Nature Reviews Cancer | AOP, published online 21 September 2012; doi:10.1038/nrc3355
OPINION
Tumorigenesis in Down’s syndrome:
big lessons from a small chromosome
Dean Nižetić and Jürgen Groet
Abstract | If assessed by a number of criteria for cancer predisposition, Down’s
syndrome (DS) should be an overwhelmingly cancer-prone condition. Although
childhood leukaemias occur more frequently in DS, paradoxically, individuals with
DS have a markedly lower incidence of most solid tumours. Understanding the
mechanisms that are capable of overcoming such odds could potentially open new
routes for cancer prevention and therapy. In this Opinion article, we discuss recent
reports that suggest unique and only partially understood mechanisms behind this
paradox, including tumour repression, anti-angiogenic effects and stem cell ageing
and availability.
Down’s syndrome (DS)1, which is caused
by trisomy of chromosome 21 (T21), is the
most common genetic cause of intellectual
disability. Across the world, approximately
one in 650 children is born with DS. This
figure is rising in the United Kingdom2 and
other countries3, as maternal age is increasing and as some parents opt to keep the
fetus, regardless of positive prenatal diagnosis174. Consequently, the eventual emergence of non-invasive prenatal diagnostic
approaches can be predicted to have a limited effect on reducing the incidence of DS4.
Life expectancy for people with DS is well
into their sixties in countries with advanced
health care5.
Multiple studies in different ethnogeographical populations have shown that
people with DS have a markedly lower
incidence of most tumours compared with
age-matched euploid individuals, with the
exception of childhood leukaemia and
germ cell cancers, which are more frequent
in people with DS. The striking paradox
of these epidemiological observations is
that — on the basis of our understanding
of tumorigenesis — the situation ought to
be quite the reverse; that is, DS should be
an overwhelmingly cancer-prone condition. This is because cells from individuals
with DS have high levels of reactive oxygen
species (ROS), increased DNA damage and
hypo-functional DNA repair mechanisms,
increased chromosomal instability, dysfunctional mitochondria, constitutional overdose
of several known oncogenes and attenuation of known tumour suppressors, and
people with DS are immunodeficient and
susceptible to infections. As most of these
characteristics are typical of cancer-prone
conditions, understanding the mechanisms
that are capable of overcoming odds that are
stacked in the favour of cancer onset and
progression could potentially help to prevent
and to fight cancer more effectively. The
purpose of this Opinion article is to review
these mechanisms, provoke thought and to
provoke debate on the paradoxical observations in DS tumorigenesis that do not fit the
accepted paradigms.
Cancer epidemiology in DS
The incidence of some types of cancer is
increased in DS. Children with DS have
an approximately tenfold to 50‑fold higher
overall incidence of leukaemias than euploid
children (TABLE 1), including most types of
acute myeloid leukaemia (AML) and acute
lymphocytic leukaemia (ALL)6–8. This
increased risk does not extend to leukaemias
or other haematological malignancies of typically adult onset6,9. Although based on small
numbers, studies of leukaemia in individuals
with DS in late adulthood do not show a clear
trend of increasing risk with advancing age
(TABLE 1). Acute megakaryoblastic leukaemia
(DS‑AMKL; also known as ML‑DS), which
is preceded by transient myeloproliferative
disorder (TMD), has a 500‑fold increased
incidence relative to euploid children10.
TMD-AMKL is a unique condition of DS that
enables the study of stages of leukaemogenesis, beginning in the fetus as pre-cancerous
hyperproliferation that manifests itself as
TMD in the first weeks postnatally and
which thereafter regresses spontaneously to
complete remission11. In 20–30% of cases of
regressed DS‑TMD, the same dormant clonal
expansions that led to TMD accumulate other
changes, and 1–4 years later cause AMKL.
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PERSPECTIVES
The spontaneous regression of TMD has
not been explained mechanistically. Several
hypothetical explanations have been proposed, including sensitization of DS‑TMD
cells to apoptosis by the ectopic expression
of MYCN (a member of the MYC protooncogene family that is typically expressed
in neural tissue), which is increased in blast
cells of DS‑TMD, but not in blast cells of
DS-AMKL12. Another explanation invokes
an aberrant fetal-stage-specific response
that is mediated by insulin-like growth factor 2 (IGF2) produced by fetal liver stromal
cells, which enhances the proliferation of
DS‑TMD blast cells. This stimulation ceases
when haematopoiesis abandons the fetal
liver after birth13.
Some aspects of both myeloid and lymphoid leukaemias in DS set them apart from
those in euploid children: T21 and in uteroacquired typical mutations in the transcription factor GATA1 (which results in the
elimination of full-length GATA1 expression
and only the truncated GATA1s protein is
expressed) are always observed in proliferating cells of DS–TMD and DS–AMKL11,14,15.
DS‑ALL shows increased mutation of the
tyrosine kinase janus kinase 2 (JAK2)16,17,
and greater abundance of rearrangements at
the cytokine receptor-like factor 2 (CRLF2)
locus18,19, than non‑DS–ALL.
Germ cell tumours are also increased in
individuals with DS. Ovarian cancer shows
a small increase in some studies20. However,
germ cell tumours (in particular dysgerminomas), despite rarely occurring in non‑DS
individuals (~1% of all ovarian cancer), are
repeatedly observed in individuals with
DS20. There is also an increased occurrence
of extragonadal (mainly intra-cranial) germ
cell tumours21. Testicular germ cell tumours
(TGCTs) have significantly increased incidence and mortality, ranging from twofold to
12‑fold, compared with age-matched euploid
males6,9,22–26. Interestingly, as with childhood
leukaemias, the pre-invasive stage of TGCTs
begins in utero as intratubular germ cell neoplasia unclassified (IGCNU) in mid-trimester
T21 fetuses27. Although cryptorchidism
(undescended testicle) is more frequent in
DS, it alone cannot explain the increased
risk in TGCTs, as only 17% of DS testicular
tumours are associated with cryptorchidism28.
Further evidence indicates that T21 might be
a direct cause of increased testicular cancer:
63–90% of non‑DS testis cancer show a gain
of Homo sapiens chromosome 21 (HSA21)
(summarized in REF. 25), and delayed maturation of germ cells29, as well as IGCNU27,
are frequently observed in mid-trimester
DS fetuses, preceding the testis descent.
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PERSPECTIVES
Table 1 | Population-based studies of the epidemiology of cancer in Down’s syndrome*
Tissue
SIR‡ (REF. 6)
SIR26
SMR§ (REF. 32)
SMOR9
Leukaemia
17.63
10.5
1.7
1.57
Leukaemia age <10 years
42.3 (observed = 30;
expected = 0.71)
32.5 (observed = 10;
expected = 0.3)
2.22 (observed = 9;
expected = 4.05)
3.31 (observed = 164)
Leukaemia age
30–49 years
0 (observed = 0;
expected = 0.82)
6.25 (observed = 5;
expected = 0.8)
1.62 (observed = 2;
expected = 1.23)
1 (observed = 47)
0 (observed = 0; expected = 0.3)
0 (observed = 0; expected = 0.79)
0.37 (observed = 30)
Leukaemia age >50 years
Testis
1.86
4.8
Ovary
1.97
0.5
Other male genital
9.8
Prostate
3.23
0.07
0.11
0
0.08
Endometrial (uterus)
0.83
0.4
0.22
Eye
3.68
0
Brain
0.3
0.4
Lung
0.24
Skin
0.25
0.2
Breast
0
0.4
0.09
1.3
0.32
Gastric
0.09
0
0.02
0.06
0.04
Stomach
1.1
1.5
0.13
Colon
0.89
1.5
0.08
2.4
0.41
Liver
Pancreas
0.9
0.14
Kidney
0.84
0.5
0.08
Bladder
1.69
0
Unspecified
3.27
0
All solid tumours
0.5
0.57
0.12
0.07
All solid tumours age
<10 years
0.7 (observed = 1;
expected = 1.42)
0 (observed = 0; expected = 0.6)
0.32 (observed = 2;
expected = 6.32)
0.09 (observed = 10)
All solid tumours age
30–49 years
0.5 (observed = 9;
expected = 17.99)
0.7 (observed = 23;
expected = 32.7)
0.16 (observed = 5;
expected = 31.17)
0.12 (observed = 132)
All solid tumours age
>50 years
0.52 (observed = 12;
expected = 22.97)
0.3 (observed = 7;
expected = 23.3)
0.11 (observed = 3;
expected = 27.67)
0.04 (observed = 172)
Total cancers observed
60
54
35
689
Total DS individuals
2,814
3,581
793
17,897
0.2
0.13
*Two population-based studies of standardized incidence ratio (SIR) and two population-based studies of standardized mortality ratio (SMR) and standardized
mortality odds ratio (SMOR) between Down’s syndrome (DS) and age-matched euploid population cohorts are shown for solid tumours and leukaemia. Only tumour
types for which at least one relative incidence and one relative mortality result was published in the four studies were listed. A relative ratio of 1 indicates equality
between DS and normal populations, and <1 indicates a relative reduction in incidence or mortality for a particular tumour type in individuals with DS. For all solid
tumours and leukaemia, SIR, SMR or SMOR is additionally indicated for different age groups (<10, 30–49 and >50 years). ‡SIR in leukaemia is calculated for age
>30 years in REF. 6; this value is shown in the 30–49 year age group. §REF. 26 calculated SMR for different age groups; <5 years (shown in the <10 year age group),
35–54 years (shown in the 30–49 year age group) and >54 years (shown here in the >50 year age group). Studies carried out in specially selected populations based
on hospital or institution records were excluded from this table.
Ovarian dysgerminomas also seem to have a
fetal origin, as indicated by the expression of
the pre-meiotic marker OCT4 (also known
as POU5F1)20. Thus, cancer types that are
increased in DS share an in utero initiation
and a fetal pre-malignant stage.
Most solid tumours occur less frequently in
DS. It is apparent that most solid tumour
types have a reduced incidence6,23,26,30,31 and
mortality 9,32 in individuals with DS, with
the exception of testis cancer (TABLE 1).
Evidence is conflicting regarding the relative incidence of other male genital cancers
(mainly penis) and stomach cancers. Some
differently designed studies (not included in
TABLE 1) found solid tumour incidence22,25
or mortality 25,33 in DS to be similar to that
in normal controls. These studies, however, were carried out on specially selected
cohorts based on hospital or institution
records, matched against specially selected
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normal controls with other diagnoses,
which potentially confounds the findings25.
However, even in these studies25, careful
re‑computing of the standardized incidence ratio (SIR; the ratio of the number
of observed cancers in DS to the expected
number based on incidence in the agematched euploid population) for all solid
tumours — after the removal of stomach,
testis and other male genital cancers —
results in the relative incidence of 0.62.
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PERSPECTIVES
In contrast to leukaemias, a reduction
in incidence of most solid tumours in DS
paediatric age groups was found by studies
in European and Japanese populations6,31.
However, similar to leukaemias, the incidence
and mortality for solid tumours do not seem
to increase in late adulthood above the levels
found in the euploid population (TABLE 1).
Skewed profile of paediatric tumours in
DS. Interestingly, when the proportion of
tumours in the paediatric age group was
compared between different tissue types
in Denmark23, France34 and the European
Union35, a strikingly skewed picture
emerged, especially for neuroblastomas and
for tumours of the central nervous system
(CNS; considered as one group): for the
Danish and French studies the expected
incidence was 30% and 45% but the
observed incidence was 1% and 0% in DS
children, respectively 23,34. The relative abundance of Wilms’ tumour is also substantially
reduced23,34. These striking findings remain
unexplained, but fuel the discussion on
the possible underlying mechanisms, as
addressed below.
DS biology predicts cancer proneness
To emphasize the extent of the paradox of
the reduced incidence of solid tissue cancers in DS, it is important to briefly review
the biological features of DS that seem to
be general characteristics of cancer-prone
conditions.
Chromosome instability. There is on-going
debate about whether aneuploidies (constitutional or acquired) contribute causatively to
cancer development and progression36,37 and
whether they are detrimental to cell growth
and proliferation38, or whether they represent
consequences of uncontrolled proliferation
that is driven by mutations and other types
of changes39. Primary leukocytes from newborns with DS have elevated rates of acquired
random aneuploidy and asynchronous subtelomeric replication (including telomere
aggregates and telomere capture)40,41, and
adult DS fibroblasts acquire mosaicism42,43.
This indicates that DS cells have a higher rate
of whole chromosome instability (WCIN).
Other viable constitutional aneuploidy
syndromes and mouse models of non‑DS
aneuploidy have rates of WCIN that are
similar to those in DS44,45. In accordance
with prevailing theoretical expectation,
other constitutional aneuploidy syndromes
also seem to be more cancer-prone than
euploids46: Edward’s syndrome (T18),
Klinefelter’s syndrome (47XXY) and Turner’s
syndrome (XO) are all associated with a
higher susceptibility to developing solid
cancer. The only exception is breast cancer
in Turner’s syndrome, but this could be due
to the underdevelopment of the gonadal and
oestrogenic-stimulatory axis. Otherwise, in
contrast to DS, individuals with Edward’s
syndrome have a higher incidence of
Wilms’ tumours46, individuals with Turner’s
syndrome develop more neuroblastomas,
childhood CNS tumours, melanomas, and
skin, bladder, urethra and uterine cancers47,
and individuals with Klinefelter’s syndrome
develop more lung cancers and breast
cancers48 than euploid populations.
Segmental chromosomal instability
(S‑CIN) incidence is also increased in DS
leukaemia: although evidence is mixed
for DS-ALL18,49, DS‑AMKL shows much
higher levels of S‑CIN than other paediatric
AMLs50. Surprisingly, however, translocations involving one gene partner from
HSA21 (such as runt-related transcription
factor 1 (RUNX1)), which occurs frequently
in non‑DS leukaemia, are rarer in DS. Also,
the incidence of prostate cancer is drastically reduced in DS, despite one of the
early events in prostate cancer (in non‑DS
individuals) being the occurrence of the
ERG‑TMPRSS2 translocation51, both
partners of which reside on HSA21.
Increased DNA damage and defective DNA
repair. Much higher levels of ROS are measured in primary DS lymphocytes, fibroblasts
and neurons, leading to lipid peroxidation,
increased rates of DNA damage52–57 and
highly elevated rates of mitochondrial DNA
mutations53,58. Increased ROS levels are
partly caused by an increased ratio of the
HSA21‑encoded superoxide dismutase 1
(SOD1) activity relative to non‑HSA21encoded glutathione peroxidases59, leading
to the accumulation of hydrogen peroxide
(H2O2). Together, this contributes to a complex mitochondrial dysfunction, including the
dysfunction of respiratory complex enzymes,
which further increases levels of ROS52,59–62.
DS cells also have defective DNA-repair pathways, including the repair of single-strand
breaks and of apurinic and apyrimidinic
sites (which are repaired by the base excision
repair pathway)56,63–65. One study demonstrated that these features could contribute
to the pathogenesis of DS‑TMD. Defective
base excision repair was found in cells from
patients with DS‑TMD, connecting the range
of GATA1 mutations (a specific hallmark of
DS‑TMD) to the combined hyperactivity
of SOD1 and cystathionine β‑synthase
(CBS; which is on HSA21), creating increased
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G:C>T:A transversions and uncorrected
uracil misincorporations66, which could cause
increased mutations.
Immunodeficiency and susceptibility to
infections. Individuals with DS have a
higher frequency, severity, duration and
mortality of infections (usually of the upper
respiratory tract)9,67, a global thymic hypofunction, T and B cell lymphopenia, and a
complex skewing of post-thymic lymphocyte
maturation68. DS immune abnormalities
are present from early development, and it
is suggested that DS should be considered
as a non-monogenic primary immuno­
deficiency 69. Peculiarly, individuals with DS
have an increased proportion of circulating
γ‑δT cells70, which are thought to have a
central role in the lymphoid stress response
and immune surveillance of tumours71.
Susceptibility to infections increases risks
during chemotherapy, counteracting the
increased DS cancer cell susceptibility to
drugs72. Also, this potentially explains the
increased rates of stomach cancer in some
studies, despite the gastric cancer-associated
trefoil factor (TFF) family of tumour suppressor genes being on HSA21, as these
genes are silenced by Helicobacter pylori
infection73, and there is evidence of higher
rates of H. pylori infection in DS74,75.
The combination of increased oxidative
DNA damage, defective DNA repair and
compromised immune responses causes several well-known cancer-predisposing conditions. However, it remains unclear why, in
individuals with DS, these factors have few
visible effects, which are restricted to specific
cell lineages of the fetal period and which fail
to increase general cancer risk.
Oncogenes on HSA21. HSA21 is frequently
gained in non‑DS testicular cancer (resulting in T21)25 and is a sole-acquired cytogenetic event in ovarian carcinoma in non‑DS
individuals, which correlates with poor
prognosis76. T21 is also one of the most frequent sole-acquired cytogenetic changes in
non‑DS ALL, occurring in 22% of cases77;
and T21 occurs in 5% of non‑DS AML78.
This indicates that genes on HSA21 might
have oncogenic effects. The overexpression of
several genes on HSA21 with classical oncogenic functions in non‑DS cancer (TABLE 2)
would therefore be expected to increase
the incidence of the types of cancer that are
associated with these oncogenes in individuals with DS; however, this is not generally
observed. This could reflect cell type- and
context-dependent differences in transcription (and thus expression) of individual
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PERSPECTIVES
Table 2 | Genes on human chromosome 21 with roles in DS and non‑DS tumorigenesis
HSA21 gene Function
Association with non‑DS cancer
Association with DS cancer
Refs
USP25
Deubiquitylating enzyme
Deleted in non-small-cell lung carcinoma
Unknown
160,161
mir-let7c
MicroRNA that downregulates
RAS expression
Suppressor in lung cancer
Unknown
162
mir-125b2
MicroRNA that downregulates
p53 and its downstream targets,
and DICER1 and ST18
Overexpressed in ETV6‑RUNX1+ ALL,
onco-miR in mouse models of B cell ALL,
stimulates growth of prostate cancer cells and
downregulated in breast cancer
Overexpressed onco-miR in
TMD-AMKL
BTG3
Anti-proliferative, also involved in
neurogenesis
Deleted in oral squamous cell carcinoma
Unknown
164
mir-155
MicroRNA that downregulates
p53INP1
Overexpressed in B cell lymphoma and
pancreatic adenocarcinoma
Unknown
165
RUNX1
Transcription factor
Gain of HSA21 or segmental amplification
near RUNX1 (proposed primary event in B
cell precursor ALL). Frequent translocations
in acute leukaemias. ETV6‑RUNX1 fusion
in normal newborns can be 100‑fold higher
than the incidence of ETV6‑RUNX1+ ALL (this
translocation is much rarer in DS‑ALL). Deleted
or mutated in AML‑M0
Earliest disturbance of cell fate
at mesodermal colony stage and
increases haemogenic progenitor
cells
SIM2
Regulator of neurogenesis
Deleted in breast cancer
Unknown
DYRK1A
Kinase. Regulates levels or activity Unknown
of the tumour suppressors REST,
p53, the DREAM complex, Notch
and caspase 9
Cooperates with genetically
engineered GATA1s and MPL
mutations to cause AMKL in vivo in
a mouse model
86,
96–100,
104
ERG
Transcription factor involved in
many cellular processes
Boosts megakaryopoiesis,
cooperates with GATA1s mutation
to immortalize foetal liver
progenitors in mouse models of
DS. Essential for megakaryocytosis
phenotype in adult T21 model mice
51,80,
82,83,
85,170,
171
ETS2
Sensitizes cells to H2O2-induced,
Forms a complex with MYC and activates the
p53‑dependent apoptosis.
telomerase reverse transcriptase promoter in
Activates the expression of the
breast cancer cells
tumour suppressor locus CDKN2A
Dose-sensitive tumour repressor
(small intestine and colorectal
cancer). Cooperates with GATA1s
mutation to immortalize foetal liver
progenitors in mouse models of DS
83,
92–95,
172
TMPRSS2
Serine protease
TMPRSS2‑ERG fusions in 50–75% of prostate
cancer cases is oncogenic by activation of MYC
Unknown
51
TFF1
Possible protective role in the
epithelium
Deleted in stomach cancer, tumour suppressor
for gastric cancer in a mouse model
Unknown
173
Fused to EWSR1 in Ewing’s sarcoma. Increased
expression in myeloid leukaemias with
complex karyotypes. ERG is in an 18-gene
‘self-renewal’ expression signature in
haematopoietic stem cells and leukaemia
stem cells. TMPRSS2‑ERG fusions in 50–75%
of prostate cancer cases is oncogenic by
activation of MYC
81,163
128,
166–168
169
ALL, acute lymphocytic leukaemia; AMKL, acute megakaryoblastic leukaemia; AML‑M0, minimally differentiated acute myeloid leukaemia; BTG3, BTG family
member 3; CDKN2A, cyclin-dependent kinase inhibitor 2A; DS, Down’s syndrome; DYRK1A, dual-specificity tyrosine-phosphorylation regulated kinase 1A;
ETV6, ETS variant gene 6; EWSR1, Ewing’s sarcoma breakpoint region 1; GATA1s, GATA binding protein 1 short mutant form; HSA21, Homo sapiens chromosome 21;
miR, microRNA; REST, RE1‑silencing transcription factor; RUNX1, runt-related transcription factor 1; SIM2, single-minded homologue 2; ST18, suppression of
tumorigenicity 18; TFF, trefoil factor; TMD, transient myeloproliferative disorder; TMPRSS2, transmembrane protease, serine 2; p53INP1 (from TP53INP1), p53
inducible nuclear protein 1; USP25, ubiquitin-specific peptidase 25.
HSA21 genes conferred by constitutional T21
(REF. 79). Although some of these genes are
overexpressed in DS‑AMKL (such as ERG80
and mir-125b2 (REF. 81)), their direct role as
oncogenes in DS‑AMKL, although probably
contributory, awaits additional confirmation. Each of the three genes: ERG, ETS2 and
mir-125b2, when artificially overexpressed
to high levels in vitro, can cooperate with
the GATA1s mutation to immortalize fetal
liver progenitors in mouse models of DS81–83.
However, when present together in a constitutionally trisomic dose in vivo (in the Tc1
mouse model) these three genes do not lead
to leukaemia, even in the presence of the
GATA1s mutation84. An adult megakaryocyte hyperproliferative phenotype is seen in
Tc1 mice and in other mouse models of DS,
which is independent of the GATA1s mutation, and does not lead to leukaemia84. This
phenotype seems to be caused by the third
copy of ERG85.
So far, the only gene not known to be
an oncogene in non‑DS individuals, but
proved as such in DS‑AMKL, is dual specificity tyrosine phosphorylation-regulated
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kinase 1A (DYRK1A). Trisomy of DYRK1A
markedly increases the proliferation of
megakaryocytes in vivo in the DS mouse
model Ts1Rhr 86. This mouse model is trisomic for a 33‑gene segment (the DS critical
region shown in FIG. 1, which was identified
in studies of partial human trisomies as the
critical set of genes necessary for the main
DS phenotypes87). DYRK1A trisomy was
found to cooperate with the GATA1s mutation (a typical mutation seen in all cases of
DS‑TMD and DS‑AMKL) to increase the
proliferation of immature megakaryocytes86.
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Gain of a short segment of HSA21, which
included DYRK1A, has also been observed
in some cases of AML‑M0 (classified as the
minimally differentiated subtype according to the French-American-British (FAB)
classification system), both in DS and in
non‑DS individuals88,89. Recently, Crispino
and colleagues86 showed that the combination of three genetically engineered events,
GATA1s mutation, overexpression of the
myeloproliferative leukaemia virus oncogene
(MPL)-W515L mutant (similar to mutations
acquired in some patients with DS‑AMKL)
and trisomy of the 33‑gene segment used in
the Ts1Rhr mouse model, was sufficient to
induce AMKL when mouse bone marrow
cells were transplanted into lethally irradiated mice86. Intriguingly, the same molecular
mechanism by which DYRK1A is thought to
cause oncogenic effects in AMKL (through
the inhibition of the nuclear factor of activated T cells (NFAT) transcription factors)86
is also responsible for its anti-angiogenic
effects in solid tumours (discussed below).
Tumour suppressive mechanisms in DS
Some basic biological features of DS cells
have the potential to protect against cancer
progression. Primary fibroblasts from individuals with DS have a reduced ability to
migrate in vitro90 and reduced proliferation
rates compared with euploid cells90,91. This
indicates the presence of genes on HSA21
that encode inhibitors of the cell cycle and
migration motility. In addition, HSA21
encodes tumour suppressor genes (proved
directly using mouse models) and genes
that could have tumour suppressive activity,
either because they are frequently deleted
or inactivated in cancer cells, or because
they regulate known tumour suppressor
genes (FIG. 1; TABLE 2). A further mechanism
by which T21 might confer suppression of
tumour progression is by attenuating angiogenesis, which is a crucial process for the
expansion and survival of solid tumours.
Tumour suppressor genes. In a set of elegant
experiments, Reeves and colleagues92
showed that when adenomatous polyposis
coli (Apc)Min mice (which have an oncogenic heterozygous mutation in Apc that
consequently induces small intestine and
colon wall tumours) were crossed with a DS
mouse model, Ts65Dn (which is trisomic for
less than 50% of mouse equivalent HSA21
genes), the resulting progeny had a 44–50%
reduction in the number of tumours. This
effect persisted when ApcMin mice were
crossed with Ts1Rhr mice (which are trisomic for 33 genes). Importantly, when mice
Deletions and mutations
in non-DS cancer
Lung Oral
cancer cancer
Breast
cancer
AML-M0
Stomach
cancer
DS critical
region
HSA21
ERG
miR-125b2
RUNX1
DYRK1A
NFAT
ETS2
miR-1246
p53
DREAM
MAD2L1
M
G2
REST
Mitochondrial
apoptosis
G1
p16
S
G0
Figure 1 | Genes on Homo sapiens chromosome 21 that have direct roles in DS‑associated
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Reviews
| Cancer
cancer. A detailed overview of all the genes with direct and indirect evidence
involvement
in
Down’s syndrome (DS) and non‑DS‑associated tumorigenesis is provided in TABLE 2. The cell cycle,
mitotic or apoptosis end points of specific gene and pathway actions are shown. Red indicates oncogenic functions and green indicates tumour suppressive or tumour repressive functions. Coloured
outlines signify genes with putative and indirect oncogenic (red) or tumour suppressive (green) roles
in cancer, and red or green filled colour signifies genes with strong evidence for their actions in cellular
or animal models. Loci on Homo sapiens chromosome 21 (HSA21) that are deleted or mutated in
non‑DS cancer are also shown. The DS critical region is a chromosomal segment that was previously
believed to be sufficient to cause, in trisomy, the most prominent phenotypic features of DS, in this
figure it is intended to correspond exactly to the syntenic segment of mouse chromosome 16, which
is triplicated in the Ts1Rhr mouse model of DS. AML‑M0, minimally differentiated acute myeloid leukaemia; DYRK1A, dual-specificity tyrosine-phosphorylation regulated kinase 1A; miR-1246, microRNA‑1246; NFAT, nuclear factor of activated T cells; REST, RE1‑silencing transcription factor; RUNX1,
runt-related transcription factor 1; T21, trisomy 21.
with monosomy of the same region (Ms1Rhr
mice) were crossed with ApcMin mice, the
number of tumours rose by 101%92. This
proves that this region of HSA21 contains
powerful, dose-sensitive tumour-suppressive
activity.
The authors then crossed the Ts1Rhr
ApcMin mice with Ets2+/− mice, which
eliminated most, but not all, of the tumoursuppressing activity. This shows that ETS2 is
a tumour suppressor in these types of cancer,
but that there are also other genes in the
33‑gene segment with tumour-suppressive
activity. The authors of this study made
additional important points92: this 33‑gene
region of HSA21 is not known to be frequently deleted in cancer; therefore, they
introduced the term ‘tumour repressor’ for
ETS2, because of its dose-dependent association with tumour frequency. Interestingly,
had DS not been viable (like most aneuploid
concepti) this tumour-repressive activity
of ETS2 would not have been discovered
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easily (if at all). Indeed, ETS2 was originally
considered oncogenic because it forms a
complex with MYC and activates the telomerase reverse transcriptase (TERT) promoter
in breast cancer cells93. The tumour-repressing
mechanism or mechanisms of ETS2 remain
unknown, but a clue to this mechanism could
be its ability to activate the p53‑mediated
apop­totic pathway by promoting the transcription of TP53 (REF. 94). Interestingly,
ETS2 can be induced by oxidative stress95,
which hints towards a possible tumourdefence mechanism in DS cells (discussed
below). More studies are needed to examine
whether the tumour-repressor effects of
ETS2 trisomy extend to other cancer types,
in order to assess its overall contribution to
the suppression of solid tumours in DS.
Indirect evidence of tumour suppressive
activity. The 33‑gene segment that is triplicated in Ts1Rhr mice contains additional
colon and intestinal tumour-suppressive
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© 2012 Macmillan Publishers Limited. All rights reserved
PERSPECTIVES
activity that cannot be explained by the
increased gene dosage of ETS2 (REF. 92), and a
plausible candidate for this additional activity is DYRK1A. There are several possible
tumour-controlling roles of DYRK1A. For
example, it regulates apoptotic processes in
development: inhibiting apoptosis in retinal
precursors by directly phosphorylating and
inhibiting caspase 9 (REF. 96), and it promotes
apoptosis by directly phosphorylating — and
thus stabilizing — p53 (REF. 97). DYRK1A
can also promote cell cycle exit by directly
phosphorylating LIN52 (a component of
the DREAM complex that represses the
expression of cell cycle-dependent genes
during quiescence)98, and by promoting the
transcription of the cyclin-dependent kinase
inhibitor CDKN1B (which encodes p27)99.
Finally, DYRK1A regulates the expression
of RE1 silencing transcription factor (REST;
also known as NRSF)100. REST controls
neurogenesis and is a potent tumour suppressor gene for mammary epithelial cell
transformation101, colon cancer 101 and lung
cancer 102. The alteration of REST expression
could also contribute to WCIN as it controls
the level of MAD2L1, an important protein
in the mitotic spindle assembly checkpoint103.
Similar alterations in REST expression can
be caused by either hyperexpression or hypoexpression of DYRK1A100,104,105 in a tissue
type- and cell type-dependent manner 104.
The mechanism by which DYRK1A regulates
REST is unknown, but it could involve a negative feedback loop105. DYRK1A also forms
a negative feedback loop with p53: DYRK1A
activates p53 by phosphorylation97, whereas
p53 induces the expression of mir-1246
which, in turn, reduces the level of DYRK1A
expression, in response to DNA damage106.
The involvement of DYRK1A in the
feedback regulation of two powerful
tumour suppressor genes predicts that the
dose of DYRK1A is strictly regulated in a
spatiotemporal manner in response to differentiation, proliferation and stress stimuli.
Moreover, through the control of REST and
p53, DYRK1A has the potential to affect
the expression of a myriad of tumourcontrolling genes. Intriguingly, the ability of
DYRK1A overexpression to inhibit another
transcription factor, NFAT, is oncogenic
for DS-AMKL86 (discussed above), but is
anti-angiogenic in solid tissues (discussed
below). Therefore, trisomy of DYRK1A has a
unique cell-context-dependent contribution
to both increase the likelihood of DS‑AMKL
and suppress solid tumours in DS107. Other
HSA21 genes with indirect evidence for
tumour suppressive activity are shown in
FIG. 1 and TABLE 2.
Trisomy 21 attenuates angiogenesis. Solid
tumour growth depends on the ability to
generate sufficient vasculature that connects
the rapidly expanding mass to the host circulation. Therefore, a plausible mechanism
for the reduction of solid tumours in DS, as
opposed to leukaemias, is the attenuation of
angiogenesis caused by T21. Attenuation
of angiogenesis cannot be responsible for
suppressing tumour initiation, but rather
for suppressing the expansion and progression of solid tumours, and must therefore
cooperate with other tumour suppressive
mechanisms to result in the epidemiological
profile of the reduced incidence of most solid
tumours in DS. Multiple T21‑driven mechanisms are independently capable of inhibiting angiogenesis. For example, higher plasma
levels of endostatin (a 20 kD C‑terminal
fragment of collagen XVIII‑α1 (COL18A1),
which is an HSA21 gene) have been found
in individuals with DS108. Endostatin has
undergone clinical trials as a potent antiangiogenic drug in cancer treatment109. This
and other mechanisms have recently been
unravelled (FIG. 2). The HSA21 gene regulator
FLT1 and KDR
NFAT
of calcineurin 1 (RCAN1) was found to
suppress vascular endothelial growth factor A (VEGFA)-mediated pro-angiogenic
signalling by the calcineurin pathway 110,111.
Calcineurin, which is inhibited by RCAN1, is
the main phosphatase of the NFAT transcription complex cytosolic component (NFATc;
the main transducer of VEGFA signalling), allowing the nuclear translocation of
NFATc by dephosphorylation. The growth
of B16F10 melanoma cells was inhibited
>sixfold when injected into Ts65Dn mice111.
When these mice were crossed with Rcan1+/−
mice (reducing the dose of Rcan1 to disomy)
tumour growth and microvessel density
was restored by approximately 50%, which
demonstrates that Rcan1 functions as an
anti-angiogenic gene, but that other HSA21
genes also have an important anti-angiogenic
role111. However, this experimental system is
not without caveats: angiogenesis attenuation
by T21 seems to be confined to xenografts of
hyperaggressive tumour cell lines111, but does
not occur in xenografts of newly derived
tumour cell lines or in endogenous tumours
that are generated in mouse models112.
P
Endothelial cell
HSA21
JAM2
ADAMTS1
RCAN1
ERG
DYRK1A
PTTG1IP
P
NFAT
Calcineurin
P
P P P
NFAT P
P
DYRK1A
COL18A1
Endostatin
VEGFA response
Endothelial cell proliferation,
migration and vessel formation
Figure 2 | Anti-angiogenic effects of genes in trisomy 21. An endothelial
cell from| tumourNature Reviews
Cancer
induced angiogenesis with the molecular involvement of Homo sapiens chromosome 21 (HSA21)encoded proteins is shown. ADAMTS1, ADAM metallopeptidase with thrombospondin type 1 motif
1; DYRK1A, dual-specificity tyrosine-phosphorylation regulated kinase 1A; FLT1, fms-related tyrosine
kinase 1; JAM2, junctional adhesion molecule 2; KDR, kinase insert domain receptor; NFAT, nuclear
factor of activated T cells; P, phosphorylation; PTTG1IP, pituitary tumour-transforming 1 interacting
protein; RCAN1, regulator of calcineurin 1; VEGFA, vascular endothelial growth factor A.
6 | ADVANCE ONLINE PUBLICATION
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PERSPECTIVES
An additional contributor to the antiangiogenic effects is DYRK1A, which phosphorylates and thereby causes the nuclear
export of NFATc113. The combined trisomy
of DYRK1A and RCAN1 amplifies the inhibition of NFAT signalling 113. Surprisingly,
the DS anti-angiogenic story does not end
here, as transchromosomic Tc1 mice bearing a supernumerary HSA21 (REF. 114)
(which was only 81% complete and lacked
RCAN1) show an equally strong inhibition
of transplanted melanoma growth, angiogenesis and VEGFA signalling 115. Using
an in vitro angiogenesis system, trisomy of
each of four HSA21 genes: ADAM metallo­
peptidase with thrombospondin type 1
motif 1 (ADAMTS1), ERG, junctional
adhesion molecule 2 (JAM2) and pituitary
tumour-transforming 1 interacting protein
(PTTG1IP) was shown to inhibit VEGFA
signalling, through unknown mechanisms115.
This demonstrates the complexity of antiangiogenic mechanisms in DS and the need
for further studies on this topic.
Stem cell availability and fitness
The combination of the pro-cancer biological features and the inhibition of angio­
genesis in trisomy 21 cells could be predicted
to increase the risk of cancers that do not
depend on angiogenesis (leukaemias) and
decrease the risk of cancers that do (solid
tumours). However, these mechanisms
cannot easily explain some prominent
epidemiological findings: why is testicular
cancer increased in individuals with DS
(despite being a solid tumour type that
depends on angiogenesis)? As all cancers
that have increased incidence in DS seem
to originate in utero, why are predominant
tumour types of neonatal and paediatric age
(neuroblastoma and Wilms’ tumour) so rare
in DS? Why do leukaemias in children with
DS have a substantially different range of
acquired oncogenic events from leukaemias
in euploid children? Is the ageing-driven
increase in cancer incidence and mortality for the DS population compared with
euploid population in line with theoretical
expectation? If not, why? Although these
questions remain unanswered, recent studies
hint at biological features of DS that provide
fresh perspectives and suggest that additional
mechanisms are involved.
Skewed progenitor cell profile. Various fetal
tumours, or fetal tissue-derived tumours,
have been described in DS116–119. Also,
almost all tumour types that are markedly
more frequent in DS are initiated in utero:
for example, TMD-AMKL15,120, ALL121,
dysgerminoma20 and TGCTs27. Indeed, the
observed fetal tumours in DS might only
be the ‘tip of the iceberg’ as up to 75% of
T21 pregnancies are lost owing to first trimester spontaneous miscarriage122, and the
contribution of uncontrolled cell growth to
this in utero mortality remains unknown.
Paradoxically, the most frequent tumours
of fetal origin in the euploid population
(neuro­blastomas, other CNS tumours and
Wilms’ tumour) are extremely rare in DS23,34.
Intriguingly, this tissue distribution is
reflected in the effects of T21 on the differentiation of embryonic stem cells (ESCs)
in vitro, in a transchromosomic model
(mouse ESC with a supernumerary HSA21).
T21‑ESCs produce defective neural stem
cells (NSCs) that exhibit high levels of
apoptosis123. This result reproduces in an
isogenic human induced pluripotent stem
cell (hiPSC) model comparing hiPSC lines
that are genetically identical and that differ only in having three or two HSA21
(D.N., unpublished observations), as well as
embryoid bodies (the first in vitro structure
obtained when ESCs stop being cultured in
pluripotent condition and are allowed to differentiate) with a significant reduction of the
neuroectodermal progenitor compartment,
suggesting aberrant DS‑ESC differentiation100. Genetic dissection in the transchromosomic ESC system has linked this cell
fate disturbance to the gene dosage and
kinase activity of DYRK1A100. Interestingly,
T21‑ESCs that are grown in vivo as teratomas have a significantly reduced proportion
of neural tissue (which was replaced by
undifferentiated embryonic carcinomalike cells)124. These models partly mirror
observations of altered neurogenesis when
primary human fetal T21‑NSCs are grown as
neurospheres125.
In addition, in NPcis genetically engineered mice — that are haploinsufficient for
Trp53 and neurofibromatosis 1 (Nf1), which
causes them to develop sarcomas, lymphomas
and carcinomas with 100% penetrance — the
tissue profile of tumours that developed was
skewed away from sarcomas originating from
neural crest cells when induced in a mouse
model of DS112. The proportion of malignant
peripheral nerve sheath tumour (MPNST),
a neuroectodermal sarcoma, was reduced by
>50% in Ts65Dn mice112. This demonstrates
a substantial shift in the profile of cancer
types, which is consistent with disturbed
differentiation within the neuroectodermal
compartment caused by T21.
An additional mechanism that might
limit the potential of some types of brain
tumours could be the defective response
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of DS NPCs to the morphogen growth factor sonic hedgehog (SHH)126, which is an
important driver of brain tumorigenesis127.
The correlation of reduced numbers and
vitality of NSCs with the paucity of neural
tumours cannot, however, explain the lack
of Wilms’ tumour in DS, as Wilms’ tumour
originates from immature mesodermal stem
and progenitor cells. Perhaps its underrepresentation in DS derives from skewed
cell fate within mesodermal colonies caused
by T21. The transchromosomic T21‑ESCs
produce mesodermal colonies with an
increased proportion of haematopoietic stem
cell (HSC) precursors and increased haematopoietic colony-forming potential, with
significantly increased numbers of immature
haematopoietic progenitors128, which is also
the case for primary cells derived from T21
fetal liver 129,130. Genetic dissection using the
transchromosomic system identified trisomy
of RUNX1 and possibly other genes, but not
trisomy of ERG or ETS2, as responsible for
these phenomena128. The fetal liver is also the
site where GATA1 mutations are acquired in
DS-TMD120, and where immature and transient progenitor cells, which are sensitive to
the effects of the same mutations in GATA1,
have been detected131. However, even in the
absence of GATA1 mutations, hydrops fetalis
leading to perinatal deaths of DS neonates
has been described to be caused by rampant
megakaryopoiesis132,133.
Increased cellularity in other haemato­
poietic compartments also occurs in DS:
80% of DS neonates have neutrophilia
(increased levels of neutrophils in the blood)
and 15–33% have polycythaemia (increased
levels of red blood cells in the blood)134. The
polycythaemia could be explained by the
congenital heart defects and hypoxia that
occur in people with DS, although the association between polycythaemia and thrombocytopenia (reduced levels of platelets in
the blood)134 fits with the cell fate skewing
at the level of megakaryocyte-erythroid progenitor (MEP), the bi‑potential precursors of
red blood cells and platelets.
Together, these data suggest that DS‑ESCs
have skewed cell fate on several levels during in vitro and in vivo differentiation, and
the resulting absolute numbers of lineagespecific stem and progenitor cells could
determine the pool size of cells that are
receptive to cancer-initiating events, increasing the numbers of some pools (for example,
haematopoietic) and severely depleting others (for example, neural) (FIG. 3). We speculate
that this would create conditions of increased
chance for the acquisition or fixation of preleukaemogenic rearrangements or mutations
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PERSPECTIVES
Neutrophilia
↓ Neuroblastomas
AML
DS-AMKL
↓ Neuroectoderm
progenitors
T21-ESC
Other hits
↑ Mesoderm
progenitors
↑ Germ cell
progenitors
?Polycythaemia
↑ Haemogenic
endothelial
progenitors
↓ Other
mesenchymal
progenitors
IGCNU, intra-cranial germ
cell tumours and dysgerminomas
↓ Wilms’
tumour
HSC
↑ CMP
↑↑ MEP
↑↑ CFU-GEMM
↑ Endothelial
stem cells
GATA1
and JAK3
mutations
DS-TMD
MPL, p53
mutations
and other hits
↑ B-precursors JAK2 and CRLF2
mutations
↑ CLP
↓ T-precursors
DS-ALL
↓ T leukaemias
Lymphangiomas
(hygromas)
TGCT
Figure 3 | Stem cell fate and ageing abnormalities in DS that might
affect tumorigenesis. Hypothetical skewing of cell fate during Down’s
syndrome (DS) embryonic stem cell (ESC) differentiation and its effect on
the resulting numbers of tissue-specific stem and progenitor cells available for tumorigenesis is shown. The hypothesis is based on concordance
between fetal and childhood DS tumour epidemiology, data on primary
DS fetal cells and transchromosomic trisomy 21 (T21) ESC mouse models.
Up arrows indicate relative excess and down arrows indicate relative
shortage of a particular stem or progenitor cell or tumour type in T21 compared with euploidy. Small groups of cells signify benign or pre-malignant
hyperproliferation, large groups of cells signify tumour types that are rarer
(such as of GATA1, JAK3, JAK2 and CRLF2
(REFS 14–19,135–137)) in both lymphoid and
myeloid lineages during fetal haematopoiesis,
contributing to the increased risk of both
types of leukaemia in children with DS.
Conversely, the pools of cells in which initiating events occur that cause Wilms’ tumour,
neuroblastoma and CNS tumours could be
reduced in children with DS.
This explanation alone cannot easily
account for the unique range of acquired
mutations in DS‑AMKL, or for the preference for specific acquired events in DS‑ALL,
which are distinct from euploid leukaemias.
One would also have to postulate that very
specific target cell types, which are responsive to exactly those mutations, are present
in higher numbers in DS haematopoiesis.
These two explanations are not mutually
exclusive: cell types that are meant to exist
only transiently in normal fetal development
Reviews of
| Cancer
(indicated in green) or more frequent (red) in DS.Nature
The acquisition
known
mutations or gene rearrangements is also indicated. ALL, acute lymphocytic leukaemia; AMKL, acute megakaryoblastic leukaemia; AML, acute
myeloid leukaemia; CFU-GEMM, colony-forming-unit of granulocyte
erythrocyte monocyte megakaryocyte (mixed lineage); CLP, common lymphoid progenitor; CMP, common myeloid progenitor; CRLF2, cytokine
receptor-like factor 2; ESC, embryonic stem cell; HSC, haematopoietic
stem cell; IGCNU, intra-tubular germ cell neoplasia unclassified; JAK,
janus kinase; MEP, megakaryocyte-erythrocyte progenitor; MPL, myeloproliferative leukaemia virus oncogene; TGCT, testicular germ cell
tumour; TMD, transient myeloproliferative disorder.
could persist and accumulate owing to differentiation retardation in individuals with DS.
Evidence for this mechanism has been seen
in the testes from fetuses with DS, which had
highly immature germ cells29, and this was
hypothesized to be an initiating factor that
leads to TGCTs in DS29. In addition, mouse
studies have indicated that transient MEPs
are the only haematopoietic cell type that is
responsive to the GATA1s mutation131.
Accelerated stem cell ageing. Age-dependent
telomere attrition in neutrophils, B lymphocytes and T lymphocytes is >threefold higher
in DS138, and the difference in telomere
length, relative to euploid controls, is detectable at fetal stage139. Adult mouse models
of DS have an accelerated stem cell ageing
phenotype, defective HSC and lymphoid
progenitor cell compartments in the bone
marrow, with lower proliferation capability
8 | ADVANCE ONLINE PUBLICATION
and a higher rate of apoptosis140. There
are also differences in telomere shortening between tissues: although primary DS
leukocytes, HSCs and NSCs lose replicative
potential faster than euploid controls125,138,139,
primary DS skin fibroblasts do not 91 (even
though they replicate more slowly). Data are
lacking for other cell types.
Compelling evidence supports the view
that stem cell ageing increases the selective
advantage and transformative success of
oncogenic mutations (reviewed in REF. 141).
As DS stem cells show accelerated ageing,
it would thus be reasonable to expect that
cancer incidence and mortality should
increase in ageing individuals with DS
over and above the rate found in the agematched euploid population. The available
epidemiological data (although scarce for
ageing individuals with DS) do not support
this expectation23 (TABLE 1). Could DS thus
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© 2012 Macmillan Publishers Limited. All rights reserved
potentially teach us a different lesson about
the relationship between cellular ageing and
tumorigenesis?
Hyper-reactive response to DNA damage. DS
cells are much more sensitive to genotoxic
stress142. Buccal fibroblasts have increased
markers of DNA damage and cell death143.
DS‑AML (but not DS‑ALL) cells are >20‑fold
more susceptible to cytotoxic cancer therapy
than euploid cells72, although the mechanism
behind this might potentially involve the
presence of GATA1s144. Mitochondria of
peripheral mononuclear cells from the blood
of individuals with DS without a leukaemia
diagnosis lose mitochondrial membrane
potential more rapidly after treatment with
cytotoxic agents61. Increased telomere attrition, as well as the apoptosis-inducing action
of several proteins encoded on HSA21 — for
example, DYRK1A97, ETS2 and PBX/knotted homeobox 1 (PKNOX1)94,95,142 — could
trigger an amplified apoptotic DNA damage
response (DDR) to genotoxic stress145–148 in
DS cells. The DDR has been shown to act
as a biological barrier against the progression of early, pre-invasive stages of human
tumours145,147. There is an interesting correlation between DS solid tumour epidemiology,
constitutive activation of the DDR mediators
p53‑binding protein 1 (53BP1) and mediator of DNA damage checkpoint protein 1
(MDC1) in tumour samples from euploid
individuals. Constitutive activation of these
mediators was seen in lung and breast cancer
(tumours that are less frequent in DS), but
not in TGCTs (which is more frequent in
DS)149, indicating that the activation of the
DDR might suppress the progression of some
types of cancers in DS.
A ‘transformation fit’ stem cell exhaustion
threshold? A picture emerges of an accelerated cellular ageing process in DS that
begins in utero, coupled with substantial
sensitivity to genotoxic stress, under conditions of constantly increased oxidative DNA
damage, which may exhaust cellular fitness
in a large proportion of cells prematurely,
creating an increasing number of cells that
have aged beyond a hypothetical ‘exhaustion threshold’, rendering them unable to
sustain oncogenic transformation (FIG. 4).
This hypothesis is highly speculative, as it is
currently difficult to find corroborative data
that are free of other confounding factors. DS
individuals obviously maintain regenerative
capacity in all tissues as they live well into
their sixties5. Although clinical features that
fit with reduced regenerative capacity are far
more abundant in DS than in age-matched
In utero
Birth
PERSPECTIVES
0–10 years
11–49 years
50–65 years
N
DS
Young stem cells
First oncogenic hit
Pre-malignant hyperproliferation
Multiple oncogenic hits
Progressive cellular ageing
Stem cell aged above the hypothetical ‘exhaustion
threshold’; no longer fit to sustain development of
intraclonal genetic diversity for oncogenesis
Malignant
tumour
Elimination (i.e. DDR apoptosis,
hypoxia, immune surveillance
or other)
Nature
Reviews
| Cancer
Figure 4 | Exhaustion-threshold model for the transformation fitness of
ageing
DS stem
cells.
A speculative attempt to explain the paradox of accelerated stem cell ageing in Down’s syndrome (DS)
that fails to increase the cancer incidence and progression in the ageing DS population above levels
of the euploid (N) population is shown. Four life stages are considered for normal and DS stem cells.
Each hypothetical cell fate can be followed in the same grid position from left to right. The numbers
of circles are for illustrative purposes only, but DS versus euploid comparisons within each specific age
group reflect differences in overall levels of stem cell ageing, rates of DNA damage accumulation, rates
of elimination through DNA damage response (DDR) signalling and other mechanisms, and the emergence of cells that passed the hypothetical ‘threshold’ (indicated by empty circles). The relative (DS
versus normal) incidence of pre-malignant and malignant tumours is not intended to exactly replicate
epidemiology (as this would be difficult to show for all tumour types) but rather to highlight the
incidence trend through the age groups.
euploids (such as chronic periodontitis,
alopecia, xerosis, delayed wound healing,
osteoporosis and immunosenescence)55,150–152,
there are other (equally good) explanations
for many of these symptoms, such as primary
immunodeficiency (with autoimmunity) and
endocrine dysfunction69,152. Arguments about
numbers and ‘fitness’ of potential target
cells that are responsive to tumour initiation
diminishing with age has been explored in
cancer pathogenesis153: young mice154 and
children155 are more susceptible to radiationinduced ALL, whereas young women156 are
more susceptible to radiation-induced breast
cancer than their respective older control
cohorts. Individuals with DS have a substantially reduced incidence of second malignancies following radiation therapy, even at a
juvenile age23. This suggests that the range
and numbers of stem cells that have the level
of fitness necessary for Darwinian selection
to drive cancer progression157 are severely
reduced in individuals with DS very early in
life (probably, on average, in young adulthood). Haematological studies for the adult
DS population are sparse, but data suggest
NATURE REVIEWS | CANCER
that myelodysplastic syndrome without progression to AML is not uncommon in adults
with DS158, and a non-malignant (including extra-medullary) hyperproliferation of
megakaryocytes has been described in aged
(15‑month-old) animals of three different
mouse models of DS that do not progress to
AMKL, even when GATA1s is expressed84.
Accelerated ageing and the extraordinary
sensitivity of DS cells to genotoxic stress
could thus reduce the numbers of susceptible
cells in older individuals with DS that are
needed to establish sufficient intra-clonal
genetic heterogeneity (variegation), thought
to be the main substrate for Darwinian selection of subclones that drive cancer progression153,157. One should emphasize that we do
not envisage this model to be an exclusive
explanation, but rather one in combination
with other described mechanisms.
Concluding remarks
Studies have barely scratched the surface of
the relationship between DS and cancer, and
much more research is needed on the action
of HSA21‑encoded oncogenes and tumour
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© 2012 Macmillan Publishers Limited. All rights reserved
PERSPECTIVES
suppressors (or repressors), as well as the
mechanisms of angiogenesis inhibition, stem
cell differentiation and ageing. The advent of
iPSC technology 159 and the development of
more refined mouse models will test some
of the above hypotheses. Also, more cancer
epidemiological and translational research is
needed on adults and ageing individuals with
DS. Nevertheless, some unique lessons have
already be learned, which have the potential
to inform our thinking about cancer therapy.
First, it is fascinating that a fairly modest
constitutive increase in the expression of a
relatively small number of genes (probably
only a subset of genes on HSA21)87 can have
a domineering effect on tumorigenesis and
tumour suppression. Second, novel tumourrepressive effects can be induced by increasing the dose of genes previously unknown to
be deleted, mutated or silenced in cancer 92.
Third, it teaches us that a combination of different cancer-protective mechanisms (decelerating cell cycle progression, increased DDR
or multiple ways of inhibiting angiogenesis)
is more powerful than the sum of its parts in
suppressing tumorigenesis, and is successful
in overcoming otherwise strong cancerpredisposing factors. Last, DS is a unique
platform in which to study the relationship
between tumorigenesis, ageing and the numbers of available cells that are fit for cancer
initiation and propagation.
Dean Nižetić and Jürgen Groet are at The Barts and
The London School of Medicine and Dentistry,
The Blizard Institute, Centre for Paediatrics, and Stem
Cell Laboratory, National Centre for Bowel Research
and Surgical Innovation, Queen Mary University of
London, 4 Newark Street, Whitechapel,
London E1 2AT, UK.
Correspondence to D.N. e-mail: [email protected]
doi:10.1038/nrc3355
Published online 21 September 2012
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Acknowledgements
The authors thank the AnEUploidy-Consortium EU‑FP6, the
Leukaemia and Lymphoma Research UK, Barts and The
London Charity, British Society of Haematology, the Jerome
Lejeune Foundation, the Kay Kendall Leukaemia Fund, and
the LonDownS Consortium strategic funding award from The
Wellcome Trust for funding their recent and current work.
Competing interests statement
The authors declare no competing financial interests.
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