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.