review
Li-Fraumeni syndrome: a paradigm for the understanding of
hereditary cancer predisposition
Jessica M. Valdez, Kim E. Nichols and Chimene Kesserwan
Division of Cancer Predisposition, St. Jude Childrens Research Hospital, Memphis, TN, USA
Summary
Li-Fraumeni syndrome (LFS) is a rare cancer predisposing
condition caused by germline mutations in TP53, the gene
encoding the TP53 transcription factor. LFS is typified by the
development of a wide spectrum of childhood and adult-
onset malignancies, which includes, among others, the lym-
phoid and myeloid leukaemias, myelodysplastic syndrome
and, to a lesser extent, lymphoma. Accordingly, it is impor-
tant that haematologists/oncologists be familiar with this
pleiotropic hereditary cancer syndrome. The high cancer risk
and variability in type and age of cancer onset have raised
questions about the underlying biology and optimal treat-
ment approaches for individuals with LFS. Since its descrip-
tion almost 50 years ago, many clinical and basic research
investigations have provided insights into the pathogenesis,
manifestations, genetic testing and management strategies for
individuals with LFS. Here we provide an update on the cur-
rent state of knowledge regarding LFS with an emphasis,
where possible, on information relevant to practicing haema-
tologists.
Keywords: Li-Fraumeni syndrome, cancer predisposition,
germline, TP53, mutation.
Li-Fraumeni syndrome (LFS) is a prototypical cancer predis-
posing syndrome first described in 1969 by Drs. Frederick Li
and Joseph Fraumeni following their retrospective analysis of
children with rhabdomyosarcoma (RMS) (Li & Fraumeni,
1969a,b). Since their initial report, many studies by these and
other investigators have revealed that LFS is a rare autosomal
dominant disorder that confers an increased risk to develop
six common core cancers, including soft tissue sarcomas
(STS), osteosarcoma (OS), premenopausal breast cancer, cen-
tral nervous system (CNS) tumours, adrenocortical carci-
noma (ACC) and leukaemia (Malkin et al, 1990). A wide
Correspondence: Chimene Kesserwan, Division of Cancer
Predisposition, St. Jude Childrens Research Hospital, Chilis Care
Center I3312, MS1170, 262 Danny Thomas Place, Memphis, TN
38105, USA.
E-mail: chimene.kesserwan@stjude.org
2016 John Wiley & Sons Ltd, British Journal of Haematology
spectrum of other benign and malignant neoplasms is also
observed (Nichols et al, 2001).
A breakthrough in the understanding of LFS occurred in
1990 when Malkin et al (1990) demonstrated that individuals
with LFS harbour germline mutations in TP53 the gene
encoding the TP53 transcription factor (tumor protein p53,
TP53; previously termed p53). Also known as the guardian
of the genome, TP53 plays a central role in cellular growth
control by regulating the expression of numerous down-
stream genes involved in cell cycle arrest, apoptosis, DNA
repair and senescence, particularly in response to DNA dam-
age and other cellular stressors (Vousden & Prives, 2009;
Reinhardt & Schumacher, 2012). TP53 was examined as an
LFS candidate gene based on observations that somatic TP53
mutations were prevalent in the majority of human cancers,
including those seen in LFS (Nigro et al, 1989). Furthermore,
transgenic mice expressing mutant Trp53 alleles developed
LFS-type cancers, including OS, STS and lymphoid neo-
plasms (Lavigueur et al, 1989). A heterozygous germline
TP53 mutation was identified in each of the five families
analysed by Malkin et al (1990), and in one family, the
mutation co-segregated with tumour formation. At the same
time, an unrelated kindred harbouring a germline TP53
mutation was reported by Srivastava et al (1990). Taken
together, these formative observations confirmed that muta-
tions in TP53 occur not only as common somatic events in
cancer, but also as rare germline events in individuals with
LFS.
The spectrum of cancers observed in LFS
One of the most striking features of LFS is the remarkable
tendency for affected individuals to develop solid and haema-
tological cancers. The risk for germline TP53 mutation carri-
ers to develop one or more neoplasms is estimated to be
50% by age 3031 years for females and age 46 years for
males (Mai et al, 2016). Remarkably, this risk nears 70100%
by age 70 years for both sexes (Mai et al, 2016). Collectively,
the core cancers comprise the majority of LFS-related
tumours (Table I) (Bougeard et al, 2015; Mai et al, 2016).
Among these, breast cancer is the most common and
accounts for approximately 2530% of all cancers in LFS
families (Gonzalez et al, 2009b). Unlike BRCA1- and BRCA2-
doi: 10.1111/bjh.14461
Review

Table I. LFS core cancer type known characteristics.

Core cancer type Prevalence in LFS Age distribution (Median) Tumour phenotype

Adrenocortical 613% (Gonzalez et al, 2009a;
carcinoma Bougeard et al, 2015;
Id Said et al, 2016;
Mai et al, 2016)
Breast cancer 2731% (Gonzalez et al, 2009a;
Id Said et al, 2016)
First 5 years of life (Rodriguez-
Galindo et al, 2005) (3 years)
Fewer than 10% of patients
are 15 years or older at diagnosis
(Ribeiro et al, 2000)
Pre-menopausal women
(33 years) (Olivier et al, 2003)
ACC harbouring somatic ATRX
mutations are larger, more likely to be
advanced stage and associated with a
poorer prognosis (Pinto et al, 2015)
Invasive ductal carcinoma commonly
ER and PR positive and/or HER2/neu
amplified (Masciari et al, 2012;
Melhem-Bertrandt et al, 2012;
Bougeard et al, 2015)

CNS tumour (choroid 914% (Gonzalez et al, 2009a;
plexus carcinoma, Bougeard et al, 2015;
medulloblastoma, Wasserman et al, 2015;
gliomas) Id Said et al, 2016)
Soft tissue sarcomas 17
827%
(rhabdomyosarcoma) (Bougeard et al, 2015;
Id Said et al, 2016)
Biphasic with first peak in childhood
and second peak at 2040 years
of age (Palmero et al, 2010)
(16 years) (Olivier et al, 2003;
Tabori et al, 2010;
McBride et al, 2014)
Prior to age 5 years
(Olivier et al, 2002;
Palmero et al, 2010) (3
6 years)
(Hettmer et al, 2014)
Medulloblastoma of Sonic hedgehog
subtype (SHH) (Zhukova et al, 2013)
and presence of chromothripsis
Non-alveolar, anaplastic
rhabdomyosarcoma (Hettmer et al,
2014), mostly embryonal
rhabdomyosarcoma (ERMS)

Osteosarcoma 13
416%
(Bougeard et al, 2015;
Id Said et al, 2016)
Leukaemia 24% (Gonzalez et al, 2009a;
Bougeard et al, 2015)
Prior to age 18 years in children
(14 years). Few reported cases
in adults up to age 55 years
(Bougeard et al, 2015)
Children and young adults
(12 years) (Bougeard et al, 2015)
No clear phenotypic differences between
OS occurring in individuals with LFS
versus those without LFS
Hypodiploid phenotype (Pui et al, 1987;
Nachman et al, 2007; Holmfeldt et al,
2013; Malkin et al, 2014)

ACC, adrenocortical carcinoma; CNS, central nervous system; ER, oestrogen-receptor; LFS, Li-Fraumeni syndrome; OS, osteosarcoma; PR,
progesterone receptor.

associated hereditary breast cancer, which can affect men as
well as women, breast cancer appears to occur exclusively in
women with LFS (Malkin, 1994). In female germline TP53
mutation carriers, the breast cancer risk increases at approxi-
mately 20 years of age and continues into adulthood, with
the median age of breast cancer onset being 33 years (Sorrell
et al, 2013; Bougeard et al, 2015). Consistent with this find-
ing, 38% of women with apparently sporadic breast cancer
who present under the age of 30 years harbour a germline
TP53 mutation (Mouchawar et al, 2010; McCuaig et al,
2012). Many LFS-associated breast cancers exhibit oestrogen
and progesterone receptor positivity, and HER2/neu amplifi-
cation (Masciari et al, 2012; Melhem-Bertrandt et al, 2012;
Bougeard et al, 2015). Malignant phyllodes tumours, uncom-
mon fibroepithelial lesions of the breast, are also infrequently
reported (Birch et al, 2001; Villani et al, 2016).
Together, STS and OS comprise 2538% of LFS-related
malignancies (Gonzalez et al, 2009a; Ognjanovic et al, 2012)
and are the most common cancers in children and adoles-
cents. The prevalence of STS has been reported to range
from 17
8% to 27%, while OS has a slightly lower prevalence
of 13
416% (Bougeard et al, 2015). RMS often occurs
before the age of 5 years (Diller et al, 1995; Ognjanovic et al,
2012; Hettmer et al, 2014) and OS before the age of 30 (Mir-
abello et al, 2015). In a study of 15 children with non-alveo-
lar anaplastic RMS, Hettmer et al (2014) found that all five
children diagnosed under 3 years of age, and six of eight
(75%) diagnosed between 3 and 7 years of age, harboured a
germline TP53 mutation. Thus, children with non-alveolar
anaplastic RMS, or individuals with early onset OS warrant
consideration for LFS, particularly if there is a positive family
history of cancer. Other STS are rarely encountered, includ-
ing, liposarcoma, leiomyosarcoma and several less well
defined subtypes (Ognjanovic et al, 2012).
Neoplasms of the CNS account for 914% (Gonzalez et al,
2009a; Sorrell et al, 2013; Bougeard et al, 2015) of LFS
tumours with the most common type being glioblastoma/as-
trocytoma. Medulloblastoma, ependymoma, supratentorial
primitive neuroectodermal tumours and choroid plexus car-
cinomas (CPC) are also reported (Sorrell et al, 2013). The
age of onset of CNS cancers is biphasic with the first peak in
childhood and a second peak at 2040 years of age (median

2 2016 John Wiley & Sons Ltd, British Journal of Haematology


16 years) (Olivier et al, 2003; Tabori et al, 2010; McBride
et al, 2014). There is a strong relationship between LFS and
CPC, with up to 100% of children with CPC harbouring a
germline TP53 mutation, regardless of whether or not there
is also a positive family history of cancer (Krutilkova et al,
2005; Gonzalez et al, 2009a; Tabori et al, 2010). Among chil-
dren with medulloblastoma, those with aberrant activation of
the Sonic Hedgehog pathway are most likely to harbour
germline TP53 mutations (Zhukova et al, 2013) as are those
whose tumours contain somatic TP53 mutations or evidence
of chromothripsis (catastrophic DNA rearrangements)
(Rausch et al, 2012; Zhukova et al, 2013).
Adrenocortical carcinoma adevelops in 613% (Kleihues
et al, 1997; Gonzalez et al, 2009a; Bougeard et al, 2015; Mai
et al, 2016) of LFS patients with a bi-modal age distribution
peaking before 5 years of age and again in the fourth to fifth
decades of life. Studies of children with what appears to be
sporadic ACC reveal a 3080% prevalence of germline TP53
mutations (Wagner et al, 1994; Libe & Bertherat, 2005; Pinto
et al, 2015; Wasserman et al, 2015). The R337H TP53 foun-
der mutation (see below, Genotype-Phenotype Correlations),
which is present in up to 0
3% of the Southern Brazilian
population, is well-recognized to be associated with the
development of ACC in Brazilian children (Ribeiro et al,
2001; Custodio et al, 2012).
Leukaemia, including acute lymphoblastic leukaemia
(ALL), acute myeloid leukaemia (AML) and myelodysplastic
syndrome (MDS), exhibit a prevalence of 24% in germline
TP53 mutation carriers (Gonzalez et al, 2009a; Ruijs et al,
2010; Bougeard et al, 2015). Lymphoma occurs slightly less
often, with a prevalence of 2% (Bougeard et al, 2015). The
median age of onset is 12 (range 235) for leukaemia and
13 years (range 242) for lymphoma (Bougeard et al, 2015).
There is a paucity of published literature detailing the AML,
MDS and lymphoma subtypes that occur in individuals with
LFS. However, when ALL occurs in the context of LFS, it
often exhibits a pre-B cell low hypodiploid phenotype in
which the leukaemic cells contain 3239 chromosomes,
although other ALL subtypes have also been described
(Holmfeldt et al, 2013; Malkin et al, 2014). In a large geno-
mic profiling study involving 124 cases of childhood hypodi-
ploid ALL, Holmfeldt et al (2013) reported that
approximately 91
2% of the low hypodiploid samples exhib-
ited somatic TP53 mutations, the majority of which were
homozygous as a result of loss of the wild-type TP53 allele.
Remarkably, almost half of the studied cases demonstrated
presence of the same TP53 mutations within non-tumour
cells, suggesting that these were germline alterations. Zhang
et al (2015) also described that 19% of children with hypodi-
ploid ALL harbour germline TP53 mutations. In the report
by Holmfeldt et al (2013), somatic TP53 mutations were also
observed in 10 of 11 (90
9%) low hypodiploid ALL samples
obtained from adult patients; however, none had evidence of
a germline TP53 mutation. Together, these findings suggest
that TP53 mutations are a hallmark of the low hypodiploid
2016 John Wiley & Sons Ltd, British Journal of Haematology
Review
phenotype and that paediatric, but not adult low hypodi-
ploid, ALL may be considered a rare manifestation of LFS.
To date, one family presenting with leukaemia as a pri-
mary manifestation of LFS has been reported. Powell et al
(2013) described a Hispanic kindred in which five individuals
were diagnosed with leukaemia. One case of ALL exhibited
doubling of a hypodiploid clone; the cytogenetic findings
related to the other cases was not discussed. Exome sequenc-
ing of this kindred revealed a p.R306X germline mutation,
which has been previously identified in both somatic and
germline samples, generally in association with the more typ-
ical cancers seen in LFS. The unique leukaemia predilection
in this kindred suggests the potential existence of an as yet
unidentified genetic modifier associated with the develop-
ment of haematopoietic cancers in the TP53 mutation carri-
ers in this family (Powell et al, 2013).
In addition to the core cancers, LFS patients develop addi-
tional malignancies, many of which occur at earlier than
expected ages, including colorectal, lung, pancreatic, mela-
noma, prostate, kidney, testicular, laryngeal, head and neck
and ovarian cancers (Varley et al, 1997; Chompret et al,
2000; Nichols et al, 2001; Olivier et al, 2003; Wong et al,
2006; Gonzalez et al, 2009a; Ruijs et al, 2010).
LFS and the risk for second primary and
therapy-associated cancers
Li-Fraumeni syndrome patients are more likely to develop
multiple primary and therapy-related cancers, a proportion
of which are haematological. Among 200 patients from 24
LFS kindreds reported by Hisada et al (1998), 30 (15%)
developed a second cancer, eight (4%) a third cancer and
four (2%) a fourth cancer. In this study, the relative risk of
occurrence of a second cancer was 5
3 times greater than that
of the general population, with a cumulative probability of
second cancer development of 57% at 30 years following the
diagnosis of a first cancer. Remarkably, the relative risk of a
second cancer was 83-times higher for individuals with LFS
who developed a first cancer during childhood. Mai et al
(2016) recently reported similar results where about 49% of
germline TP53 mutation carriers with a first cancer devel-
oped at least one other cancer after a median time period of
10 years.
Data describing the factors contributing to development
of therapy-related cancer in LFS are limited; however, it is
probable that these partly result from the carcinogenic effects
of the radiation (RT) and/or chemotherapy used to treat the
previous cancer(s). Findings supporting this notion include
laboratory data in which RT-treated fibroblasts from LFS
patients exhibit compromised cell cycle arrest and increased
chromosomal aberrations compared to wild-type fibroblasts
(Boyle et al, 2001; De Moura et al, 2010). Following a single
exposure to 1 or 4 Gy of irradiation, Trp53 heterozygous
mice exhibit a marked reduction in tumour latency when
compared to wild-type Trp53 animals (Kemp et al, 1994).
3
Review

Consistent with these findings, several case reports and small
case series describe an increased prevalence of solid cancers
in LFS patients who receive RT versus those who do not,
with some tumours arising within the radiation field (Hey-
mann et al, 2010; Pierce & Haffty, 2011). Despite these
observations, little remains known about the true prevalence
of RT-induced cancers, as well as their relationship to radia-
tion dose, age at treatment with RT, and/or the tissue being
radiated.
Germline TP53 mutations may also contribute to therapy-
associated leukaemias and MDS. Towards this end, a study
of 53 patients with therapy-associated myeloid neoplasms
revealed four (7
5%) harboring germline TP53 mutations
(Schulz et al, 2012). Similarly, a study of 47 breast cancer
survivors with secondary leukaemia identified three (6%)
individuals with germline TP53 alterations (Churpek et al,
2016). In the latter study, two of these three individuals
developed ALL, an unusual treatment-related haematopoietic
malignancy. Compared to primary ALL developing in chil-
dren with germline TP53 mutations, these two cases of pre-
sumed therapy-related leukaemia did not exhibit a
hypodiploid phenotype. Hence, for cancer patients who
develop secondary ALL, regardless of its cytogenetic make-
up, consideration should be given to germline TP53 testing
(for further discussion see below, Clinical Management).
The TP53 gene and its encoded protein
TP53 is located at chromosome 17p13.1 and spans approxi-
mately 20 kb of genomic DNA. It is composed of 14 exons
including ten that encode the full length 393-amino acid
TP53 protein, one non-coding exon (exon 1) and three alter-
native exons (exons 2/3, 9b, 9c) (Hainaut & Pfeifer, 2016).
The TP53 functional domains consist of an N-terminal tran-
scriptional activation domain, proline-rich region, DNA
binding domain, tetramerization domain and C-terminal reg-
ulatory domain (Fig 1) (Beckerman & Prives, 2010). It was
initially proposed that TP53 functioned as an oncogene given
the finding that many tumours expressed increased levels of
the TP53 protein (Rotter, 1983; Eliyahu et al, 1984).
However, Baker et al (1989) showed that there was muta-
tional inactivation of one TP53 allele with loss of the second
wild-type allele in two colorectal cancers studied. Around
this time, Finlay et al (1989) demonstrated that oncogene-
driven cellular transformation could be inhibited by forced
expression of wild-type TP53. Collectively these and other
observations revealed that TP53 served as a tumour suppres-
sor and not as an oncogene as originally proposed.
In unstressed cells, TP53 levels are kept low via a nega-
tive-regulatory feedback mechanism mediated by the E3
ubiquitin ligase Mouse Double Minute 2 homolog (MDM2),
whose expression is induced by TP53. MDM2 binds to the
N-terminal domain of TP53 and covalently attaches ubiqui-
tin, thus marking TP53 for degradation by nuclear and cyto-
plasmic proteasomes (Fig 2). Accordingly, in normal cells,
TP53 is very unstable, with a half-life ranging from 5 to
30 min (Moll & Petrenko, 2003). Following exposure to
genotoxic stressors, such as ionizing radiation, oxidative
stress and nucleotide depletion, TP53 and MDM2 become
phosphorylated. As a result, the MDM2-TP53 interaction is
weakened. This weakening lessens TP53 degradation, allow-
ing TP53 to accumulate, self-associate and bind to specific
DNA sequences. Functional TP53 tetramers then induce the
expression of numerous downstream target genes that regu-
late critical cellular processes, such as cell cycle arrest, apop-
tosis and DNA repair.
The role of TP53 in the haematopoietic
compartment
The haematopoietic compartment exhibits a remarkable and
dynamic capacity for regeneration. Under normal conditions,
haematopoietic stem cells (HSC), the precursors from which
all blood cells arise, remain quiescent with only a small frac-
tion entering the cell cycle and giving rise to differentiating
progenitors that replenish cells that are lost due to normal
processes, such as aging. In contrast, under conditions of
stress, such as trauma or exposure to cytotoxic therapies,
HSC must proliferate to maintain and/or expand their pool
while replacing those cells that are actively damaged or lost.

Transcriptional activation TP53 DNA-binding Nuclear Regulation

domain domain localization signal domain

50 100 150 200 250 300 350

Proline-rich region Zinc binding site Oligomerization domain

Fig 1. Schematic depicting the TP53 protein (Zhou et al, 2016). TP53 is comprised of 393 amino acids and contains several functional domains,
including: (i) N-terminal transcriptional activation domain; (ii) Proline rich region; (iii) DNA binding domain; (iv) Oligomerization domain,
which facilitates the formation of TP53 dimers and tetramers; and (v) C-terminal domain involved in down-regulation of DNA binding. TP53
also contains critical zinc binding sites, which enables the proper protein folding that is required for site-specific DNA binding and transcriptional
activation. The nuclear localization signal facilitates movement into the nucleus, where TP53 can exert its effects. Numbers represent position of
amino acid residues from N- to C-terminus. (Figure re-drawn from https://pecan.stjude.org/proteinpaint/TP53.)

4 2016 John Wiley & Sons Ltd, British Journal of Haematology

 Review

UV Radiation Hypoxia

DNA Damage Oncogenes

TP53 Degradation

Wt- Wt-
TP53 TP53
Wt- Wt- Mut- Mut-
TP53 TP53 TP53 TP53
Wt- Wt-
TP53 TP53
Wt- Wt- Wt- Wt-
TP53 TP53 TP53 TP53
Wt- Mut-
TP53 TP53

MDM2 MDM2
DNA Repair
Wt- Wt- Mut- Wt-
TP53 TP53 TP53 TP53
Normal Impaired
Cell Cycle Arrest Function Function
Wt- Wt- Wt- Mut-
TP53 TP53 TP53 TP53

Apoptosis

(A) (B)

Fig 2. Functions of TP53. (A) In response to cellular stress signals, wild-type TP53 tetramers bind to DNA (in green) and trigger the activation
of genes responsible for a myriad of functions including DNA repair, cell cycle arrest, apoptosis and senescence. During the course of these activi-
ties, TP53 induces expression of MDM2, leading to TP53 degradation through proteasomal degradation. (B) In contrast to wild-type TP53,
mutant TP53 proteins cannot bind effectively to DNA (in grey), resulting in impaired functions, including poor induction of MDM2 and hence
TP53 accumulation.

Within the haematopoietic compartment, TP53 is mainly
expressed in HSC, where it is essential for maintaining HSC
quiescence, self-renewal and genomic integrity (Asai et al,
2011; Pant et al, 2012). Evidence for the importance of
TP53 in HSC quiescence comes from the study of mice in
which Trp53 or the genes encoding TP53 regulators such as
Mdm2 have been deleted, overexpressed or mutated.
Towards this end, Trp53-null HSC enter the cell cycle more
readily than wild-type cells (Liu et al, 2009). Consistent
with these findings, Trp53-null mice exhibit a two- to
three-fold increase in Lineage Sca-1+ c-kit+ (LSK) cells (a
bone marrow population containing HSC) as well as
CD150+ CD48 LSK, which are enriched for long term
repopulating cells (Liu et al, 2009; Asai et al, 2011). Addi-
tional proof that TP53 is important in HSC comes from
bone marrow transplantation studies in which TP53-defi-
cient bone marrow cells out compete TP53-expressing cells
in competitive repopulation assays (Liu et al, 2009). Based
on these findings, it has been suggested that the transient
inhibition of TP53 function could be used to promote bone
marrow recovery following chemo- or radiation therapy by
allowing for increased HSC proliferation and/or self-
renewal. Indeed, small molecule inhibitors known as
pififthrins are under development for these purposes (Asai
et al, 2011).
In addition to its role as a regulator of HSC quiescence
and self-renewal capacity, TP53 is important for regulating
HSC fitness, where too little or too much TP53 activity can
compromise the ability of HSC to repopulate the marrow. As
noted above, Trp53-null HSC exhibit increased proliferative
and short term repopulating capacity. Nonetheless, they are
inferior to their Trp53-sufficient counterparts when it comes
to long-term repopulation (Asai et al, 2011). Similarly, too
much TP53 is detrimental. The latter is made evident in
mice with high basal levels of TRP53 activity, such as those
harbouring additional copies of the Trp53 gene or animals
haploinsufficient for the TP53 inhibitor Mdm2, which exhibit
enhanced radiosensitivity and poor haematopoietic recovery
following exposure to low levels of ionizing radiation. Collec-
tively, these and other studies reveal that TP53 is a critical
protein whose levels and activity must be carefully regulated
within HSC to prevent leukemogenesis and promote home-
ostasis of the haematopoietic compartment under normal
and stressful conditions (Asai et al, 2011; Pant et al, 2012).
Mechanism by which TP53 contributes to
tumour formation
There are several proposed mechanisms by which the mutant
TP53 protein promotes tumour formation. These

2016 John Wiley & Sons Ltd, British Journal of Haematology 5

Review
mechanisms include the loss of its tumour suppressor func-
tion (LoF) or conversely, the acquisition of dominant nega-
tive (DN) or gain of function (GoF) effects. The loss of
tumour suppressor function is caused by reduced TP53
expression or altered TP53 function. Reduced expression can
result from genomic deletions that remove all or part of
TP53, while altered function stems from missense mutations
that affect its functional domains. Consistent with the latter,
many LFS-associated TP53 mutations reside within the criti-
cal DNA binding domain. These mutations produce mutant
TP53 proteins with impaired DNA binding and thus altered
regulation of downstream target genes.
Missense mutations in TP53 can also exert a DN effect in
which the mutant TP53 protein physically interacts with and
inhibits the function of wild-type TP53. This property was
initially shown by Milner et al (1991), where in vitro co-
translation of wild type and mutant TP53 enabled the forma-
tion of complexes containing both proteins. Willis et al
(2004) provided further insights into the properties of these
aberrant complexes. By examining the functions of cell lines
expressing both wild-type and mutant TP53, these investiga-
tors demonstrated that the presence of mutant TP53 greatly
reduced the ability of the wild-type protein to bind to pro-
moters of TP53-responsive target genes. Indeed, the DN
effect may explain why some TP53 mutation carriers exhibit
retention of the wild-type TP53 allele within their tumours.
Towards this end, Varley et al (1997) demonstrated that only
57% of tumours from patients with germline TP53 muta-
tions showed loss of the wild-type allele and retention of the
mutated allele. A subset of these patients was also analysed
by Birch et al (1998), who noted that all tumours that
retained both TP53 alleles developed in individuals who har-
boured germline missense mutations within the DNA bind-
ing domain. This was in contrast to individuals harbouring
null mutations, where loss of both alleles was invariably seen
in the tumours (Birch et al, 1998).
The GOF effect is characterized by acquisition of novel
properties by mutant TP53 independent of the presence of
the wild-type TP53 protein. Early evidence supporting the
oncogenic function of mutant TP53 was derived from the
observation that introduction of mutant TP53 into Trp53-
null cells allowed for tumour outgrowth in mice. Cells com-
pletely devoid of TP53 form tumours that spontaneously
regress. In contrast, cells expressing mutant TP53 exhibit
lethal outgrowth (Wolf et al, 1984). Brosh and Rotter (2009)
elegantly review the properties by which mutant TP53 medi-
ates the GOF effect. One key mechanism involves the inacti-
vation of TP63/TP73 (p63/p73) proteins by mutant TP53;
TP63 and TP73 are considered TP53-related proteins. When
overexpressed, TP63/TP73 induce growth arrest and apopto-
sis in a TP53-like manner. Mutant TP53 binds to TP63/TP73
and aborts their ability to dampen cell proliferation and pro-
mote apoptosis. Another important mechanism involves the
modulation of expression specific target genes by mutant
TP53. Once such example includes transcriptional up
6 2016 John Wiley & Sons Ltd, British Journal of Haematology
regulation of the ATP binding cassette subfamily B member
1 gene (ABCB1; also termed multidrug resistance 1 gene,
MDR1) by mutant TP53, which confers drug resistance to
cancer cells harbouring somatic TP53 mutations (Chin et al,
1992). Additional genes that are aberrantly regulated by
mutant TP53 include NFKB1, MYC, EGR1 and TERT, among
others (Brosh & Rotter, 2009). Therefore, whereas wild-type
TP53 regulates the expression of genes that mediate growth
suppression, apoptosis and DNA repair, mutant TP53,
through mechanisms that are not completely defined, regu-
lates the expression of genes that enable cell proliferation,
drug-resistance, survival and metastasis.
Regardless of the mechanism of action, mutations affecting
TP53 perturb its many functions, leading to aberrant tran-
scription, altered MDM2-TP53 interactions, mutant TP53
accumulation, deregulated cell cycle progression and
impaired mechanisms of DNA repair (Fig 2).
The spectrum of TP53 mutations in individuals
with LFS
The distribution of TP53 germline mutations in LFS is simi-
lar those identified in tumours, with the majority clustered
within the DNA binding domain where there are six recur-
rent hotspot mutations involving codons 175 (R175H), 245
(G245S), 248 (R248Q, R248W), 273 (R273H) and 282
(R282W) (Wasserman et al, 2015). Functional studies reveal
that, among the mutations most commonly examined, the
majority exerts a DN effect (Petitjean et al, 2007). Mutations
in intronic or regulatory regions are also reported; however,
their functional significance remains to be elucidated. The
International Agency for Research on Cancer (IARC) main-
tains a well-established repository of somatic and germline
TP53 mutations. The current release (R18, April 2016, http://
p53.iarc.fr) includes 885 families harbouring 360 unique
TP53 mutations. Among the germline TP53 mutations
included, missense alterations constitute about 73%, non-
sense 8
89%, splice site 8
16%, frameshift 5
66%, silent
0
55%, large deletions 0
73%, intronic 0
61% and other
mutations (complex rearrangement, insertions, deletions)
2
07%.
Genotypephenotype correlations in LFS
In keeping with experimental data that not all TP53 mutants
function equally, several genotype-phenotype studies involv-
ing LFS families have suggested that the type of germline
TP53 mutation may serve as a predictor of tumour type and
age of cancer onset. Birch et al (1998) examined 34 families
meeting classic clinical criteria for LFS and observed that
families harbouring missense mutations within the TP53
DNA binding domain had a more highly penetrant pheno-
type than families with other (nonsense or truncating) or no
mutations. Most recently, Bougeard et al (2015) observed a
significantly earlier age of tumour onset for patients with

missense mutations (mean age of tumour onset 23
8 years)
compared to those with frameshift or in-frame deletions/in-
sertions, nonsense mutations and genomic rearrangements
(28
5 years). The difference was even greater when missense
mutations were compared to genomic rearrangements corre-
sponding to extreme forms of null alterations (35
8 years).
Additionally, patients whose mutations were known to exert
a DN effect exhibited an even earlier age at cancer onset
(21
3 years). Interestingly, ACC appear to be the only type of
LFS-associated cancer consistently associated with germline
mutations occurring outside the DNA-binding domain, with
the majority of patients carrying mutations that are not
dominant-negative missense mutations (Bougeard et al,
2015).
The concept that different germline TP53 alterations con-
fer variable oncogenic potential is further illustrated in the
unique phenotype of carriers of the TP53 R337H mutation,
which exhibits a high prevalence as a founder mutation in
Southern Brazil (Ribeiro et al, 2001). This mutation is
located within the tetramerization domain and was first iden-
tified by its strong association with an increased risk for
childhood ACC. A recent study showed that among 292 chil-
dren diagnosed with paediatric cancer in Southern Brazil, 11
(3
7%) carried TP53 R337H, nine of whom were diagnosed
with ACC and two with CPC (Giacomazzi et al, 2013). The
fact that none of the carrier parents in this study had cancer
at the time of writing of this report suggested that the TP53
R337H mutation was associated with a lower penetrance
compared to other germline TP53 mutations. Although ini-
tial reports suggested that the main cancer risk associated
with the TP53 R337H mutation was the development of
childhood ACC, more recent studies reveal that this muta-
tion can be also be identified in patients with CPC, OS,
breast cancer and, more recently, neuroblastoma (Giacomazzi
et al, 2013; Seidinger et al, 2015; Andrade et al, 2016). All
told, it is likely that TP53 R337H predisposes to the more
typical cancers seen in LFS, albeit with a lower penetrance.
Genetic modifiers influencing the phenotype in
germline TP53 mutation carriers
The variability in age of onset and type of cancers occurring
in TP53 mutation carriers, even those within the same fam-
ily, has supported the notion that factors other than the
germline TP53 mutation influence disease presentation.
Indeed, many studies have sought specific genetic modifiers
and examined their effect on disease penetrance and expres-
sivity, as well as on the levels or function of mutant TP53. In
this regard, a single nucleotide polymorphism (SNP) within
the first intron of MDM2 (NM_002392.3:c.14+309T>G;
SNP309; rs2279744) has been associated with an earlier age
of tumour onset in LFS (Bond et al, 2004; Bougeard et al,
2006; Ruijs et al, 2007). Bond et al (2004, 2006) studied 88
individuals with LFS and demonstrated an accelerated age of
cancer onset in association with SNP309. Specifically,
2016 John Wiley & Sons Ltd, British Journal of Haematology
Review
individuals harbouring the heterozygous G/T or homozygous
G/G genotype developed STS an average of 12 years earlier
and breast cancer 10 years earlier than those carrying the
homozygous wild-type T/T genotype. In LFS patients with
STS, the number of primary tumours was also higher in
those with SNP309G/T or G/G. Mechanistic studies have
revealed that the G allele for SNP309 results in higher levels
of MDM2 mRNA and protein, resulting in increased degra-
dation of TP53 and thus defective TP53-mediated apoptosis
(Bond et al, 2004, 2006). The early age at cancer onset con-
ferred by MDM2 SNP309 is further amplified by presence of
a common polymorphism in codon 72 of TP53
(NM_000546.5 (TP53): c.215C>G ;rs1042522) in which the
proline (P) at codon 72 is replaced by arginine (R). Thus,
compared to TP53 containing P72, TP53 R72 binds MDM2
with higher affinity, resulting in enhanced degradation. The
presence of MDM2 SNP309 and TP53 R72 was shown to
have a cumulative effect and associated with earlier age of
cancer onset (Malkin, 2011).
Recently, a second MDM2 polymorphism, denoted
SNP285G>C (rs117039649), was reported to be in linkage
with the SNP309G allele. In a large study of 195 LFS
patients, this haplotype was shown to influence cancer onset
with cancers occurring 5 years earlier in those with the
MDM2 285309 GG haplotype compared to other haplo-
types (Renaux-Petel et al, 2014). In this study, the interaction
between this MDM2 haplotype and the TP53 codon 72 poly-
morphism was not examined. Additional genetic factors have
been reported as potential modifiers of the LFS phenotype,
including a 16-base pair insertion/duplication in intron 3 of
TP53 (rs17878362) (Marcel et al, 2009), a SNP within a
microRNA known as miR-605 (rs2043556) (Id Said et al,
2016), and the presence of germline DNA copy number vari-
ants (Malkin, 2011). The extent to which these modifiers
reliably and consistently influence LFS phenotype remains to
be determined.
To date, there are no reports of genetic modifiers linked
specifically to the development of haematopoietic cancers in
individuals with LFS.
Genetic testing for LFS
Following the discovery of TP53 as the causative gene in LFS
in 1990, there was caution regarding the provision of germ-
line genetic testing because, at the time, there was limited
understanding of how genetic test results would influence
clinical management and significant concerns regarding the
psychological effects associated with a positive test result.
With time, however, a better understanding has emerged
regarding the natural history of LFS and the possible
approaches to tumour surveillance and cancer risk reduction.
In addition, studies of the psychological and emotional con-
sequences of testing, while limited, have revealed that adults
undergoing LFS testing do not experience long-term adverse
psychological consequences (Lammens et al, 2010a).
7
Review
Accordingly, pre-symptomatic and diagnostic germline TP53
testing are now more widely accepted by families and health-
care providers. Given the clinical and psychological complex-
ities of LFS, it is strongly recommended that genetic testing
for this condition be completed by haematologists, oncolo-
gists, genetics professionals or other providers who are famil-
iar with this condition and only in the context of pre- and
post-test genetic counselling (Malkin, 2011).
One of the key issues to be contemplated when offering
germline TP53 genetic analysis to a patient with leukaemia
or MDS is that testing cannot always be performed using a
sample of blood. In patients with active disease or positive
minimal residual disease (MRD) status, it may be difficult to
determine whether an identified mutation is constitutional or
originating from circulating neoplastic cells. Indeed, with the
increased sensitivity of next generation sequencing, it is now
possible to detect mutations present at a frequency of 10%
or less. Therefore, presence of a TP53 mutation could reflect
germline mosaicism or alternatively, presence of a leukaemic
or MDS clone. Saliva samples and cells obtained by buccal
swabbing are often considered as alternative sources of DNA
for genetic testing. Unfortunately, neoplastic cells may also
contaminate these samples. Ideally, testing should involve the
analysis of skin fibroblasts obtained from a punch skin
biopsy. This procedure is more invasive and requires 6
8 weeks to generate cells for testing; however, it provides the
best chances for the most accurate diagnosis.
LFS classification criteria
To facilitate the identification of individuals and families
with suspected LFS and provide guidelines for germline TP53
genetic testing, several classification systems have been devel-
oped (Table II). According to the classic and most stringent
criteria, LFS is defined by the presence of: (i) a proband with
a sarcoma diagnosed before the age of 45 years; (ii) a first
degree relative with any cancer before the age of 45 years;
and (iii) a first- or second-degree relative with any cancer
before the age of 45 years or a sarcoma at any age (Li et al,
1988). More inclusive classification systems have been created
for those families that do not meet classic criteria, but
nonetheless exhibit an LFS-like or LFL phenotype. The first
was reported by Birch et al (1994), and includes families in
which the proband has: (i) any childhood cancer or a sar-
coma, CNS tumour or ACC diagnosed before the age of
45 years; (ii) a first or second degree relative with an LFS-
type tumour at any age; and (iii) a first or second degree rel-
ative with any cancer before the age of 60 years. The second
was reported 1 year later (Eeles, 1995) and includes families
with two-first or second degree relatives with an LFS tumour
at any age. A more recent classification scheme, was put
forth by Chompret et al (2001) and revised in 2009 (Tinat
et al, 2009). Although more restrictive than the Birch or
Eeles criteria in terms of the cancer types and ages of onset
in the proband, the Chompret criteria take into account the
8 2016 John Wiley & Sons Ltd, British Journal of Haematology
fact that some individuals with LFS do not necessarily need a
positive family of cancer in order to warrant consideration of
germline TP53 testing. The revised Chompret criteria recom-
mend testing for a proband with: (i) an LFS-type tumour
diagnosed before the age of 46 years and at least one-first or
second degree relative with an LFS-type tumour before the
age of 56 years or with multiple primary tumours; (ii) multi-
ple primary tumours diagnosed before the age of 46 years,
two of which are LFS component tumours, regardless of the
family history; or (iii) an ACC or a CPC at any age, regard-
less of the family history (Tinat et al, 2009).
Currently, germline TP53 testing is most commonly con-
sidered for individuals meeting classic or Chompret criteria
or to any females with early-onset breast cancer who lack a
BRCA1 or BRCA2 mutation. As noted above, children with
low hypodiploid ALL or any individuals with therapy-
Table II. Li-Fraumeni syndrome diagnostic and testing criteria.
Classic LFS criteria (Li et al, 1988)
Proband diagnosed with sarcoma before age 45 years
AND first degree relative with a cancer diagnosed before age
45 years
AND a first-degree or second-degree relative with any cancer
with onset before age 45 years
OR a sarcoma at any age
70% probability of identifying a germline TP53 mutation
(Varley, 2003)
Birch LFL criteria (Birch et al, 1998)
Proband with any childhood cancer, sarcoma, brain tumour or
adrenocortical carcinoma with onset less than 45 years of age
AND a first-degree relative with either breast cancer, sarcoma,
brain tumour, adrenocortical carcinoma or leukaemia with onset at
any age
AND a first-degree relative with any cancer with onset before
60 years of age
2040% probability of identifying a germline TP53 mutation
(Varley, 2003)
Eeles LFL criteria (Eeles, 1995)
Two first-degree or second-degree relatives with either breast
cancer, sarcoma, brain tumour, or leukaemia at any age
2040% probability of identifying a germline TP53 mutation
(Varley, 2003)
2009 Chompret criteria (Tinat et al, 2009)
Proband with core LFS tumour (premenopausal breast cancer,
soft tissue sarcoma, osteosarcoma, brain tumour, leukaemia
or adrenocortical carcinoma) before 46 years of age
AND at least one-first-degree or second-degree relative with
LFS-core tumour (except breast cancer if the proband has
breast cancer) before 56 years of age
OR with multiple tumours
Proband with multiple tumours (except multiple breast tumours),
two of which are core LFS tumour types, first of which had to
occur prior to age 46 years
Any patient with adrenocortical carcinoma or choroid plexus
tumour irrespective of family history.
8295% sensitivity and 4758% specificity (Gonzalez et al, 2009a;
Tinat et al, 2009; Ruijs et al, 2010)
LFL, Li-Fraumeni syndrome-like; LFS, Li-Fraumeni syndrome.

associated leukaemia or MDS also warrant strong considera-
tion, especially when there is a personal or family history of
LFS-associated cancers. As might be expected, the chances of
finding a germline TP53 mutation differ depending upon the
criteria used to guide testing, with about 6080% of individ-
uals meeting classic and 2030% meeting Chompret criteria
harbouring a germline TP53 mutation (Olivier et al, 2003;
Varley, 2003; Mai et al, 2012). Most LFS mutations are
inherited with the frequency of de novo mutations at around
720% (Gonzalez et al, 2009b).
Given the observation that a sizable proportion of individu-
als with an LFS or LFS-like phenotype lack identifiable germ-
line TP53 mutations, it is very likely that other genetic
aberrations exist to explain cancer development. These aberra-
tions might include mutations in non-coding regions of the
genome that negatively influence TP53 expression or, alterna-
tively, mutations in genes other than TP53 itself. Therefore,
families who test negative for germline TP53 mutations,
including those presenting with leukaemia as the sole manifes-
tation, should be carefully evaluated and offered testing for
other cancer predisposing conditions, where appropriate.
Familial testing for LFS may identify asymptomatic indi-
viduals who carry a germline TP53 mutation. Such informa-
tion has significant health implications and these individuals
should be offered surveillance and for women, the possibility
of prophylactic mastectomy, as would be done for TP53
mutation carriers who have already developed one or more
cancers (Villani et al, 2016).
For individuals of reproductive age, genetic counselling
should be offered to discuss recurrence risks. Parents with an
identified germline TP53 mutation can consider prenatal test-
ing, which includes analysing DNA extracted from fetal cells
obtained by amniocentesis at 1518 weeks gestation or by
chorionic villus sampling at ten to 12 weeks gestation, as well
as pre-implantation genetic diagnosis.
Cancer surveillance in LFS
The goals of cancer surveillance are to improve overall out-
comes by enabling the early detection and treatment of
tumours. In general, surveillance is best suited for solid neo-
plasms, where prognosis may be better following complete
resection of the presenting tumour. Indeed, such is the case
with many LFS-associated solid tumours including certain sar-
coma subtypes, glioma, medulloblastoma, CPC and ACC
(McBride et al, 2014). Smaller completely resected tumours
may require reduced or even no chemo- or radiation therapy.
In theory, this could minimize the risk for therapy-associated
second cancers. Although the diversity of cancer types and age
at cancer onset make screening in LFS challenging, Villani et al
(2016) recently reported that a multi-modal screening proto-
col is feasible and associated with a significantly improved sur-
vival for individuals with LFS. Using what is now referred to
as the Toronto protocol, these investigators monitored carri-
ers of a germline TP53 mutation using physical examination
2016 John Wiley & Sons Ltd, British Journal of Haematology
Review
in conjunction with frequent blood work and imaging studies
(Table III). A total of 40 asymptomatic tumours were detected
in 19 (32%) of 59 patients who underwent surveillance, while
61 symptomatic tumours were detected in 43 (88%) of the 49
patients who initially declined surveillance (19 of these subse-
quently crossed over to the surveillance arm). Notably, the 5-
year survival was 88% for those undergoing and 59
6% for
those declining surveillance (Villani et al, 2011). The results of
this study are promising and provide the first evidence in sup-
port of the potential survival benefits of surveillance for carri-
ers of germline TP53 mutations. Nonetheless, this screening
protocol is not without its limitations, with one patient having
false negative and two patients false positive results. Further-
more, there were a number of incidental findings identified by
whole body magnetic resonance imaging (WBMRI; a compo-
nent of the screening protocol), the majority of which required
dedicated follow-up imaging. Currently, several trials are
ongoing to further investigate the utility of WBMRI with or
without other screening modalities as a means of tumour
surveillance in LFS and to identify the optimal types and fre-
quencies of screening procedures (Villani et al, 2016).
In the report by Villani et al (2016), two individuals devel-
oped AML and two MDS. Only one of these survived: an adult
with MDS who chose not to undergo surveillance. Currently,
it remains unknown whether surveillance for haematopoietic
malignancies confers a medical benefit for those affected with
LFS. Nonetheless, consideration should be given to regular
monitoring of peripheral blood counts. In addition, patients
should undergo periodic physical examinations to evaluate for
the signs and symptoms of a haematopoietic cancer, such as
fever, pallor, petechiae, easy bruising, lymphadenopathy and
hepatosplenomegaly. If any of these are present, or if there are
persistent changes in the blood counts from baseline, a bone
marrow aspirate and biopsy should be performed.
It is important to recognize the emotional, psychological
and financial burdens that frequent screening evaluations cre-
ate. These tests require multiple visits to the clinic and are
fraught with the possibility of false positive results. In a study
of high-risk women who were proven germline TP53 muta-
tion carriers and those at 50% risk, Lammens et al (2010b)
observed that 90% of participants surveyed believed in the
value of surveillance to detecting early stage tumours. Fur-
thermore, 84% stated that surveillance gave them a sense of
control and 70% indicated a sense of security. In this study,
there were no significant differences in the levels of distress
or worry between women who chose and those who did not
choose to undergo surveillance as recommended by their
health care providers. While limitations exist in terms of
sample size, these findings are reassuring. As pertains to chil-
dren, there is concern that frequent screening may increase
anxiety and reduce the quality of life (McBride et al, 2014).
Further research is needed to objectively evaluate these con-
cerns, as children and adolescents are at a formative, yet psy-
chologically vulnerable period in their lives and may require
life-long cancer monitoring.
9
Review

Table III. Villani et al (2016) surveillance protocol based on tumour prophylactic mastectomy (Thull & Vogel, 2004). For those
type. who develop a breast cancer, mastectomy should be encour-
Adrenocortical carcinoma aged over lumpectomy to lessen the risks for development of
 Children (birth to 18 years old) and adults (1840 years old) new primary breast cancers or radiation-induced secondary
Ultrasound abdomen and pelvis every 34 months malignancies (Schneider et al, 1993).
Blood/urine tests to be completed every 34 months There are no consensus recommendations regarding the
acute management of solid cancers in patients with germline
17 OH-progesterone, total testosterone, dehydroepiandros-
terone sulphate, androstendione, 24-h urine cortisol TP53 mutations. When possible, it is prudent to reduce
Brain tumour
exposure to ionizing radiation to help decrease the risk for
secondary tumours within the radiation field. Concern also
 Children and Adults
exists regarding the choice of chemotherapeutic agents, par-
Annual Brain MRI
ticularly alkylating agents, whose use is associated with the
Breast cancer possible risk of inducing leukaemia or myelodysplasia (Felix
 Adults et al, 1996; Schulz et al, 2012; Kamihara et al, 2014). Regard-
Monthly breast self-examination (18 years +) less of these risks, it is currently recommended that cure of
Clinical breast examination, annual mammography and breast the existing malignancy must remain the top priority.
MRI screening* In terms of LFS-associated leukaemia, the treatment of
Twice a year starting at age 20 OR hypodiploid ALL has been challenging, with survival rates of
510 years before earliest known breast cancer in family 50% or less despite the use of intensive chemotherapeutic
Soft tissue and bone sarcoma regimens (Pui et al, 1987; Nachman et al, 2007). Further-
 Children more, until recently, there were no known prognostic mark-
Annual rapid whole body MRI ers to help direct therapy. Mullighan et al (2015) reported
that the outcome of children with hypodiploid ALL could be
 Adults (18 years+) stratified based on the MRD level at the end of leukaemia
Annual rapid whole body MRI induction (Mullighan et al, 2015). In this study, 20 children
Ultrasound of abdomen and pelvis every 34 months
with hypodiploid ALL, including 12 with the low hypodi-
Leukaemia or lymphoma ploid subtype (only one of whom had a documented germ-
 Children and adults line TP53 mutation) were treated according to the St Jude
Blood tests to be completed every 34 months TOTAL Therapy Studies. Patients with MRD 1% after com-
Complete blood counts, erythrocyte sedimentation rate, pletion of induction were offered the option of allogeneic
lactate dehydrogenase haematopoietic stem cell transplantation (allo-SCT).
Colorectal cancer Although all 20 patients achieved a clinical remission at the
 Adults end of induction, only 14 were found to have a negative
Colonoscopies every 2 years starting at age 25 years OR

MRD status. Survival was significantly better for those with
10 years before earliest known colon cancer in the family negative MRD (85
5%) versus those with a positive result
Melanoma (44
4%). The one patient with a germline TP53 mutation
 Adults experienced a relapse. Although numbers are small, this
Annual dermatological examination study suggests that, as with other forms of ALL, MRD serves
an important prognostic indicator for childhood hypodiploid
General assessment
ALL, an aggressive and very difficult-to-treat leukaemia sub-
 Adults and children type.
Complete physical examination every 34 months The published literature as to whether the presence of a
Prompt medical assessment with primary care doctor for any germline TP53 mutation confers a poorer prognosis in
concerns patients with haematopoietic cancers is limited. Similarly,
there is little information regarding the optimal treatment
MRI, magnetic resonance imaging.
approaches for primary or therapy-related disease in germ-
*Breast MRI to alternate with annual rapid whole-body MRI.
line TP53 mutation carriers. At present, it is not clear
whether treatment regimens should be altered to avoid or
lessen exposure to DNA damaging chemotherapeutic agents,
Recommendations for cancer prevention and
as is done with patients who have Fanconi anaemia or Ataxia
treatment
Telangiectasia. In addition, it remains to be determined
Currently there are limited options for cancer prevention in whether allo-SCT will improve the outcomes for patients
LFS. Given the high risk for breast cancer development in with relapsed or refractory leukaemia. When allo-SCT is
women with LFS, females harbouring a germline TP53 muta- being considered, it is important to offer relatives targeted
tion should be counselled about the option of risk-reducing TP53 genetic testing prior to harvesting to avoid the

10 2016 John Wiley & Sons Ltd, British Journal of Haematology

 Review

possibility of collecting and inadvertently transplanting TP53
mutation-containing stem cells. Finally, it was recently
reported that low hypodiploid ALL cells exhibit activation of
Ras and PI3K pathways and are susceptible to inhibition of
PI3K and/or mTOR signalling (Holmfeldt et al, 2013). These
data suggest that therapeutic targeting of these pathways
could prove beneficial as a treatment for patients with low
hypodiploid ALL, positive MRD and/or recalcitrant disease.
Conclusions and future directions
Much has been learned about TP53 and its central role in
maintaining genomic stability and suppressing malignant
transformation. Nonetheless, it is impossible to predict with
certainty when and which TP53 mutation carriers will
develop a first or subsequent cancer, how to delay or prevent
these cancers from occurring, and how to treat them most
effectively. Future collaborative studies that integrate clinical,
genomic and biological information will undoubtedly shed
light onto this challenging cancer predisposition syndrome.
Towards this end, the increased application of high through-
put molecular approaches will provide new insights into the
genetic and epigenetic events that drive tumour formation.
This information may also help to explain the diverse mani-
festations of LFS, including the differences in disease pene-
trance, heterogeneity of tumours formed and the disparity in
age of cancer onset among germline TP53 mutation carriers.
A better understanding of how these factors influence disease
phenotype may permit the development of individualized
monitoring protocols. Finally, with the advent of genome
editing and induced pluripotent stem cell technologies, it is
now possible to generate and possibly reverse specific germ-
line TP53 mutations. These technologies will allow for the
modelling of tumour formation in LFS and the dissection of
critical cellular pathways and processes that can be then tar-
geted to treat or even prevent tumour formation. Looking to
the future, there is no doubt that LFS will remain as a para-
digm for the exploration and understanding of TP53-asso-
ciated solid and blood cancers and heritable cancer risk.
Acknowledgements
We gratefully acknowledge Brandon Stelter from the Depart-
ment of Biomedical Communications at St. Jude, who helped
create the images in Figs 1 and 2. We also thank Gerry Zam-
betti, Emilia Pinto, Emily Quinn, Rose McGee, Regina Nuc-
cio, Kayla Hamilton, Victoria Liddle and Stacy Hines-Dowell
for their careful review of this manuscript.
Author contributions
All authors contributed equally to the design of the study
and writing of this review. All authors critically reviewed
the manuscript and agreed to submit the paper for publi-
cation.

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