. The
corresponding control DNAs were obtained from either their peripheral
blood after complete remission (n = 17) or during their chronic phase
(n = 5). The clinical subtypes of ATL were based on the diagnostic
criteria proposed by the Lymphoma Study Group of Japan.34
Cytogenetic data were available from five patients. All five
cases showed chromosomal abnormalities: patient O,
45X,add(X),-4, -6,del(7)(p15),add(10)(p11), add(11)(q23),
add(12)(q11),add(14)(p11),- 21, add(22)(p11),+2mar[6]/46XY[7];
patient P, 45XY,-3; patient Q, 45X,-Y,add(3)(p11q21), add(7)(p11),
del(9)(q13q21),add(10)(p13),add(12)(q13), der(15)t(3;15)(p14;p11),-20,+mar[14]/46, idem+Y[10]/46XY[10]; patinet S, 48XY,+2,-3,-6, +add(6)(q32),-10,+add(7)(p13),
add(7)(q32),-10, +add(10)(q22), +13,-15,-18,-21,+6,mar; patient U,
47XX,+mar[1]/46XX[3].
Allelic loss analysis.
Primers for polymerase chain reaction (PCR) amplification of
microsatellite markers, chosen to represent at least two loci on each
chromosomal arm, were obtained from Research Genetics (Huntsville, AL).
Ninty-four markers distributed among all 39 autosomal chromosome arms,
except for nonacrocentric arms, were analyzed. These markers and their
chromosomal regions are detailed in Table
1. PCRs were performed as described.35 Briefly, total reaction volumes were 20 µL containing 25 ng DNA, 1.5 mmol/L
MgCl2, 10 pmol/L of each of the primers, 2 nmol/L of each
of the four deoxyribonucleotide triphosphates (dNTP; Pharmacia,
Stockholm, Sweden), 1 U of Taq DNA polymerase (GIBCO-BRL, Gaithersburg,
MD), and 2 µCi 32P-labeled deoxycytidine triphosphates
(dCTP) (3,000 µCi/mmol; New England Nuclear/Dupont, Boston, MA) with
specified buffer provided by the supplier. To ascertain either LOH or
duplication of the region, PCR reaction was performed in a multiplex
fashion for some of the markers; the reaction mixture contained two
primer sets. PCR consisted of 40 seconds at 94°C, 30 seconds at
55°C, and 1 minute at 72°C for 27 to 33 cycles in a
Programmable Thermal Controller (MJ Research Inc, Water Town, MA) in
order to examine the products in the linear range of signals. PCR
products were mixed with a formamide gel-loading solution, heat
denatured at 94°C, separated on a denaturing 5% to 8%
polyacrylamide gel, and visualized by autoradiography. Allele losses
were determined by visual inspection. When visible reduction of
radiographic signal was equivocal, a radioanalytic imaging detector
(Ambis, Ambis Inc, San Diego, CA) was used to confirm our
interpretation. All positive results were repeated for confirmation.
| |
RESULTS |
A panel of 94 highly informative microsatellite markers representing
every autosomal chromosome were used to screen 22 matched ATL samples.
Although PCR allelotyping is capable of showing losses of genetic
material in tumors, it is unsuitable for detection of gene
amplifications. To rule out the possibility of gene amplification, we
performed multiplex PCR to compare the intensity of two loci. Because
gene amplification was not found, each of the allelic imbalances were
determined to be LOH. Representative examples of autoradiograms
demonstrating LOH are shown in Fig 1.
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| Fig 1.
Autoradiographs from LOH analysis with microsatellite
markers. PCR products were separated by polyacrylamide gel
electrophoresis, showing examples of allelic loss found in patient E. DNA samples isolated from leukemic cells in the acute phase are
labelled as A and those DNA samples isolated from corresponding normal
peripheral leukocytes after complete remission are designated as C. Microsatellite markers are indicated above the autoradiograms. Arrows,
loss of one allele.
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For each patient, we obtained information for at least 30 (76.9%)
chromosomal arms (Table 2). All but two
ATLs (patients N and U) showed evidence of a deletion at one or more
loci with loss(es) occurring in one to 13 chromosomal arms. Sixteen
samples showed losses in more than two different chromosomal arms.
Patients E and G had allele loss affecting over 30% of informative
chromosomal arms.
Of the 39 chromosomal arms anaylzed, 29 (74.4%) showed LOH in one or
more samples. Figure 2 summarizes the
percentage of allelic loss at each chromosomal arm, which was
calculated by dividing the number of tumors with LOH at any marker on
the chromosmome arm by the total number of informative cases. Frequency
of LOH for individual chromosomal arms varied between 0% (1p, 1q, 3p, 5p, 11p, 11q, 15q, 16q, 19q, and 21q) and 47.6% (17p). Over 30% of
informative acute/lymphomatous samples showed LOH at chromosomal arms
6q (9/22, 40.9%) and 17p (10/21, 47.6%). Of the 22 samples, five,
six, and four cases had LOH on 6q alone, 17p alone, and both 6q and
17p, respectively. In total, 15 samples had LOH on 6q and/or
17p.
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| Fig 2.
Frequency of allelic loss on each chromosome arm in 22 acute/lymphomatous ATLs. Percentage of LOH was calculated for each
chromosome arm by dividing the number of tumors with LOH at any marker
on the chromosmome arm by the total number of informative cases. ( )
p; ( ) q.
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Fractional allelic loss (FAL) was calculated as the ratio of
chromosomal arms that showed loss among all informative arms for each
patient, as described by Vogelstein.2 The FAL values in our
samples varied from 0 to 0.371, with a mean of 0.109 (Table 2).
| |
DISCUSSION |
To our knowledge, this is the first genomic search in ATL using
microsatellite markers; the aim was to identify chromosomal regions
likely to contain important tumor suppressor genes involved in the
progression of acute/lymphomatous ATL. The analysis showed two
hot-spots of LOH (>30%), one on 6q and the other one on 17p. Although it is possible that candidate tumor suppressor genes are
present in the undeleted segments of DNA, our result suggests that
tumor suppressor genes for progression of acute/lymphomatous ATL
probably reside on chromosome 6q and 17p.
With regard to tumor suppressor genes, mutations of p53 are among the
most common genetic changes in human tumors.36 The greatest
frequency of LOH in acute/lymphomatous ATL was observed at the TP53
locus (seven of 15, 46.7%) on chromosome 17p. This result is congruent
with previous reports by ourselves and others that the p53 gene was
mutated in about 40% of acute/lymphomatous ATL
samples.26-28 Although point mutations of the p53 gene in
our samples were not examined, we suspect that those with LOH at TP53 had mutations of the gene.
The high frequency of allelic loss affecting 6q is a novel finding in
ATL and suggests that this is the site of an as yet uncharacterized
tumor suppressor gene(s). The LOH for 6q is in keeping with results in
several other types of tumors, including those of the
kidney,37 breast,4,38 ovary,39,40
liver,41 and prostate,42 as well as
melanoma,43-46 lymphoma/lymphoblastic leukemia,47-52 and parathyroid adenoma.53
Further studies are required to define the altered gene on chromosome
6q in ATL and determine whether inactivation of the same gene occurrs
in all of the cancer types with LOH in this chromosomal region.
The tumor suppressor gene p16INK4A was mapped to chromosome
9p21.54,55 We previously found that this gene was deleted
in about 35% of acute/lymphomatous ATL samples.28,29 In
this study, we analyzed for LOH at D9S171, which maps to 9p21 about 1 megabase proximal to the p16INK4A gene. Only eight cases
were informative at D9S171 and two of them had LOH. The frequency of
heterozygosity for this locus is lower than that in the Genome Database
(0.79). Such discordance could be due to homogeneity of the Japanese
population. In addition, we may have missed some homozygous deletions
because homozygous deletions for a polymorphic marker may appear as
retention of heterozygosity as a consequence of amplification of DNA
from the contaminating normal cells. Therefore, we could have
underestimated the frequency of LOH at D9S171.
ATL is frequently characterized by an acquisition of nonrandom
chromosomal changes,56 but cytogenetic changes from chronic to acute ATL have been rarely reported. Additionally, small deletions are below the limits of resolution of cytogenetic analysis. Karyotype analyses were available for only five samples in our study. As expected, in four of these five samples, LOH studies identified additional abnormalities not detected in the cytogenetic analysis. Thus, cytogenetic studies have probably missed most of the interstitial deletions. Nevertheless, some of the chromosomal deletions shown by
cytogenetic analyses were not detected by our LOH analyses. Most of
these samples had noninformative microsatellite loci in these regions.
The discrepancy between cytogenetic and LOH studies in several samples
can be ascribed to a failure to examine a microsatellite marker in the
deleted chromosomal region.
The mean FAL was 0.109 in acute/lymphomatous ATL, which is lower than
that in solid tumors.4,7,10,57,58 This suggests that ATL
cells may be genetically more stable than those of solid tumor cells.
In summary, the comprehensive allelotyping of ATL has provided novel
signposts for future efforts at positional candidate cloning of human
tumor suppressor genes involved in progression of ATL. Likewise, these
genes will be likely targets for development of other hematologic
malignancies, as well as other human tumors.
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FOOTNOTES |
Submitted July 15, 1997;
accepted May 5, 1998.
Supported in part by Grants No. CA26038, CA42710, and CA70675
from the National Institues of Health, Bethesda, MD;
the Concern Foundation, Beverly Hills, CA; and the Parker Hughes Fund,
Glendale, CA.
Address reprint requests to Yoshihiro Hatta, MD, Division
of Hematology/Oncology, Department of Medicine, Cedars-Sinai Research Institute, UCLA School of Medicine, 8700 Beverly Blvd, B-208, Los
Angeles, CA 90048.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
REFERENCES |
1.
Knudson AG:
Mutation and cancer. Statistical study of retinoblastoma.
Proc Natl Acad Sci USA
68:820,
1971[Abstract/Free Full Text]
2.
Fearon ER,
Cho KR,
Nigro JM,
Kern SE,
Simons JW,
Ruppert JM,
Hamilton SR,
Preosomger AC,
Thomas G,
Kinzler KW,
Vogelstein B:
Identificaion of a chromosome 18q gene that is altered in colorectal cancers.
Science
247:49,
1990[Abstract/Free Full Text]
3.
Steck PA,
Pershouse MA,
Jasser SA,
Yung WKA,
Lin H,
Ligon AH,
Langford LA,
Baumgard ML,
Hattier T,
Davis T,
Frye C,
Hu R,
Swedlund B,
Teng DHF,
Tavtigian SV:
Identificaion of a candidate tumor suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers.
Nat Genet
15:356,
1997[Medline]
[Order article via Infotrieve]
4.
Theile M,
Seitz S,
Arnold W,
Jandrig B,
Frege R,
Schlag PM,
Haensch W,
Winzer K-J,
Barett JC,
Scherneck S:
A defined chromosome 6q fragment (at D6S310) harbors a putative tumor supressor gene for breast cancer.
Oncogene
13:677,
1996[Medline]
[Order article via Infotrieve]
5.
Vogelstein B,
Fearon ER,
Kern SE,
Hamilton SR,
Preisinger AC,
Nakamura Y,
White R:
Allelotype of colorectal carcinomas.
Science
244:207,
1989[Abstract/Free Full Text]
6.
Cliby W,
Ritland S,
Hartmann L,
Dodson M,
Halling KC,
Keeney G,
Podratz KC,
Jenkins RB:
Human epithelial ovarian cancer allelotype.
Cancer Res
53:2393,
1993[Abstract/Free Full Text]
7.
Nawroz H,
van der Riet P,
Hruban RH,
Koch W,
Ruppert JM,
Sidransky D:
Allelotype of head and neck squamous cell carcinoma.
Cancer Res
54:1152,
1994[Abstract/Free Full Text]
8.
Knowles MA,
Elder PA,
Willamson M,
Cairns JP,
Shaw ME,
Law MG:
Allelotype of human bladder cancer.
Cancer Res
54:531,
1994[Abstract/Free Full Text]
9.
Mitra AB,
Murty VVVS,
Li RG,
Pratrap M,
Luthra UK,
Chaganti RSK:
Allelotype analysis of cervical carcinoma.
Cancer Res
54:4481,
1994[Abstract/Free Full Text]
10.
Fujino T,
Risinger JI,
Cliins NK,
Liu F-S,
Nishii H,
Takahashi H,
Westphal E-M,
Barett JC,
Sasaki H,
Kohler MF,
Berchuck A,
Boyd J:
Allelotype of endometrial carcinoma.
Cancer Res
54:4294,
1994[Abstract/Free Full Text]
11.
Seymour AB,
Hruban RH,
Redston M,
Caldas C,
Powell SM,
Kinzler KW,
Yeo CJ,
Kern SE:
Allelotype of pancreatic adenocarcinoma.
Cancer Res
54:2761,
1994[Abstract/Free Full Text]
12.
Osborn RJ,
Leech V:
Polymerase chain reaction allelotyping of human ovarian cancer.
Br J Cancer
69:429,
1994[Medline]
[Order article via Infotrieve]
13.
Takeuchi S,
Bartram CR,
Wada M,
Reiter A,
Hatta Y,
Seriu T,
Lee E,
Miller CW,
Miyoshi I,
Koeffler HP:
Allelotype analysis of childhood acute lymphoblastic leukemia.
Cancer Res
15:5377,
1995
14.
Pabst T,
Schwaller J,
Bellomo MJ,
Oestreicher M,
Mühlematter D,
Tichelli A,
Tobler A,
Fey MF:
Frequent clonal loss of heterozygosity but scarcity of microsatellite instability at chromosomal breakpoint cluster regions in adult leukemia.
Blood
88:1026,
1996[Abstract/Free Full Text]
15.
Mori N,
Morosetti R,
Lee S,
Spira S,
Ben-Yahuda D,
Schiller G,
Landolfi R,
Mizoguchi H,
Koeffler HP:
Allelotype analysis in the evolution of chronic myelocytic leukemia.
Blood
90:2010,
1997[Abstract/Free Full Text]
16.
Litt M,
Luty JA:
A hypervariable microsatellite revealed by in vitro amplification of a dinucleotide repeat within the cardiac muscle actin gene.
Am J Hum Genet
44:397,
1989[Medline]
[Order article via Infotrieve]
17.
Weber JL,
May PE:
Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction.
Am J Hum Genet
44:388,
1989[Medline]
[Order article via Infotrieve]
18.
Uchiyama T,
Yodoi J,
Sagawa K,
Takatsuki K,
Uchino H:
Adult T-cell leukemia: Clinical and hematologic features of 16 cases.
Blood
50:481,
1977[Free Full Text]
19.
Hattori T,
Uchiyama T,
Tobinai T,
Takatsuki T,
Uchino H:
Surface phenotype of Japanese ATL cells characterized by MoAbs.
Blood
58:645,
1981[Abstract/Free Full Text]
20.
Miyoshi I,
Kubonishi I,
Yoshimoto S,
Akagi T,
Ohtsuki Y,
Shiraishi Y,
Nagata K,
Hinuma Y:
Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukemic T cells.
Nature
294:770,
1981[Medline]
[Order article via Infotrieve]
21.
Yoshida M,
Miyoshi I,
Hinuma Y:
Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease.
Proc Natl Acad Sci USA
79:2031,
1982[Abstract/Free Full Text]
22.
Popovic M,
Sarin PS,
Robert-Guroff M,
Kalyanraman VS,
Mann D,
Minowada J,
Gallo RC:
Isolatioin and transmission of human retrovirus (human T-cell leukemia virus).
Science
219:856,
1983[Abstract/Free Full Text]
23.
Tajima K,
The T- and B-cell malignancy Study Group:
The fourth nationwide study of adult T-cell leukemia/lymphoma (ATL in Japan): Estimates of the risk of ATL and its geographical and clinical features.
Int J Cancer
45:237,
1990[Medline]
[Order article via Infotrieve]
24.
Tokudome S,
Tokunaga O,
Shimamoto Y,
Miyamoto Y,
Sumida I,
Kikuchi M,
Takeshita M,
Ikeda T,
Fujiwara K,
Yoshihara M,
Yanagawa T,
Nishizumi M:
Incidence of adult T-cell leukemia/lymphoma among human T-lymphotropic virus type 1 carriers in Saga, Japan.
Cancer Res
49:226,
1989[Abstract/Free Full Text]
25.
Okamoto T:
Multi-step carcinogenesis model for adult T-cell leukemia.
Jpn J Cancer Res
80:191,
1989[Medline]
[Order article via Infotrieve]
26.
Sakashita A,
Hattori T,
Miller CW,
Suzushima H,
Asou N,
Takatsuki K,
Koeffler HP:
Mutation of p53 gene in adult T-cell leukemia.
Blood
79:477,
1992[Abstract/Free Full Text]
27.
Nagai H,
Kinoshita T,
Imamura J,
Murakami Y,
Hayashi K,
Mukai K,
Ikeda S,
Tobinai K,
Saito H,
Shimoyama M,
Shimotohno K:
Genetic alteration of p53 in some patients with adult T-cell leukemia.
Jpn J Cancer Res
82:1421,
1991[Medline]
[Order article via Infotrieve]
28. Yamato K, Oka T, Hiroi M, Iwahara Y, Sugito S, Tsuchida N,
Miyoshi I: Aberrant expression of the p53 tumor suppressor gene in
adult T-cell leukemia and HTLV-I-infected cells. Jpn J cancer Res 84:4,
1993
29.
Hatta Y,
Hirama T,
Miller CW,
Yamada Y,
Tomonaga M,
Koeffler HP:
Homozygous deletions of the p15 (MTS2) and p16 (CDKN2/MTS1) genes in adult T-cell leukemia (ATL).
Blood
85:2699,
1995[Abstract/Free Full Text]
30.
Yamada Y,
Hatta Y,
Murata K,
Sugawara K,
Ikeda S,
Mine M,
Maeda T,
Hirakata Y,
Kamihira S,
Tsukasaki K,
Ogawa S,
Hirai H,
Koeffler HP,
Tomonaga M:
Deletions of p15 and/or p16 genes as a poor-prognosis factor in adult T-cell leukemia.
J Clin Oncol
15:1778,
1997[Abstract/Free Full Text]
31.
Hatta Y,
Yamada Y,
Tomonaga M,
Koeffler HP:
Extensive analysis of the retinoblastoma gene in adult T-cell leukemia/lymphoma (ATL).
Leukemia
11:984,
1997[Medline]
[Order article via Infotrieve]
32.
Uchida T,
Kinoshita T,
Watanabe T,
Nagai H,
Murate T,
Saito H,
Hotta T:
The CDKN2 gene alterations in various types of adult T-cell leukemia.
Br J Haematol
94:665,
1996[Medline]
[Order article via Infotrieve]
33.
Hatta Y,
Spirin K,
Tasaka T,
Morosetti R,
Said JW,
Yamada Y,
Tomonaga M,
Koeffler HP:
Analysis of p18INK4C in adult T-cell leukemia (ATL) and non-Hodgkin's lymphoma.
Br J Haematol
99:665,
1997[Medline]
[Order article via Infotrieve]
34.
Shimoyama M,
Members of the Lymphoma Study Group (1984-87):
Diagnostic criteria and classification of clinical subtypes of adult T-cell leukemia-lymphoma.
Br J Haematol
79:428,
1991[Medline]
[Order article via Infotrieve]
35.
Hatta Y,
Takeuchi S,
Yokota J,
Koeffler HP:
Ovarian cancer has frequent loss of heterozygosity at chromosome 12p12.3-13.1 (region of TEL and Kip1 loci) and chromosome 12q23-ter: Evidence for two new tumor suppressor genes.
Br J Cancer
75:1256,
1997[Medline]
[Order article via Infotrieve]
36.
Hollstein M,
Sidransky D,
Vogelstein B,
Harris CC:
p53 mutations in human cancers.
Science
253:49,
1991[Abstract/Free Full Text]
37.
Morita R,
Ishikawa J,
Tsutsumi M,
Hikiji K,
Tsukada Y,
Kamidono S,
Maeda S,
Nakamura Y:
Allelotype of renal cell carcinoma.
Cancer Res
51:820,
1991[Abstract/Free Full Text]
38.
Devillee P,
van Vliet M,
van Sloun P,
Kuipers Dijkshoon N,
Hermans J,
Pearson PL,
Cornelisse CJ:
Allelotype of human breast carcinoma: A second major site for loss of heterozygosity is on chromosme 6q.
Oncogene
6:1705,
1991[Medline]
[Order article via Infotrieve]
39.
Lee JH,
Kavangah JJ,
Wildrick DM,
Wharton JT,
Block M:
Frequent loss of heterozygosity on chromosome 6q, 11, and 17 in human ovarican carcinoma.
Cancer Res
50:2724,
1990[Abstract/Free Full Text]
40.
Saito S,
Saito H,
Koi S,
Sagae S,
Kudo R,
Saito J,
Noda K,
Nakamura Y:
Fine-scale deletion mapping of the distal long arm of chromosome 6 in 70 human ovarian cancers.
Cancer Res
52:5815,
1992[Abstract/Free Full Text]
41.
De Souza AT,
Hankins GR,
Washington MK,
Fine RL,
Orton TC,
Jirtle RL:
Frequent loss of heterozygosity on 6q at the mannose 6-phosphate/insulin-like growth factor II receptor locus in human hepatocellular tumors.
Oncogene
10:1725,
1995[Medline]
[Order article via Infotrieve]
42.
Visakorpi T,
Kallioniemi AH,
Syvänen A-C,
hyytinen ER,
Karhu R,
Tammela T,
Isola JJ,
Kallioniemi O-P:
Genetic changes in primary recurrent prostate cancer by comparative genomic hybridization.
Cancer Res
55:342,
1995[Abstract/Free Full Text]
43.
Trent JM,
Thompson FH,
Meyskens FL Jr:
Identification of a recurring translocation site involving chromosome 6 in human malignant melanoma.
Cancer Res
49:420,
1989[Abstract/Free Full Text]
44.
Millikin D,
Meese E,
Vogelstein B,
Witkowski C,
Trent J:
Loss of heterozygosity for loci on the arm of chromosome 6 in human malignant melanoma.
Cacner Res
51:5449,
1991[Abstract/Free Full Text]
45.
Ray ME,
Su YA,
Meltzer PS,
Trent J:
Isolation and characterization of genes associated with chromosome-6 mediated tumor suppression in human malignant melanoma.
Oncogene
12:2527,
1996[Medline]
[Order article via Infotrieve]
46.
Healy E,
Belgaid CE,
Takata M,
Vahlquist A,
Rehman I,
Rigby H,
Rees JL:
Allelotypes of primary cutaneous melanoma and benign melanocytic nevi.
Cancer Res
56:589,
1996[Abstract/Free Full Text]
47.
Gaidano G,
Hauptschein RS,
Parsa NZ,
Offit K,
Rao PH,
Lenoir G,
Knowles DM,
Chaganti RSK,
Dalla-Favera R:
Deletions involving two distinct regions of 6q in B-cell non-Hodgikin lymphoma.
Blood
80:1781,
1992[Abstract/Free Full Text]
48.
Offit K,
Parsa NZ,
Gaidano G,
Filippa DA,
Louie D,
Pan D,
Jhanwar SC,
Dalla-Favera R,
Chaganti RSK:
6q deletions define distinct clinico-pathologic subsets of non-Hodgikin's lymphoma.
Blood
82:2157,
1993[Abstract/Free Full Text]
49.
Menasce LP,
Orphanos V,
Santibanez-Koref M,
Boyle JM,
Harrison CJ:
Common region of deletion on the long arm of chromosome 6 in non-Hodgkin's lymphoma and acute lymphoblastic leukemia.
Genes Chromosom Cancer
10:286,
1994[Medline]
[Order article via Infotrieve]
50.
Li H,
Lahti JM,
Valentine M,
Saito M,
Reed SI,
Look AT,
Kidd VJ:
Molecular cloning and chromosomal localization of the human cyclin C (CCNC) and cyclin E (CCNE) genes: Deletion of the CCNC gene in human tumors.
Genomics
32:253,
1996[Medline]
[Order article via Infotrieve]
51.
Guan X-Y,
Horsman D,
Zhang HE,
Parsa NZ,
Meltzer PS,
Trent JM:
Localization by chromosome microdissection of a recurrent breakpoint region on chromosome 6 in human B-cell lymphoma.
Blood
88:1418,
1996[Abstract/Free Full Text]
52.
Gerard B,
Cave H,
Guidal C,
Dastugue N,
Vilmer E,
Grandchamp B:
Deletion of a 6cM commomly deleted region in childhood acute lymphoblastic leukemia on the 6q chromosomal arm.
Leukemia
11:282,
1997
53.
Tahara H,
Smith AP,
Gaz RD,
Cryns VL,
Arnold A:
Genomic localization of novel candidate tumor suppressor gene loci in human parathyroid adenomas.
Cancer Res
56:599,
1996[Abstract/Free Full Text]
54.
Kamb A,
Gruis NA,
Weaver-Feldhaus J,
Liu Q,
Harshman K,
Tavtigian SV,
Stockert E,
Day RS,
Johnson BE,
Skolnick MH:
A cell cycle regulator potentially involved in genesis of many tumor types.
Science
264:436,
1994[Abstract/Free Full Text]
55.
Nobori T,
Miura K,
Wu DJ,
Lois A,
Takabayashi K,
Carson DA:
Deletion of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers.
Nature
368:753,
1994[Medline]
[Order article via Infotrieve]
56.
Sadamori N:
Cytogenetic implication in adult T-cell leukemia: A hypothesis of leukemogenesis.
Cancer Genet Cytogenet
51:131,
1991[Medline]
[Order article via Infotrieve]
57.
Yamaguchi T,
Toguchida J,
Yamamuro T,
Kotoura N,
Takada N,
Kawaguchi N,
Kaneko Y,
Nakamura Y,
Sasaki M,
Ishizaki K:
Allelotype analysis in ostosarcomas: Frequent loss on 3q, 13q, 17p, and 18q.
Cancer Res
52:2419,
1992[Abstract/Free Full Text]
58.
Tsuchiya E,
Nakamura Y,
Weng S-Y,
Nakagawa K,
Tsuchiya S,
Sugano H,
Kitagawa T:
Allelotype of non-small cell lung carcinoma: Comparison between loss of heterozygosity in squamous cell carcinoma and adenocarcinoma.
Cancer Res
52:2478,
1992[Abstract/Free Full Text]
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Abstract
Introduction
Abstract