[CANCER RESEARCH 40, 4796-4803,
0008-5472/80/0040-OOOOS02.00
December 1980]
Site-directed Chromosome Rearrangements in Skin Fibroblasts from
Persons Carrying Genes for Hereditary Neoplasms1
M. S. Sasaki,2 Y. Tsunematsu, J. Utsunomiya, and J. Utsumi
Radiation Biology Center, Kyoto University, Sakyo-ku,
Tokyo Medical and Dental University, Bunkyo-ku,
Kyoto 606 [M. S. S.]: National Children's
ABSTRACT
Chromosomal variability was studied in cultured skin fibroblasts in members of two unrelated families associated with
hereditary neoplasms, one with familial childhood leukemia and
the other with medullary thyroid cancer syndrome. Nonconstitutional chromosome rearrangements occurred with consistent
frequency in the patients and obligate carriers. The G-banding
analysis showed that the chromosome rearrangements were
not random, and site of rearrangements tended to cluster to
band p22 of chromosome 1 in the carriers of childhood leu
kemia gene and to band q23 of chromosome 17 in the patient
with medullary thyroid cancer. The de novo rearrangements of
chromosomes and their tendency to cluster to particular chro
mosomal sites strongly point to the possibility that the procancer type-dominant mutations responsible for these diseases
have a mutator function analogous to the property of some
insertion mutations or transposable elements.
INTRODUCTION
A growing list of monogenie cancer syndromes provides
compelling evidence for a wide variety of genetic factors in the
etiology of cancer (31). Among these, a defect in DNA repair
or chromosomal instability has been suggested to be an integral
component of several recessive diseases (10, 34). Also noted
was the susceptibility to cancer imparted by inherent immune
deficiency or chromosomal disorders (1,9,19,
30). However,
in the dominant diseases, the nature of the genetic factors
(germinal mutations) and their role in the etiology of cancer are
by no means clear and constitute one of the most significant
unanswered questions in cancer research. In this regard, of
particular importance are the recent findings of the intrinsic
predisposition of certain inborn chromosome abnormalities to
particular types of embryonal tumors, such as partial deletion
of chromosome 13 to retinoblastoma (14, 24; see Ref. 39 for
a review), loss of a part of chromosome 11 to aniridia-associated Wilms' tumor (8, 32), and translocation between chro
mosome 3 and 8 to renal clear-cell carcinoma (5). These are
the only instances in humans which show that chromosome
mutation at a particular site consistently predisposes to a
specific tumor.
In this paper, we describe the unusually high frequencies of
de novo clones of cells with chromosome rearrangements in
cultured skin fibroblasts obtained from persons inheriting can
cer-predisposing mutations, i.e., those for childhood leukemia
and MTC.3 The importance of the present observations lies in
' Supported
by a grant-in-aid
for cancer research from the Ministry of Edu
cation, Science, and Culture of Japan.
2 To whom requests for reprints should be addressed.
3 The abbreviations used are: MTC. medullary thyroid cancer; PHA, phytohemagglutinin.
Received May 15, 1980; accepted August 25. 1980.
4796
Hospital, Setagaya-ku,
Tokyo 113 [J. U.]; and Niigata Cancer Center, Kawagishi-cho,
Tokyo 154 [Y. T.]; School of Medicine,
Niigata 951 [J. U.J, Japan
their site-directed chromosome rearrangements which seem to
be specific for a specific type of procancer class of mutations
of the dominant trait.
MATERIALS
AND METHODS
Childhood Leukemia (Family SBR). The family pedigree is
shown in Chart 1. The genealogical and clinical information
was assembled through interviews with relatives and exami
nation of pertinent medical records. The family history contains
no suggestion of consanguinity. The proband, Case V-8, a 28month-old girl, was admitted to the National Children's Hospital,
Tokyo, in April 1978, with a general hemorrhagic state. Com
plete remission was achieved with prednisolone and vincristine.
Case V-6, brother of the proband, was admitted to the hospital
at age 3 years in 1969 with enlargement of the lymph nodes
and died 21 months later. Case V-7, brother of the proband,
was also admitted to the hospital in 1970 at age 15 months
with recurrent bleeding. Complete remission was obtained with
6-mercaptopurine and prednisolone, but he relapsed and died
12 months later. Case V-11, paternal first-degree step-cousin
of the proband, was admitted to Niigata Cancer Center, Niigata,
in June 1978 at 3.5 years of age with recurrent bleeding. A
complete remission was obtained with prednisolone and vin
cristine. All of these patients were diagnosed to have acute
lymphatic leukemia. In the proband and Case V-11, it was
confirmed to be null cell type. Although the causes are uncer
tain, an unusual clustering of deaths in infancy is noted in this
family. One of these, Case IV-11, is highly suggestive of leu
kemia because his illness included abdominal distention due
to blood disease. The pedigree data suggest the autosomal
dominant mode of inheritance with limited degree of penetrance.
MTC (Family SMD). The index case was a 21-year-old male
who was characterized by a fairy-like facial appearance and
Marfan's syndrome-like habitus. Multiple mucosal neuroma
had been noted in the eyelids and tongue early in his life. At
age 16 years, MTC was found in the right lobe of the thyroid,
and he was referred to Cancer Institute Hospital, Tokyo, for a
thyroidectomy. He was the first child in a sibship of 2 boys; no
other family members were similarly affected. The patient was
thus recognized as a sporadic case of prezygotically deter
mined MTC syndrome or multiple endocrine neoplasia of the
clinical entity of type 2B or type 3 (4, 23). Skin biopsies were
obtained from the patient, his unaffected brother, and their
parents.
Cytogenetic Studies. Skin biopsies were obtained from the
forearm of patients and their family members, and fibroblast
cultures were established by culturing the biopsies. The culture
medium was Leibovitz's L-15 medium supplemented with 10%
NCTC-109 and 15% fetal calf serum. The cultures were main-
CANCER
RESEARCH
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Chromosome Rearrangements
GH
and Hereditary Neoplasms
Ó
IV
Chart 1. Pedigree of the family with childhood leukemia showing the proband (arrow) and 4 previous generations. Upper numeral applied to each individual, a
consecutive identification number at each generation; lower numeral, age in years; t. death at indicated age; •and •,leukemia; K?.suspected leukemia: "". stomach
cancer; 9, uterine cancer; ®,biliary cancer; 0 and 0, examined but normal; symbols with small circles, persons having mutant karyotypes in their skin cells.
tainted at 37° in a humidified atmosphere with the aeration of
95% air:5% CO2. Chromosomes were studied in the early
passage levels, not later than the fifth passage. At the second
day after passage, the cells were exposed to Colcemid (0.5
fig/ml) for 4 hr, treated in 0.075 M KCI for 15 min, and fixed in
methanol:acetic acid (3:1). The cells were air dried onto glass
slides. For conventional karyotyping, slides were stained in 3%
Giemsa at pH 6.4. For banding analysis, slides were processed
for G-banding procedure according to a modification of the
method of Seabright (33). Karyotypes were determined under
the microscope, and the cells with abnormal karyotypes were
photographed for the detailed analysis by photoprints.
RESULTS
Table 1 summarizes the results of chromosome analyses in
cultured skin fibroblasts. None of the patients or unaffected
family members showed constitutional or prezygotically deter
mined chromosome abnormalities, but both conventional and
banding analyses revealed the chromosome abnormalities in a
significant fraction of cells in the patients and some unaffected
family members. Typical chromosome abnormalities found in
the cultured skin fibroblasts are shown in Figs. 1 to 3. As seen
in these figures, the chromosome abnormalities were usually
euploid rearrangements, including reciprocal translocations or
inversions, and were nonconstitutional.
Some appeared as
clones where the identical karyotype was present in more than
one cell. Although their frequencies varied among individuals,
the cells with such abnormal karyotypes were found in the
patients and obligate carriers. Their occurrence was thus as
sociated with the presence of cancer-predisposing
genes and
not related to the donor's age alone; yet, when present, their
frequencies tended to be higher in the older persons as re
flected by more types of rearrangements in larger clones. An
aberrant clone found in the leukemia patient, Case V-11, was
the only clone of cells with aneuploid structural changes in
which an extra marker chromosome of unknown origin was
present in addition to a reciprocal translocation between chro
mosomes 1 and 8 (Fig. 2A).
Chromosome abnormalities varied in type, but a significant
feature was a nonrandom pattern of chromosome rearrange
ments. In the family of childhood leukemia, chromosome 1 was
frequently involved. More particularly, a specific site, band
p22, of chromosome 1 tended to be involved in chromosome
rearrangements with unusually high frequency. Such site-di
rected chromosome
DECEMBER
rearrangements
are clearly seen in Chart
2 where the participation of chromosomes and the distribution
of breakpoints in the formation of chromosome rearrangements
are presented. In the family of childhood leukemia, among 15
types of identified rearrangements, 8 occurred at band p22 of
chromosome 1, and 2 occurred at band p11 of chromosome
2. Although band p22 of chromosome 1 was not involved in
the rearrangements so far found in the leukemia patients, the
findings point to a tendency toward inherent gene-associated
regional specificity in the chromosome rearrangements. In the
patient with MTC, chromosome abnormalities were found in
20% of the cells. They were composed of 2 types of clones of
euploid rearrangements, one with t(4;17) and the other with
t(7;17). In this case, band q23 of chromosome 17 was specif
ically involved in both rearrangements (Fig. 3, A and B).
In the leukemia patient, Case V-8, chromosomes were also
studied in the circulating leukemic cells after incubation of
peripheral blood leukocytes for 6 hr in culture medium without
PHA. No karyotypic abnormality was found in conventional
karyotyping of 100 leukemic cells. Chromosomes were also
studied in PHA-stimulated peripheral blood lymphocytes in
Case V-8, her unaffected sister, Case V-9, and their parents in
Family SBR as well as the MTC patient and his parents in
Family SMD. The karyotypic mosaicism such as that found in
skin fibroblasts was not observed in these people whose cells
(50 each) were studied by conventional karyotyping.
DISCUSSION
The association of the presence of germinal mutations of
potential propensity to cancer and the occurrence of cytogenetically marked clones in the skin fibroblasts is of great
concern to us especially in view of the nature of the procancer
class of germinal mutations of the dominant trait. The occur
rence of cytogenetically marked nonconstitutional clones is
well documented in cultures derived from irradiated human
skin (3, 7, 37) and skin from patients with genetically deter
mined chromosomal instability (2, 11 -13,17). However, atten
tion has recently been drawn to their presence in some cultured
fibroblast cell lines established from skin of apparently normal
healthy persons (18, 22, 27). Harnden era/. (18) have reported
a study in which they found a substantial amount of such
clones in some adult cell lines but none in fetal cell lines and
concluded that such mutant karyotypes most probably are
related to the donor's age and that their occurrence was an
age-related expression of a normal phenomenon.
Apart from the age effect, the presence of such de novo
1980
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4797
M. S. Sasak/ ef al.
Table 1
Types and frequencies of chromosome abnormalities in cultured skin fibroblasts
karyotypSubjects
inyr)Conventional
(age
ingaBanding
analysis9KaryotypeNo.
cellsFamily
of
leukemia)III-25III-32IV-3IV-10IV-13IV-14IV-15V-86V-9V-10V-11b(64)(57)(35)(41)(29)(29)(28)(3)(1)(6)(4)11/50
SBR (childhood
(22.0%)0/500/509/50 (35.0%)0/500/10022/100
(18.0%)2/50
(22.0%)10/100
(4.0%)0/500/502/50
(10.0%)0/500/503/80
(4.0%)1/100
(3.8%)0/1000/505/150
(1.0%)0/502/50
(4.0%)35/100
V-13
(4)
Family SMD (MTC)
Patient"«1)
0/50
10/50 (20.0%)
(3.3%)t(1;10Xp22;p13)t(1;2Xp22;p21)t(1;6Xp32;p21)inv(1Xp22;q32)K2;2Xp11;q33)«1
0/50
10/50 (20.0%)
t(7;17Xq22;q23)
t(4;17Xq21;q23)
Brother (17)
0/50
0/50
Mother (49)
0/50
0/50
Father (56)
0/50
0/50
* Frequencies are expressed as number of cells with aberrant karyotypes to total number of cells
analyzed.
'' Index patient.
clones of cytogenetically abnormal cells has also been noted
in cultured fibroblasts derived from unaffected skin of patients
with other hereditary neoplasms of a dominant mode of inher
itance, such as nevus basal cell carcinoma syndrome (21),
prokeratosis of Mibelli (35), and familial polyposis coli (36).
These findings are particularly important since they emerge
without any indication of an increased tendency to chromo
some breakage. In the present observations, the appearance
of mutant karyotypes was not related to the donor's age but
was restricted to the patients and obligate carriers. Moreover,
in our separate observations on another family with childhood
leukemia (data not presented here) in which 2 of a sibship of
4 children were affected and homozygosity of the recessive
trait was suggested from the pedigree data, none of the patients
or other family members with ages ranging from 1 to 64 years
showed cytogenetically marked clones. Abnormal clones were
not found as well in skin fibroblasts from 3 patients with
neurofibromatosis and a patient with tuberous sclerosis, which
are 2 other cancer-predisposing diseases of dominant inherit
ance. These lines of evidence indicate that the age alone is not
responsible for the occurrence of aberrant karyotypes, but
their emergence in fibroblasts is somehow related to the pres
ence of certain types of cancer-prone mutations.
Of significance in the present study may be the clearly
nonrandom chromosome aberrations and the tendency for the
site of chromosome rearrangements to cluster to a specific
position of a specific chromosome. The chromosomal sites
selectively involved in the rearrangements seem to be specific
for specific inherent mutations rather than for tissue. The site
4798
specifically involved in chromosome rearrangements was band
p22 of chromosome 1 for familial leukemia and band q23 of
chromosome 17 for MTC. The site-specific chromosome rear
rangements were well documented in PHA-responsive T-lymphocytes of patients with ataxia telangiectasia (17, 20). In
these cells, chromosomes 14 and/or 7 are specifically involved
in chromosome rearrangements. Similar karyotypic changes
were also noted in cultured skin fibroblasts of the patients (2,
6). Ataxia telangiectasia is a recessively transmitted cancerpredisposing disease. However, similar aberrations were found
in the possible heterozygotic carriers (2). This is also in line
with the idea that the sites of hot spots are not specific for
tissue but rather specific for certain types of inherent mutations.
The clustering of aberrations to specific chromosomes has
been noted in human tumors as well as experimental and
spontaneously occurring tumors of laboratory animals (25, 26,
29). However, those aberrations are in tumor cells and are
essentially different from those found in the present study,
where chromosome rearrangements are present in apparently
normal tissues.
The clustering of the breakpoints and their presumed disease
specificity must have some biological significance. At this mo
ment, we are not in a position to draw any conclusions about
the genesis of such regional specificity in chromosome rear
rangement. Yet, it is tempting to correlate such a site-specific
recombination with a cytological manifestation of the site-di
rected mutability as afforded by mutations responsible for
hereditary tumors as is the case for the so-called control
elements in Zea mays (28) or male recombination mutation in
CANCER
RESEARCH
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VOL. 40
Chromosome Rearrangements
and Hereditary Neoplasms
be another facet of their function. It is thus expected that, in
the carriers of such procancer genes, clones of cells with a
mutant karyotype accumulated in number and grow in size
according to the age of donor and the time after the mutant
cell emerged, respectively. Apart from the function of prime
importance in cancer development, the mutator function of the
inherent procancer mutation of the dominant trait is an attrac
tive idea to explain site-directed chromosome recombinations
in skin fibroblasts. However, it is obviously premature to enter
upon speculation on this point, and it is hoped that, as more
data accumulate, the significance of the site-directed chromo
some recombinations associated with the procancer class of
genes will be elucidated.
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Fig. 1. Partial karyotypes
in her father, Case IV-10.
showing chromosome
rearrangements
found in Family SBR. A, t(7;14) found in Case V-8; B to E, chromosome
Frg. 2. Partial karyotypes showing chromosome rearrangements found in Family SBR. A, t(1 ;8) and supernumerary
t(1;12) found in his mother, Case IV-13; C and D, chromosome rearrangements found in his grandmother, Case III-25.
Fig. 3. Karyotypes showing chromosome
4800
rearrangements
marker chromosome
rearrangements
found
found in Case V-11 ; fl,
found in patient with MTC. A, t(7;17); B, t(4;17).
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Site-directed Chromosome Rearrangements in Skin Fibroblasts
from Persons Carrying Genes for Hereditary Neoplasms
M. S. Sasaki, Y. Tsunematsu, J. Utsunomiya, et al.
Cancer Res 1980;40:4796-4803.
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