Discussion
The current case report aimed to
provide oncologists with information about possible incidental findings
including germline mutation.
TP53 is an extremely important tumour suppressor gene. Germline
mutation in the TP53 gene causes Li-Fraumeni syndrome, a rare
hereditary cancer syndrome. Somatic deleterious mutation in both alleles
of the TP53 gene is commonly observed in sporadic cancer.TP53 mutations, which are
detected in only 5%–10% of AML cases, are associated with complex
cytogenetic abnormalities and poor outcomes. AML with a complex
karyotype accounts for 10%–15% of all adult AML cases. TP53somatic mutation was identified in about 60% of patients with AML
patients who had a complex karyotype.5 According to this report,TP53 mutation is strongly correlated with a complex karyotype.
AML associated with TP53 mutation is associated with a poor
response to chemotherapy and short overall survival. Moreover, it is
highly associated with therapy-related AML. However, our patient did not
have a previous history of malignancy. Treatment with TP53mutation has been challenging in patients with AML. Nevertheless,
induction chemotherapy was more challenging because leukaemia had been
complicated by severe infection including appendicitis. Wei et al.
showed that CAG regimen was effective and safe for patients with AML,
and it may be more effective than non-CAG regimens.6
A new therapeutic strategy, including epigenetic drugs, has been found
to be effective in targeting TP53 -mutated AML. Venetoclax is a
bcl-2 inhibitor, and azacitidine is a hypomethylating agent.7 Venetoclax
combined with hypomethylating agents including azacitidine has a
promising therapeutic effect. Apoptosis mediated by venetoclax may be
independent of TP53 . Combination therapy with these drugs has
been recently approved for the treatment of AML by the National Health
Insurance of Japan. Azacitidine–venetoclax therapy can be used as a
maintenance therapy. In our case,
the TP53c.566C>T mutation in AML cells was heterozygous.
Nevertheless, no other TP53 mutations were detected. If one
allele of the TP53 gene was a wild type and had a normal
function, the prognosis of this patient might have been better than that
of patients with homozygous or compound heterozygous mutation. However,
we cannot rule out the risk of loss of function without mutation
including epigenetic silencing. TP53 mutations occur in 8% of de
novo AML cases. In other solid malignancies, TP53 mutation is
found in more than half of cases. TP53 abnormalities without
mutation occur more frequently than expected.8 Several mechanisms
underlying TP53 dysfunction have been reported. An algorithm for
the TP53 -based diagnostic workup and treatment of AML was
developed. Hence, the mutated or nonmutated disfunction of TP53must be identified for the treatment of AML.
Based on data in ClinVar, TP53c.566C>T mutation was
considered a variant with uncertain significance. To the best of our
knowledge, three cases with germline TP53 c.566C>T
mutation have been reported in detail.1-3 No case has met the classical
criteria of Li-Fraumeni syndrome. Miyaki et al.1 reported a case of
multiple colorectal cancer in a 73-year-old man, and examination results
showed that tumour cells had a compound heterozygous mutation. Cho et
al.2 presented a case of unilateral breast cancer in a 47-year-old
woman, and assessment findings revealed that tumour cells had a
homozygous mutation. The patient’s father and brother had oesophageal
and lung cancer, respectively. Her offspring underwent genetic
counselling and genetic testing. Choi et al.3 showed a case of fallopian
tube cancer in a 56-year-old patient who had germline pathogenic
mutation in the BRCA1 gene. The patient’s sister had ovarian
cancer. TP53 mutation
c.566C>T may be found
incidentally. However, there can be no association between this mutation
and carcinogenesis. In our case, leukaemia cells only exhibited
heterozygous mutation. New somatic mutation did not occur in theTP53 gene of leukaemia cells. However, loss of function without
mutation cannot be ruled out. Not only TP53 mutation but also
epigenetic deregulation of TP53 expression is responsible for
clinical heterogeneity.9 It was challenging to perform appropriate
genetic counselling and surveillance on the patient and her family.
Based on the family history, some members developed and colorectal
cancer at > 50 years of age.
In previously reported cases,
colorectal cancer was diagnosed at the age of 73 years old and breast
cancer at the age of 47 years. This mutation may be correlated with
relatively late-onset cancer. According to the family history of our
patient and previous case reports, annual screening for breast and
colorectal cancer may be recommended if a patient has germlineTP53 c.566C>T
mutation. Momozawa et al.4 showed that TP53 c.566C>T
mutation was found in 19 of 7051 women with breast cancer. Moreover,
they revealed that the mutation was found in 17 of 11241 controls in a
Japanese population. The odds ratio was 1.8 (0.9–3.7), and the P value
was 0.088. Hence, the results between the two groups did not
significantly differ. About 1 in 660 healthy women had the mutation,
which may not be a pathogenic variant for Li-Fraumeni syndrome or
Li-Fraumeni-like syndrome. The association between the mutation and
breast cancer can possibly be weak. In AML or other malignancies, the
effect of the mutation was unclear. In the current case, the patient was
informed about the mutation. Hence, her offspring was recommended to
undergo genetic counselling, and cancer screening must be discussed.
Moreover, the patient and her family should be informed that future
studies may change the current interpretation of the mutation.
Several companion diagnostic tests, which are used to assess a specific
biomarker for qualifying a patient to receive a specific, associated
therapy, have been applied in clinical settings. Most of them are
somatic and/or germline genetic tests. In Japan, two gene panel tests
for genomic profiling have recently been covered by the National Health
Insurance. In other countries, the number of patients who undergo such
gene panel tests is increasing.
Hence, the number of germline
mutation found incidentally will also increase. It is more challenging
to interpret VUS found incidentally than pathogenic mutation. Therefore,
patients with such incidental findings should undergo adequate genetic
counselling.