1
DNA COPY NUMBER AMPLIFICATIONS IN HUMAN NEOPLASMS
— A REVIEW OF
COMPARATIVE GENOMIC HYBRIDIZATION STUDIES
As published in Am J Pathol 152:1107-1123, 1998
Sakari Knuutila,* Anna-Maria Björkqvist,* Kirsi Autio,* Maija Tarkkanen,* Maija Wolf,*
Outi Monni,* Jadwiga Szymanska,* Marcelo L. Larramendy,* Johanna Tapper,* ‡
Heini Pere,*‡ Wa’el El-Rifai,* Samuli Hemmer,*§ Veli-Matti Wasenius,*§ Virve
Vidgren,* Ying Zhu*
From the Laboratory of Medical Genetics,* the Department of Obstetrics and
Gynecology,‡ and the Department of Oncology,§ Helsinki University Central Hospital,
Helsinki, Finland
Supported by the Sigrid Jusélius Foundation, the Finnish Cancer Society and the
Helsinki University Central Hospital, Helsinki, Finland.
ABSTRACT
This review summarizes reports of recurrent DNA sequence copy number
amplifications in human neoplasms detected by comparative genomic hybridization.
Some of the chromosomal areas with recurrent DNA copy number amplifications
(amplicons) of 1p22-p31, 1p32-p36, 1q, 2p13-p16, 2p23-p25, 2q31-q33, 3q, 5p,
6p12-pter, 7p12-p13, 7q11.2, 7q21-q22, 8p11-p12, 8q, 11q13-q14, 12p, 12q13-q21,
13q14, 13q22-qter, 14q13-q21, 15q24-qter, 17p11.2-p12, 17q12-q21, 17q22-qter,
18q, 19p13.2-pter, 19cen-q13.3, 20p11.2-p12, 20q, Xp11.2-p21, and Xp11-q13, and
genes therein are presented in more detail. The paper with its 160 references and
two tables can be accessed from our web site
http://www.helsinki.fi/~lgl_www/CMG.html. The data will be updated biannually until
the year 2001.
INTRODUCTION
Gene amplification is an essential mechanism of oncogene activation, in
addition to structural alterations, loss of control mechanisms, insertional
mutagenesis, and chromosome translocations. Amplifications of the MYC, ERBB2
and RAS genes have been found in various types of tumor.1 Other examples of
amplified oncogenes are listed in Table 1. Comparative genomic hybridization
(CGH), a powerful technique for studying amplified DNA sequences, reveals
chromosomal areas which contain amplified cellular oncogenes. 2-8 Visakorpi et al9
were the first to apply CGH to the search for novel cancer genes. They found that
the androgen receptor gene was amplified in prostate cancers that had recurred
during androgen deprivation therapy. Another early report was on the BCL2 gene in
diffuse large B-cell lymphoma. Monni et al. used Western blotting to demonstrate
increased expression of the BCL2 gene in lymphomas in which CGH had shown an
amplification in 18q21-q23 (BCL2 is mapped to 18q21.3).10,11 Another example is
the KRAS2 gene amplification detected using Southern blotting in non-small cell lung
cancer tumors, which showed a copy number amplification in 12p. 12 So far more
than a hundred reports on different tumors have revealed recurrent DNA copy
number increases indicating areas that may harbor novel oncogenes. This review
lists in table form a summary of the amplified chromosomal areas detected using
CGH as reported in 113 papers published prior to November 1997.
2
COMPARATIVE GENOMIC HYBRIDIZATION AND DNA COPY NUMBER
AMPLIFICATIONS
Comparative genomic hybridization (CGH) allows DNA copy number losses
and gains to be studied in one hybridization experiment. For CGH, total DNA is
extracted from fresh or paraffin-embedded tumor material. Tumor DNA (labeled
green) and normal reference DNA (red) are hybridized simultaneously onto normal
metaphase cells on a slide. The two DNAs are hybridized in a competitive manner
whereby a DNA copy number increase becomes visible by the heightened intensity
of the green hybridized tumor DNA. Detailed analysis is performed using a sensitive
monochrome CCD camera and automated image analysis software. The system
measures the green-to-red ratios along the entire length of each chromosome.
Methodological reviews can be found at
http://www.nhgri.nih.gov/DIR/LCG/CGH/technology.html. Chromosomal areas are
usually interpreted as overrepresented when the ratio exceeds 1.15 (DNA copy
number gain) or 1.5 (DNA copy number amplification). Most DNA copy number
amplifications in this review refer to gains that reach the ratio of 1.5. As CGH
recognizes only proportional changes in copy number, the ratio profiles do not
indicate the absolute copy number changes. Our experience is that in diploid and
near-diploid cells, a ratio of 1.5 indicates at least a 100% increase in the copy
number of an entire chromosome arm or of a region of a chromosome the size of a
chromosome band, but that the threshold is not reached if the increase is only 50%
(e.g. chromosomal trisomy). When a DNA copy number increase is restricted to a
small chromosome area representing, for example, amplification of a single gene,
the copy number increase should be 10-fold or higher. To be detected using CGH,
the total amount of amplified DNA has to be at least 2 Mb (amplicon size x level of
amplification).3 It has to be pointed out that the selected ratio of 1.5 is more or less
arbitrary as no uniform criteria for the definition of an amplification exists in the
current literature. The ratio limits applied in some publications have been lower
depending on the software used and, finally, in some publications no distinction has
been made between gains and amplifications. Therefore, even though we have not
strictly adhered to the 1.5 limit, the data presented may be biased towards articles
where the 1.5 ratio cut-off has been used.
The discussion in this review focuses on amplifications detected using CGH
(ratio approximately 1.5 or more) which have been established to be recurrent and
restricted to small chromosomal areas. In addition, Table 2 summarizes all the
amplifications reported in 113 articles. Other DNA copy number changes (gains and
losses) are not presented in this review, but gains are shown in Table 2 if they affect
the same chromosomal areas as the amplifications. By amplicon we refer to any
chromosome region (e.g. the 12q13-q22 amplicon, the 17q12-q21 amplicon, the 8q
amplicon or the 20q amplicon) that shows a DNA copy number amplification. The
description of a region, e.g. 12q13-q22, implies that in a variety of cases the
amplicon was located within the area but did not necessarily affect the whole area in
all cases (applies also to Table 2). The described regions may therefore not be
considered analogous with minimal overlapping areas.
THE MOST RECURRENT DNA COPY NUMBER AMPLIFICATIONS
DNA copy number amplifications have been reported in almost every
chromosome and in a wide variety of chromosomal areas. Most of the amplifications
have only been reported once, most probably because the number of cases studied
so far is very small. Approximately 30 amplicons are better established
(chromosomal areas showing recurrent amplifications). Some of them are discussed
in detail below.
3
The 1p32-p36 amplicon
Amplifications in 1p32-p36 have been reported in several different kinds of
malignancy, such as carcinomas of the lung, squamous cell carcinoma of the head
and neck, pancreatic carcinoma, testicular carcinoma, follicular lymphoma, and
sarcomas (Table 2). The amplification seems to occur most frequently in small cell
lung carcinoma, osteosarcoma, and squamous cell carcinoma of the head and neck.
In other neoplasms amplification in 1p32-p36 has been detected only once. The
amplified region contains several candidate genes such as MYCL1 and JUN.
Amplification of MYCL1 has been demonstrated in small cell lung carcinoma. 13
1q amplicons in sarcomas
In different types of soft tissue and bone sarcoma recurrent gains and
amplifications have been demonstrated in 1q21-q23 and 1q21-q31 (Table 2).
Several genes of potential significance in sarcoma development and/or progression
have been localized in the 1q21-q23 region. These include the octamer-binding
transcription factor OTF1 and the NTRK1 gene encoding neurotrophic tyrosine
kinase receptor type I as well as several members of two multigene families, the
SPRR family encoding small proline-rich proteins and the S100 family of
calcium-binding proteins, e.g., the CACY and CAPL genes.14-20 The elevated
expression of calcyclin, a cell cycle-regulating protein, has been observed in highly
metastatic melanoma cell lines.21 Recently the 1q amplicon in human sarcomas has
been characterized using molecular analysis.22 FLG, NTRK1, and SPRR3, located
in 1q21, were the most frequently amplified, although none of these genes were
amplified in all the samples with an increased copy number at 1q21-q22.22 It has
been suggested that there could be a common, as yet unknown, target gene for the
1q21-q22 amplicon or, alternatively, that various selection mechanisms affecting
more than one gene could be involved.
The 2p13-p16 amplicon in non-Hodgkin’s lymphoma
Amplification of 2p13-p16 has been found frequently in non-Hodgkin’s
lymphoma (Table 2). This region includes the REL gene which belongs to the
Rel/NFB protein family of transcription factors. REL amplification has been found in
23% of diffuse large B-cell lymphomas using Southern blot hybridization.23 Two
cases of mediastinal thymic B-cell lymphoma, in which an amplification of 2p13-p16
was detected by CGH, showed five- to ten-fold amplification of the REL oncogene
using Southern blot hybridization.24 Amplification involving bands 2p13-p16 is rarely
seen in other tumor types but has been detected in single cases of neuroblastoma,
ovarian cancer, squamous cell carcinoma of the head and neck, non-small cell lung
cancer, and synovial sarcoma.25-29
The 2p23-p25 amplicon in neuroblastoma and in small cell lung cancer
Gains of the entire chromosome 2 or of the whole of 2p, and amplifications
of the region 2p23-p25 occur repeatedly in neuroblastoma and small cell lung cancer
(Table 2). Amplification of the MYCN gene, mapped to 2p24, has been observed in
several studies of neuroblastoma.27,30,31 MYCN amplification has also been
detected in small cell lung cancer.32 The presence of double minute chromosomes
or a homogeneously staining region on a metaphase spread are indications of gene
amplification. In neuroblastoma this usually reflects MYCN amplification.33
The 3q amplicon
4
Gains and amplifications in 3q have been detected in many tumor types
including ovarian carcinoma, carcinoma of uterine cervix, lung cancer, squamous cell
carcinoma of the head and neck, and in non-Hodgkin's lymphoma (Table 2).
A gain of 3q has been observed in 40-50% of serous ovarian and serous
endometrial carcinomas.34-37 In carcinoma of the uterine cervix, a gain of 3q was
the most common copy number aberration (77% of the cases). 38 Amplifications at
3q have been seen in these tumors as well. Heselmeyer et al. found that gain in 3q
was frequently present when dysplastic uterine cervical cells progressed into
invasive cancer.38 One of the most interesting candidate genes is the telomerase
RNA gene (HTR) at 3q26, which has been found to be amplified in some of these
tumors.39
Gains and amplifications of 3q occur frequently in small cell lung carcinoma
and squamous cell carcinoma of the lung, but to a lesser extent in adenocarcinoma
and large cell anaplastic carcinoma of the lung. In most of these cases the amplicon
includes the band 3q26.12,29,40-45 The genes MME, SI, BCHE, SLC2A2, KNG,
HRG, HTR, and the gene encoding translation initiation factor eIF-4gamma, all
located in 3q25-qter, have been shown to be amplified in squamous cell carcinoma
of the lung.39,46,47
Amplifications and gains in 3q are also frequently found in squamous cell
carcinomas of the head and neck, with amplicons at 3q24 and 3q26.3-qter.25,48,49
In marginal zone B-cell neoplasms amplifications have been observed at
3q21-q22 and at 3q26-q27, which includes the BCL6 oncogene at 3q27.50 A study
of mantle cell lymphoma showed gains of 3q in more than half of the cases and in
most of them the gain started at 3q13.3-q23 and continued to qter.51 The genes
involved in these amplifications have not been identified.
The 5p amplicon
Amplification of 5p has been detected in many different tumors and it is a
recurrent established amplicon in lung cancer, squamous cell carcinoma of the head
and neck, carcinoma of the uterine cervix, osteosarcoma, and malignant fibrous
histiocytoma of soft tissue (Table 2). In some of these tumors the entire p-arm is
amplified, whereas in others the amplicon is restricted to specific bands. One
candidate gene mapped to 5p13 is SKP2. The gene encodes a protein associated
with cyclin A-CDK2. The protein has been shown to be essential for entry into the Sphase.52
The 6p12-pter amplicon
The amplicon 6p12-pter is found in several types of malignancy, such as
lymphomas, sarcomas, non-small cell lung carcinoma, bladder, breast, and ovarian
carcinomas, and melanoma (Table 2). Amplification in 6p has been detected most
often in melanoma in 48% of the studied cases. 53,54 NRASL3, which belongs to the
RAS superfamily, is one of the genes that might be amplified in this region.
The 8q amplicon
Gains and amplifications of 8q are frequently seen in many different kinds of
tumor (Table 2). Very often the whole of the long arm is affected and sometimes
there is simultaneous loss of DNA copy number in 8p, suggesting the formation of an
isochromosome. One of the most important target genes in this amplicon is MYC at
8q24.
The 12p amplicon
Amplification of 12p seems to be characteristic of testicular germ cell tumors
(TGCTs) but it has also been detected in other tumor types, such as neuroglial
5
tumors, ovarian cancer, osteosarcoma, squamous cell carcinoma of the head and
neck, and non-small cell lung cancer (Table 2). In testicular tumors the amplicon
sometimes involves the whole of the short arm of chromosome 12 but the minimal
common region can be restricted to the chromosomal bands 12p11.2-p12.1.55
Candidate genes located in this region are parathyroid hormone-related polypeptide
(PTHLH) and KRAS2. The role of PTHLH in TGCTs is unclear since expression of
this gene has been found only in seminomas.56 In non-small cell lung cancer
amplification of KRAS2 has been found in two adenocarcinomas that showed
amplification in 12p by CGH.12
The 12q13-q21 amplicon in sarcoma
One of the very first amplicons demonstrated using CGH was 12q13-q21,
typically seen in different sarcoma types, especially in lipomatous tumors and
osteosarcomas (Table 2). This amplicon is very complex with the presence of several
separate amplicons and losses of DNA segments in the region. 57,58 Several genes,
e.g. MDM2, HMGIC, CDK4, SAS, CHOP/GADD153, GLI, and A2MR/LRP1, are known
to be variously involved in the amplicon.59-69 The latest studies have refuted the
hypothesis that one or more genes located between CDK4 and MDM2 could
represent a common amplification target in tumors with 12q13-q15 amplification but
indicate that CDK4/SAS and MDM2 may represent two independent targets for
amplification.57,70 In addition to sarcomas, the 12q13-q15 amplification has also been
reported in neuroglial tumors.71,72
The 17p11.2.-p12, 17q12-q21 and 17q22-qter amplicons
Three different amplicons have been found in chromosome 17. The
amplification of 17p with the minimal common region 17p11.2-p12 is a recent finding
in sarcomas. It is most frequently seen in osteosarcoma and leiomyosarcoma (Table
2). In osteosarcomas this amplification is found in 13%-18% of cases73,74 and in
24% of leiomyosarcomas.75 Gains affecting this region are also frequent in
sarcomas.73,74,76 In addition to sarcomas, the 17p11.2-p12 amplification has been
reported in 5% of astrocytomas.77 These findings seem to indicate that this region
contains a novel oncogene which is involved through amplification in the
development and/or progression of sarcomas.
Amplification of 17q is frequent in stomach, breast and testicular cancer
(Table 2). There have been single reports of 17q amplifications in colorectal and
bladder cancer 78,79 but this amplification has not been observed in other types of
human cancer. In stomach cancer the amplified region involves 17q12-q21 in which
the putative candidate genes GAS and ERBB2 have been found to be amplified.80,81
Interestingly, this amplicon was also seen in severely dysplastic adenomas 82 but not
in the hereditary form of stomach cancer.83 Minimal common region of amplification
in breast cancer has been shown to involve the bands 17q22-q24.84-87 Amplification
of 17q11-q12, which involves the ERBB2 gene, has also been observed.84 Gains of
17q were seen as frequently in primary breast cancer tumors as in metastases
obtained from the same patient.88 In transitional cell carcinoma of the bladder the
amplification has also been seen in 17q22-23,79 and another study has reported
amplification of ERBB2.89 In testicular cancer the amplification of 17q24-qter was
only found in two out of eleven tumors55 suggesting that different genes might be
involved in the pathogenesis of testicular cancer, because the amplified region was
more telomeric than that in breast or bladder cancer, or in carcinomas of the
digestive tract.
The 18q amplicon in non-Hodgkin’s lymphoma
6
Amplification of 18q seems to be frequent only in non-Hogdkin's lymphoma.
Only single occurences have been observed in colorectal cancer or in gastric cancer
(Table 2). So far, ten cases of non-Hodgkin's lymphoma with amplification of the
18q21-23 region have been reported.10,11,50,90 In eight out of the ten cases the
amplicon involved the BCL2 gene at 18q21.3. The amplification is not restricted to a
specific subtype, because 18q amplifications have been found in diffuse large B-cell
lymphomas, follicular lymphoma, marginal zone B-cell lymphomas, and in mantle cell
lymphoma.10,11,50,90 In diffuse large B-cell lymphoma, Monni et al. reported that the
amplification of BCL2 only occurred in cases where the translocation
t(14;18)(q32;q21) was not observed; in the cases with t(14;18) there was no
amplification of BCL2. Western blot analysis detected the overexpression of BCL2
protein in cases with amplification or translocation, suggesting that, in addition to
t(14;18), amplification is another mechanism that causes overexpression of BCL2
protein.11
The 20q amplicon
Gains and amplifications in 20q have been reported in breast, colon,
stomach, and ovarian cancer, and in osteosarcoma (Table 2). In breast cancer
these changes have been reported to correlate with poor prognosis.91 This
chromosomal region is thought to contain one or more genes which are
overexpressed in several types of epithelial cancer. In breast cancer, the amplified
region of 20q is known to harbor specific genes. AIB1, a steroid receptor coactivator
and BTAK, a serine/threonine kinase have been shown to be amplified and
overexpressed in breast cancer.92,93 The PTPN1 gene located at 20q12 is a
nonreceptor tyrosine phosphatase involved in growth regulation 94 and has recently
been reported to be overexpressed in 72% of breast carcinomas. 95 Another
candidate gene is MYB12, at 20q13, which encodes a transcription factor and plays
an important role in cell cycle progression.96 Furthermore, the human cellular
apoptosis susceptibility gene (CAS)97 has been mapped to this same region.
The Xp11-q13 amplicon in prostate cancer
Visakorpi and coworkers have demonstrated that the Xp11-q13 amplicon, in
which the androgene receptor gene is located, is present only in relapsed prostate
cancer cases, not in primary tumors.98 When prostate cancer is treated with
androgene depletion therapy, amplification of the androgene receptor gene enables
the cell to recover from the depletion therapy.9 This is a finding with evident
therapeutic implications.
Other recurrent DNA copy number amplifications
The above-mentioned amplifications are already considered established
amplicons. Table 2 shows other recurrent amplicons, the tumors in which these
DNA copy number amplifications have been observed and the amplified genes
therein. These areas are 1p22-p31, 2q31-q33, 7p12-p13, 7q11.2, 7q21-q22,
8p11-p12, 11q13-q14, 13q14, 13q22-qter, 14q13-q21, 15q24-qter, 19p13.2-pter,
19cen-q13.3, 20p11.2-p12, and Xp11.2-p21.
CONCLUDING REMARKS
Since the first CGH paper by Kallioniemi et al.2 appeared, no more than five
years ago, this technique has been shown to be a very powerful tool in screening for
DNA copy number changes. Even when screening for DNA copy number
amplifications can still be considered to be in the opening stages, these studies have
shown several novel DNA copy number amplifications. The screening procedure
7
has opened a new avenue for characterizing the role that cellular oncogenes and
other genes have in the development of tumors. The Xp11-q13 amplicon in prostate
cancer is one example of how CGH has helped to explain why androgen depletion
treatment is not a final cure for prostate cancer.9 The 18q21-q23 amplicon is an
example of how a gene amplification, in addition to the known gene fusion
mechanism, can cause overexpression of the protein. 11 It is clear that the
characterization of chromosomal amplicon areas will provide the means to discover
mechanisms which activate several cellular oncogenes and other genes. We also
believe that precise characterization of the amplicon areas will be of prognostic and
therapeutic value. Information of biologically and clinically significant amplicons will
make it possible to construct microarray tests that are likely to revolutionize clinical
molecular genetics in oncology.99
8
Table 1
Oncogenes known to be activated by amplification
Cellular
oncogene
ABL
BCL1
Location
Protein function
Type of cancer
9q34.1
11q13.3
protein tyrosine kinase
G1/S-specific cyclin D1
CDK4
EGFR/ERBB-1
12q14
7p12
cyclin-dependent kinase
epidermal growth factor receptor
ERBB2(NEU)
17q12-q21
growth factor receptor
HSTF1
INT1/WNT1
INT2
11q13.3
12q13
11q13.3
fibroblast growth factor
probably growth factor
fibroblast growth factor
MDM2
MET
12q14.3-q15 p53-binding protein
7q31
hepatocyte growth factor receptor
MYB
6q22-q23
chronic myeloid leukemia
breast cancer, squamous cell carcinoma of the head and neck, bladder
cancer
sarcomas
glioblastoma multiforme, epidermoid carcinoma, bladder cancer, breast
cancer
breast cancer, ovarian cancer, stomach cancer, renal adenocarcinoma,
adenocarcinoma of salivary gland, colon carcinoma
breast cancer, esophageal carcinoma
retinoblastoma
breast cancer, esophageal carcinoma, melanoma, squamous cell
carcinoma of the head and neck
sarcomas
amplified in cell lines from human tumors of non-hematopoietic origin,
particularly gastric tumors.
leukemias, colon carcinoma, melanoma
MYC
8q24.12q24.13
MYCN
2p24.3
DNA-binding protein
MYCL1
MYCLK1
RAF1
HRAS1
KRAS2
NRAS
REL
1p32
7p15
3p25
11p15.5
12p12.1
1p13
2p12-p13
DNA-binding protein
small-cell lung cancer, giant cell carcinoma of lung, breast cancer, colon
carcinoma, acute promyelocytic leukemia, cervical cancer, gastric
adenocarcinoma, chronic granulocytic leukemia
neuroblastoma, small-cell lung cancer, retinoblastoma, medulloblastoma,
glioblastoma, rhabdomyosarcoma, adenocarcinoma of lung, astrocytoma
small-cell lung cancer
serine/threonine protein kinase
GTPase
GTPase
GTPase
DNA-binding protein
non-small cell lung cancer
bladder cancer
adrenocortical tumor, giant cell carcinoma of lung
breast cancer
non-Hodgkin’s lymphomas
DNA-binding protein (essential for
normal hematopoiesis)
DNA-binding protein
9
Table 2
Chromosomal areas containing DNA copy number amplifications
(amplicons) in human neoplasms evaluated by CGH
Recurrent established amplicons (at least three cases and frequency
more than 5%) in bold
Tumor
Amplicon
Number of
cases with
the
amplicon/
cases
studied
Amplified
genes (studied
from the same
case/s)
Reference
Ref. of gain/s
detected in the
same chromosomal
location
Hematologic
neoplasms
Acute myeloid
leukemia
8q24
11q23-qter
1/1
1/1
MYC
100
101
101-103
103
Acute lymphoid
leukemia
8
10
12p12-p13
18
21
X
1/72
1/72
1/13
1/72
2/72
1/72
104
104
105
104
104
104
104,105
104,105
104
104,105
104,105
104,105
Chronic
lymphocytic
leukemia
none
0/25
12p11-p12, p13 1/42
CCND2
106
90,107
106,107
14q31-q32
1/42
IGH
90
90
Myeloma and
plasma cell
leukemia
none
0/8
Diffuse large cell
lymphoma
2p13-p15
6p23-ter
10p12-p14
12q13-q14
17p11.2
18q11.2-qter
Xp11-p21
Xq22-ter
Xq26-q28
1/1
1/32
1/32
1/46*
1/32
5/34
1/46
1/32
1/46
1p36
2p13-p16
2p22-p24
3q12-q13
4q32-q35
6p21
8q23-q24
8q24
12q13-q14
14q21-q24
15q23-q24
18q21-q23
19q13
Xq21-q24
1/28
3/46
1/46
1/46
1/46
1/28
1/46
2/28
1/28
1/46
1/46
2/46
1/46
1/46
2p23-p24
3p14-p22
1/5
1/27
Follicular
lymphoma
Mantle cell
lymphoma
108
REL
BCL2
MYC
GLI
MYCN
23
10
10
90
10
10,11
90
10
90
109
90
90
90
90
109
90
109
90,109
90
90
90
90
90
90
51
10
10
10
10
10
10
10
10
109,110
109,110
110
109,110
109,110
109,110
109,110
109
109,110
109
109,110
51
51
10
3q26-q29
8q23-ter
9
12p13
13q22-q32
15q22-ter
18q21-q23
19q13
20q13.1
Xq26-q28
1/5
1/27
1/27
1/27
2/27
1/27
1/5
1/5
1/27
2/5
Mediastinal thymic
B-cell lymphoma
2p13-p16
9p23-p24
Xp11-p21
Xq22-q28
2/26
1/26
1/26
1/26
Marginal zone
B-cell lymphoma
3q21-q22
3q26-q27
6p11-p21
9q31-q33
18q12-q23
X
1/25
1/25
1/25
1/25
2/25
1/25
2p23-p25
1/15
1p32-p36
1q24
1q21-q24
1q32
1q41-qter
2p23
2q32-q35
3q26.3-qter
5p
6q21
6q25
7q11.2
8q21
8q24
9q21-q22
9q31
11q11-q14
12p
13q33-q34
14q12-q21
15q24-qter
17q21
17q25
19p12
19q13.1
20p11
21q21-q22
22q11
Xp11.2
Xq23-qter
1p32-pter
1q
1q21-q22
Burkitt's lymphoma
Respiratory tract
Small cell lung cancer
Non-small cell
lung cancer
90
51
51
51
51
51
90
90
51
90
51
51
51
51
24
24
24
24
24
24
24
24
50
50
50
50
50
50
50
50
50
50
50
50
90
90
6/35
1/13
1/22
1/13
1/22
3/35
1/22
3/35
5/35
1/13
1/13
3/35
1/22
3/35
2/35
1/22
2/35
2/35
3/35
1/13
2/35
1/22
1/22
2/22
10/35
1/22
2/35
2/35
1/13
1/22
40,41
40
41
40
41
40,41
41
40,41
40,41
40
40
40,41
41
40,41
40,41
41
40,41
40,41
40,41
40
40,41
41
41
41
40,41
41
40,41
40,41
40
40,41
40-42
40-42
40-42
40-42
40-42
40,41
40,41
40-42
40-42
40-42
40-42
40,41
40-42
40-42
40,41
40,41
40,41
40-42
41
40-42
40,41
40,41
40,41
40,41
40,41
40,41
40-42
40,41
40-42
40-42
1/50
1/9
2/50
45
44
45
12,43,45
12,29,43,45
12,29,43,45
BCL2
REL
BCL6
BCL2
MYCN
51
51
51
11
1q31-qter
2pter-q13
2q12-q14.1
2q14.1-q21
2q22-q31
2q31-q32
2pter-q21
3q26.1-q26.3
2/94
1/10
1/50
1/50
1/50
1/50
1/10
26/103
3qcen-q23
3q23-qter
5p
5p15.3
5p12-p15.1
6p12-p21.2
6p12
6p21.1
6p22-pter
7p
7q11.2
7q32-q35
8p12-q12
8p11.2-p12
8q22.1-q24.2
9p21-pter
9q22
9q31-q34
11q13-q14
11q21-qter
12cen-p13
12p12-p13
12p11.2-p12
12q14-q21
12q24.1-24.3
13q12-q21
13q22-qter
14q13-q21
14q32
15q25-qter
16p
17p
17q12-q21
17q24-q25
18p11.2
18q11.2
18q12
19p13.1-13.2
19qcen-q13.3
20p11.2-p12
20p
20q12-qter
20q
21q
22q11.2
Xp
Xq26-qter
Xqcen-q23
1/10
2/10
5/49
6/44
4/50
1/44
4/50
1/9
1/44
1/30
4/60
1/50
1/30
1/50
14/124
1/50
1/44
1/10
4/50
1/44
2/30
2/44
4/50
2/30
2/50
1/10
4/54
4/50
2/50
1/50
1/50
1/50
2/50
6/50
2/50
1/50
1/50
1/50
6/104
6/50
1/10
2/94
1/10
1/30
1/50
1/10
2/44
2/10
MME, KNG,
HRG, SI,
BCHE, SLC2A2
KRAS2
43,45
29
45
45
45
45
29
43-46
12,29,43,45
12,29,43,45
12,43,45
12,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
29
29
12,29,44
43
45
43
45
44
43
12
45,29
45
12
45,29
12,43,45
45
43
29
45
43
12
43
45
12,45
45
29
29,43
45
45
45
45
45
45
45
45
45
45
45
29,43,45
45
29
43,45
29
12
45
29
43
29
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
29,43,45
29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,43,45
12,43,45
12,29,43,45
12,29,43,45
12,29,43,45
43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
12,29,43,45
43,45
29,43,45
29,43,45
29,43,45
29,43,45
29,43,45
45
29,43,45
12,29,45
12,29,43,45
12,29,43,45
12
Pleural
mesothelioma
11qcen-q14
11q23-qter
12pcen-p12
1/34
1/34
1/34
12
12
12
12
12
Squamous cell
carcinomas of
the head and neck
1p32
1p35-p36
1q21-q23
2p16-p21
2q31-q33
2q33-q36
3q24
3q26.3-qter
3q27-qter
4qcen-q13
5p15
7q21-q22
7q33-qter
8q21-q23
8q24.3
9p
9q34
10p11-p13
10q21-q22
10q25-q26
11q13-q14
12p12-pter
12q13-q14
13q32-qter
14q32
15q26
17q12-q21
17q25
20p12-pter
1/30
1/30
3/30
1/30
3/30
1/13
3/30
3/13
6/30
1/30
3/30
6/43
1/13
1/30
3/30
1/13
2/30
1/30
2/30
1/30
4/43
4/43
1/30
1/13
1/30
2/30
1/30
2/30
1/30
25
25
25
25
25
49
25
49
25
25
25
25,49
49
25
25
49
25
25
25
25
25,49
25,49
25
49
25
25
25
25
25
48
25
25,48,49
25,48,49
25,48,49
25,48,49
25,48,49
25,48,49
25,48,49
25,48
25,48,49
25,48,49
25,49
25,48,49
25,48,49
25,48
25,48,49
25,49
11q12
12p11
14q12
19q13.1
1/50
1/50
1/50
2/50
111
111
111
111
111
2q32-q34
3q24-q26.3
4p
7q11-q31
8
11q11-q31
12q23-qter
17q
20q
1/5
1/5
2/5
1/5
1/5
1/5
1/5
1/5
3/5
112
112
112
112
112
112
112
112
112
2p23-ter
13q21-q31
17q12-q21
18q21-ter
20q
1/35
1/35
3/35
1/35
3/35
80
80
80,81
80
80
7p14-pter
8q
13
20
1/3
1/3
1/3
1/3
Digestive tract
Hepatocellular
carcinoma
Adenocarcinoma
gastroesophageal
junction
(xenografts)
Stomach carcinoma
Stomach
carcinoma
(xenografts)
GAS, ERBB2
112
112
112
112
25,48,49
25,48,49
25,48,49
25,48,49
25,48,49
25
25,48,49
25,49
48,49
111
111
112
112
112
112
112
112
80,113
80,113
80,113
80,113
112
112
13
Stomach
carcinoma;
hereditary
non-polyposis
colorectal cancer
patients
none
0/12
83
Stomach
adenoma
13
17cen-q22
20q12-qter
1/16
1/16
1/16
82
82
82
Gastrointestinal
stromal tumor
3q26-q29
3q
5
5p
8q
Xp
1/16
1/16
1/16
1/16
1/16
1/16
114
114
114
114
114
114
114
114
114
114
114
114
Colon carcinoma
7p
8q24.1-q24.3
12q13
17q21
18q23
20q13.1-q13.3
1/16
4/16
1/16
1/16
1/16
5/16
78
78
78
78
78
78
78
78
78
78
Colon adenoma
2p21
1/12
78
Endocrine glands
Adrenocortical
adenoma
carcinoma
none
none
0/14
0/8
115
115
Thyroid
follicular adenoma
follicular carcinoma
none
none
0/29
0/13
116
116
116
116
1p32-p34
6q24
7q22
12p13
22
1/27
1/27
1/27
1/27
2/27
117
117,119
117
117
117
118
Urinary tract
Renal cell carcinoma
6p12-p22
1/25
120
120
Wilms’ tumor
none
0/54
121,122
Bladder carcinoma
3p22-p24
6p22
8q21.3-q22
10p13-p14
12q13-q15
16q21-q22
17q22-q23
18p11
20q12-qter
22q11-13
1/14
2/33
1/26
1/14
1/14
1/7
1/14
1/14
1/26
1/14
79
2,123
123
79
79
2
79
79
123
79
123
79,123
79,123
79,123
123
79
79,123
123
79,123
Breast carcinoma
1q32
6p21.2-pter
2/20
2/49
84
85,125
84-86,88,124
84,124,125
Pancreatic adenocarcinoma
CMYB
78
117
117
117
14
Female genital organs
Ovarian cancer
Endometrium
serous cancer
endometrioid
cancer
Uterine cervix
cancer
Male genital organs
Testis
6cen-p21.2
6q12-q13
7p21
8p11-p12
8q
8q21.3-q23
8q23-qter
10p
11q13-q14
1/33
1/33
1/33
8/53
14/48
1/33
5/69
1/20
8/101
85
85
85
84,85
86
85
84,85,125
84
84-86
84,85,124
85,86,124
84-86,88,124
84-86,124,126
84-86,88,124
84,85
84,85,126
86,124
84-86,124,126
12p11-pter
12q15
15q24-qter
17q11-q12
17q12-qter
17q22-q25
19q13.1-qter
20q12-q13
2/36
1/20
3/33
2/20
1/16
8/101
1/33
17/96
84,125
84
85
84
125
84-86
85
85-87
86
85,86
84,86
86,88,126
1q23-q32
2p15-p22
3qcen-q23
6p21
8q
12p12
3/24
1/24
1/24
2/24
1/24
9/47
26
26
26
26
26
34
26,34,35
26,34,35
26,34,35
26,34,35
26,34,35
26,34,35
2q31
3q24-q26.3
6p
8q22-q24.1
15q25-qter
18p11.2
18q11.2-q12
20q13.1-qter
2/24
1/24
1/24
2/24
1/24
1/24
1/24
1/24
37
37
37
37
37
37
37
37
37,127
37,127
37,127,128
37,127,128
127
37,127,128
127
37,127
1q31
5p14-p15
6p21-p23
2/24
1/14
1/24
37
128
37
37,127,128
37,127
37,127,128
3q24-q28
3q26.1-q27
5p13-pter
8p
8q
9p23-pter
11q22-q23
12p13
14q
17q
19q13.1-qter
20p11.2-pter
20q
3/10
4/30
5/30
1/30
2/30
2/30
1/30
2/30
1/30
1/30
1/30
1/30
2/30
129
38
38
38
38
38
38
38
38
38
38
38
38
38,129
38,129
129,38
38
38
38,129
1p34-pter
2p21-pter
4q12-q21
6p11-p22
1/11
1/11
1/11
1/11
55
55
55
55
55
55,130
55,130,131
55,130,131
MYC
BCL1, INT2,
CYCD1
ERBB2
84,85,88
84-86,126
38
38
38,129
38,129
38,129
38,129
15
Prostate cancer
Nervous system
Neuroglial tumors
Medulloblastoma
Neuroblastoma
MPNST
Eye
Melanoma
7p12-pter
7q
8
10
12p11.2-p12.1
12p11.23
14q12-qter
15q15-qter
16p12-pter
17q24-qter
19p13.2-pter
19q13.1-qter
21q11.2-qter
22q11.2-qter
Xp11.2-pter
Xq
Ypter-q11.2
2/11
1/11
3/11
1/11
10/11
1/1
2/11
2/11
2/11
2/11
4/11
1/11
2/11
1/11
2/11
1/11
2/11
55
55
55
55
55
132
55
55
55
55
55
55
55
55
55
55
55
55,130,131
55,130,131
55,130,131
55,130
55,130-132
55,130,131
55,130
55,130
55
55
55,130
55,130
55,130
55,130
55,130,131
55,130,131
55
Xp11-q13
Xq23-qter
1/9
1/9
98
98
9,98,133,134
98,133
1q32
4p
4q12
5p
7p12
7p13
7q21.1-q21.3
7q31-qter
8q23-qter
8q
9p
11p
11q13
11q22-q23
12p
12q13-q15
12q22-qter
13q32-q34
18p
22q12
2p24
5p15.3
8q24
11q22.3
1/9
1/24
2/9
2/24
8/29
10/24
3/29
2/15
3/38
2/24
1/24
1/24
1/20
1/20
6/24
7/44
1/15
3/15
1/15
1/9
2/18
2/27
3/18
1/27
135
72
135
72
71,135
72
71,135
136
71,138
72
72
72
71
71
135,136
71,72
136
136
136
135
139
140
139
140
71,72,135,136
72,135
72
71,137
71,135,137,138
72,136-138
71,72,135-138
71,72,135-138
72,135-137
136
71,135-138
71,135-138
2p13-p14
2p23-p25
3q24-q26
4q33-q35
6p11-p22
1/35
30/85
1/35
1/29
1/29
27
27,30,31,141
27
31
31
27,30,31
30,31
27,30,31
30, 27,31
27,30,31
17q24-qter
5/7
142
6p
6p21-pter
8q
8q24-qter
4/10
6/11
10/10
7/11
53
54
53
54
EGFR
MYC
MYCN
MYC
MYCN
137
136-138
71,72,136,137
137
137
135
136
140
139
139,140
140
16
Skin
Melanoma
7q32-q34
1/3
143
Bone and soft tissue
Osteochondroma
none
0/15
144
3q26-q28
7q36
12q12-q13
12q13-q14
12q14-q15
1/1
1/1
1/1
4/6
1/1
73
73
73
145
73
1p22-p31
1q22-q24
1q32-q42
3q24-q26
4q31
5p12-p13
5p14-pter
6p11.2-p12
8cen-p12
8q21.3-q23
9p21-pter
11q22-qter
12p13
12q12
12q13-q15
13q33-q34
14q31-q32
15q23-qter
16q
17p11.2-p12
18q
20p12-p13
20q12-q13.1
22q13
Xp11.2-p21
Xq12
Xq25-qter
3/31
2/31
1/31
1/31
1/31
1/31
2/31
3/31
1/31
3/31
1/31
1/31
3/31
1/31
2/31
1/31
2/31
1/31
1/31
4/31
1/31
1/31
2/31
2/31
4/31
2/31
2/31
74
74
74
74
74
74
74
74
74
74
74
74
74
74
74
74
74
74
74
74
74
74
74
74
74
74
74
73,74,76#
73,74,76
73,74
73,74
73,74
73,74,76
73,74
73,74,76
73,74
73,74,76
73,74
73,74
73,74
73,74,76
73,74,76
73,74
73,74
73,74,76
73,74
73,74,76
1p33-p35
2p23-pter
4p
6p22-pter
12cen-q15
18q12-q22
19p13.2
19q13.2
20q13.1
1/29
1/29
1/29
1/29
2/29
1/29
1/29
1/29
1/29
146
146
146
146
146
146
146
146
146
146
146
146
146
146
146
Ewing family of tumors
1q21-q22
6p
8q13-q24
19
3/37
1/37
1/37
1/37
147,148
147,148
147,148
147,148
147,148
147,148
147,148
Malignant fibrous
histiocytoma of bone
1q21-q23
3p13-p21
4cen-q13
6p12-p21.3
2/26
1/26
1/26
1/26
149
149
149
149
149
Parosteal
osteosarcoma
Osteosarcoma
Chondrosarcoma
143
145
145
145
74
73,74
73,74
73,74
146
149
149
17
7p11.2-p21
8q21.2-q22
12p11.2-p12
13q32-qter
15q11.2-q13
16p11.2-pter
22q
Xp11.4-p21
1/26
2/26
1/26
1/26
1/26
1/26
1/26
1/26
149
149
149
149
149
149
149
149
149
149
149
1q12-q24
3p13-q11.2
5p14-p15
5q33
6p23-p24
7p12-p21
8
11q13-q22
12p12-pter
13q31-qter
14q24-q31
15q25-q26
17p
18p11
19p12-p13.2
19q13.2-qter
22q11.2
Xp21
1/58
1/58
3/58
1/58
2/58
2/58
1/58
2/58
1/58
4/58
1/58
2/58
2/58
2/58
1/58
2/58
2/58
2/58
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
151
Lipoma
none
0/12
152
Liposarcoma
1p33-pter
1q21-q24
12q14-q21
19
Xp21
1/14
5/22
7/30
1/14
1/14
153
152,153
58,152,153
153
153
Leiomyoma
none
0/14
155
Leiomyosarcoma
1q
4p13-q25
5p
6p
6q21-qter
7
8q
10p
14
16p
17p
19q11-q13
X
3/29
1/29
2/29
1/29
1/29
1/29
6/29
1/29
1/29
2/29
7/29
1/29
2/29
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
Synovial sarcoma
1q21-q25
1q41-qter
2p24-pter
2p21-q14
4cen-q13
7pter-q31
8q
9
1/67
1/67
1/67
1/67
1/67
1/67
4/67
1/67
28
28
28
28
28
28
28
28
28
28
28
28
Malignant fibrous
histiocytoma of soft
tissue
CDK4, MDM2
149
149
149
151
151
151
151
151
151
151
151
151
151,153
151,152
151-154
28
28
18
12q15
21
Xp
Xq23-qter
1/67
2/67
1/67
1/67
28
28
28
28
8q
12q13-q15
1p36
1q21
2p24
8q13-q21
12q13-q15
13q14
13q32
5/10
1/10
4/16
1/14
5/14
1/14
7/14
4/16
2/14
156
156
156,157
156
156
156
156
156,157
156
Alveolar soft part
sarcoma
none
0/13
159
Solitary fibrous tumor
none
0/15
160
Hemangiopericytoma
none
0/11
160
Rhabdomyosarcoma
embryonal
alveolar
90*,
PAX7
FKHR
28
28
28
141
141,158
the total amount of aggressive lymphomas is 46, including diffuse large B-cell
lymphoma and follicular lymphoma; 76#, 3 primary tumors, 1 metastasis, 10
xenografts. No distinction between gain and amplification; MPNST, malignant
peripheral nerve sheath tumors from patients with von Recklinghausen’s
neurofibromatosis
19
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Reardon DA, Michalkiewicz E, Boyett JM, Sublett JE, Entrekin RE, Ragsdale
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Larramendy ML, Tarkkanen M, Blomqvist C, Virolainen M, Wiklund T, AskoSeljavaara S, Elomaa I, Knuutila S: Comparative genomic hybridization of
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Suijkerbuijk RF, Olde Weghuis DEM, Van Den Berg M, Pedeutour F, Forus
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Sarlomo-Rikala M, El-Rifai W, Lahtinen T, Andersson LC, Miettinen M,
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Weber-Hall S, Anderson J, McManus A, Syuiti A, Nojima T, Pinkerton R,
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