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P
ediatric
cancer
and
L
i
-F
raumeni
/L
i
-F
raumeni
-
like
syndromes
:
a
review
for
the
pediatrician
R
ev
A
ssoc
M
ed
B
ras
2015; 61(3):282-289
285
Clinical diagnosis
Clinical suspicion of LFS/LFL is raised by the diagnosis
of tumors strongly associated with these syndromes. Any
infant, child or adolescent presenting with adrenocorti-
cal carcinoma, choroid plexus carcinoma or anaplastic
rhabdomyosarcoma, irrespective of a positive familial his-
tory of cancer must be investigated for the possibility of
LFS or LFL.
29
In addition, cancer-affected children with
a family history of LFS/LFL-spectrum tumors following
certain pattern of ages at diagnosis, degrees of related-
ness between cancer-affected relatives (fulfilling clinical
criteria for these syndromes) indicates analysis of germ-
line
TP53
mutations.
10,30-33
A definitive diagnosis of LFS/
LFL is established only when a germline
TP53
mutation
is identified.
Assessment of a suspected LFS/LFL case
The first step in the assessment of a patient with suspect-
ed LFS/LFL should be a thorough analysis of the cancer
family history in a pedigree including at least three gen-
erations. All reports of cancer in the family should be con-
firmed by medical records, pathology reports and/or death
certificates. In addition to tumor type and site, the age at
diagnosis and current age (or age at death) of each affect-
ed individual should be recorded. Differential diagnosis
may include other hereditary cancer syndromes since
some phenotypic features are overlapping among these
(i.e. LFS/LFL
vs
. hereditary breast and ovarian cancer or
breast and colon cancer syndrome in families with early
onset breast cancer).
34
Molecular diagnosis
The
TP53
gene is located on chromosome 17 (17p13.1)
and spans approximately 20Kb. It comprises 11 exons
that encode p53, a transcription factor structurally de-
fined by 5 domains. The DNA-binding domain is the site
of over 90% of the somatic mutations observed in spo-
radic tumors and also of the majority of germline muta-
tions. In Brazilian families fulfilling LFS/LFL criteria, a
mutation outside the DNA-binding domain, in exon 10
(which encodes for the oligomerization domain) is the
most common alteration.
35
Clinical criteria for LFS/LFL can be used to estimate
the likelihood of germline
TP53
mutations. Approximate-
ly 70% of families that meet criteria for classical LFS, 32
and 25% of those meeting the Chompret criteria (original
Chompret and modified Chompret criteria, respectively),
25% of those meeting the Birch criteria and 14 and 8% of
those meeting the Eeles criteria (Eeles 1 and Eeles 2 crite-
ria, respectively) will carry germline
TP53
mutations.
36-39
The gold-standard method for detection of patho-
genic mutations in patients fulfilling LFS/LFL criteria is
sequencing of the entire coding region of the
TP53
gene.
Testing for gene rearrangements (large deletions and du-
plications) in
TP53
should be considered in families whose
phenotype elicits a strong clinical suspicion (for exam-
ple: with multiple early onset tumors) and where sequenc-
ing of the coding region did not result in the identifica-
tion of mutations;
40
supplemental methods, such as MLPA
(multiplex ligation-dependent probe amplification), are
required for diagnosis of gene rearrangements.
Genetic counseling and management of families with LFS/LFL
De novo
mutation accounts for approximately 7% of pa-
tients with LFS/LFL-spectrum tumors diagnosed at a
young age.
41
In this setting, siblings will be at a very low
risk of the condition, although some risk exists due to
the possibility of germline mosaicism for the mutation
in one parent. The majority of persons with LFS/LFL,
however, have multiple affected relatives, usually across
two or more generations. The risk to siblings of a LFS/
LFL mutation carrier will depend on the parental geno-
type. If either parent is a carrier, the proband’s siblings
will have a 50% chance of having also the condition.
Once a
TP53
mutation has been identified, the key
focus of LFS/LFL management is attempted modifica-
tion of cancer risk. Carriers of germline
TP53
mutations,
particularly mutations affecting the DNA-binding do-
main of p53, have a lifetime risk of cancer that exceeds
by far the risks for the general population.
Although LFS/LFL is unquestionably associated with
a higher risk of cancer, the potential risks and actual ben-
efits of cancer screening strategies in these patients have
not been established definitively.
34
The core benefits of
cancer screening are based on the concept of early detec-
tion of tumors. Due to the diverse range of tumors found
in the LFS spectrum, a thorough assessment of the can-
cer family history is essential, as established diagnoses in
other family members has been used with caution to guide
screening strategies for asymptomatic relatives.
Several cancer screening strategies for patients with
LFS/LFL have been published in recent years, including
the NCCN guidelines, and excellent management reviews
in GeneReviews and Orphanet. In 2011, Villani et al.
showed for the first time that a laboratory- and imaging-
based screening protocol was able to detect tumors at
very early stages in
TP53
germline mutation carriers. This
strategy had a significant impact on survival rates (100%
in screened
versus
21% in unscreened patients).
42
The
screening protocol proposed for children involves abdom-