Reviewer’s report
Title: 
First case of endometrial cancer after yolk sac tumor in a patient with Li-
Fraumeni Syndrome
Version: 
0 
Date: 
24 Oct 2022
Reviewer's report:
The authors propose a case report entitled « First case of endometrial cancer after
yolk sac tumor in a patient with Li-Fraumeni Syndrome ».
The author report the case of a young female who developed two distinct tumors,
one of them containing a TP53 mutation p.(R282W). They indicate (l.125-125)
that the mutation was hemizygous. They conclude she has a Li-Fraumeni
syndrome (LFS) because the TP53 mutation is a germline one.
However, throughout the article it never appears that the patient benefited from a
germline analysis. 
It is essential to clarify this point before to include this case report as a LFS
patient.
The authors indicate that familial scrrening is not possible because of the death
of the father and the paternal grandmother. If the patient really carry a germline
TP53 mutation with a VAF around 50%, knowing incomplete penetrance of
these mutations, a genetic test could be proposed to the mother, which would
make it possible to exclude this family branch.
To conform the international recommendations for nomenclature, brackets need
to be used for p. nomenclature and reference sequences need to be indicated, for
all the genes ; for TP53 c.844C>T, p.(R282W)with NM_000546.5. The gene
names should be italicized.
The table 1 should include a legend, a modified title and present all the somatic
mutations detected. It is not clear if somatic informations were obtained for 688
genes, or if 688 genes were tested and only 6 were relevant. More details about
reference sequence, VAF, classification... should be included in this table that
should be the main table of this report. 
For the conclusion, the authors should clarify the message of this case report.
Other points need to be clarify and improved.
In this manuscript, datas are missing about yolk sac tumors epidemiology, a rare
tumor.
l.61-3: « Computed tomography (CT) revealed a 14 cm solid cystic mass in the
right adnexa with increased alpha fetoprotein (AFP) (Figure 1). » and « Figure 1
» Computed tomography reveals a 14 cm solid cystic mass in the right adnexa
(red arrow) with increased AFP.
The increased AFP was not revealed by CT scan. The authors shouls modify the
sentences to clarify.
l.63, l.99 : the authors should indicate indicate the significance of YST and EC
(as they appear in the text for the first time)
l.74-75 « moderately differentiated adenocarcinoma », then l.84 « endometrioid
adenocarcinoma », the authors shouls indicate in the text the time betwwen these
2 examinations.
IHC results should be included in a table that would help to compare the results,
as p53 IHC showed 90 versus 60% positivity.
l.87-88 : results for MLH1, MSH2, MSH6, PMS2...IHC should replace «
Mismatch repair deficiency (MMRd) was not detected. » 
l.93 : it would be important to explain the choice of therapy including
bevacizumab.
l. 98-99 : « genetic screening of formalin-fixed paraffin-embedded (FFPE) EC
tissue », indicate the technique in this sentence.
l.99_101 : « This screening detected 688 genes related to the occurrence,
development, treatment, and prognosis of solid tumors, and the test results were
analyzed in detail. » include these results in the table 1.
l.112-113 « The TP53 mutation p. R282 W (c.844C>T) was found in a germline
mutation, inheritance of which is autosomal dominant » the identification of a
germline mutation is really not clear ; 
« The patient was hemizygous for the disease-causing gene », l.125-126 « In this
case, genetic screening revealed a hemizygous pathogenic TP53 mutation
(p.R282 W). » 
It is probably the tumor which is hemizygous ; that's why VAF is important and
as well as germline confirmation.
l.113_115 « Based on her father's and grandmother's cancer histories, it is very
likely that her patrilineal family carried the TP53 gene mutation and passed it on
to the patient, » The family history is not very evocative of a Li-Fraumeni
syndrome, does not correspond to Chompret's criteria. The young age of tumor
onset in the father and paternal grand-mother should be highlighted. Moreover,
the presence of an ovary cancer in two members of this family should led the
authors to search for additional germline mutated gene.
l.115-116 « she got YST accompanied by subsequent EC that is associated with
LFS. » the author should indicate here that EC is rarely found in LFS patients.
l.116_118 « family verification could not be performed. In particular, there were
6 somatic point mutations in this case, PTEN was one of them (Table 1). » This
sentence is not clear. The authors should explain what they want to indicate.
l.120-121 « The patient is being closely followed up now was because of this
syndrome. » the authors should provide details about follow up.
l.135-136 : « It is recommended that family members take a systematic approach
to cancer screening and participate in TP53 research projects » There is no
consensus to recommend to LFS patient to participate to research projects.
l.143-144 : « The p. R282 W mutation has been regarded as a hotspot variant at
both germline and somatic levels », l.148... paragraph « Pathological
consequences of p53 mutation... »
It is important to remember that TP53 is the most mutated gene in tumors with
some hot spots, that the frequence of TP53 mutations in ovary tumors is very
high, that TP53 is a TSG and that the 2 alleles are usually inactivated in tumors
(here the R282W is hemizygous, so that a LOH has occured in the second
allele). More details about litterature on R282W IHC are also of importance.
It is essential to confirm germline status before publication.
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Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
No
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes