LFS is a typical hereditary tumor susceptibility syndrome with autosomal dominant inheritance, first discovered and reported by Frederick Pei Li and Joseph F. Fraumeni, Jr in 1969 [3]. LFS has been confirmed as associated with multiple tumors clinically and patients with LFS have high incidence of malignancies often with onset at the early age [4]. The two patient of our case both have the onset of childhood. According to the classic criteria [5], LFS is considered as present if the proband is diagnosed with sarcoma before 45 years old and a first/second-degree relative was diagnosed with any type of cancer or sarcoma before 45 years old. Recently, Chompret criteria has been suggested to clinically diagnose LFS [6]. In this criteria, tumors in the proband are not limited to sarcomas, also include brain tumor, breast cancer, and adrenocortical carcinoma(ACC). But they have younger age cutoff than the classical one. In case 1, the child was diagnosed as CPC at the age of two and his sister in case 2 was diagnosed as glioblastoma, which complied with the Chompret criteria.

Germline mutations in the tumor suppressor gene TP53 on chromosome 17 are now widely recognized as the pathogenic gene of LFS [7]. This germline pathogenic mutations can be detected in 70%-80% of families with LFS [3]. The mutation site spectrum of TP53 is quite extensive and more than 1,800 different mutations have been reported by far. At present, six hotspot mutations have been found in 20% of patients with TP53 mutations, including p.R175H, p.G245S, p.R248Q, p.R248W, p.R273H and p.R282W [8, 9]. But in this case, the c.375G > A mutation, which the two patients carried, is non-hotspot mutation. The variant, located at the last base of exon 4. After the mutation, the amino acid change is p.Thr125Thr, which is actually a type of synonymous mutation and did not cause a change in the encoded amino acid. But the mutation will cause the donor site of the splice site to disappear, thereby affecting the splicing. We also drew a diagram for TP53 protein with all known domains, and indicate where this mutation is located (Fig. 7). This variant is included in the dbSNP database(rs55863639), and the frequency of this SNP in general population is 0.000007, but there is no frequency information in the gnomAD and ExAC databases, indicating that the frequency of the mutation population is extremely low. The Human Gene Mutation Database includes this variant as a pathogenic variant of LFS, in addition, the Clin var database includes this variant as a pathogenic variant for LFS based on the results of multiple submitters in clinical testing.. In summary, according to the AGMG standard, we classified the c.375G>A mutation of the TP53 gene as a pathogenic variant. We also used CADD and SIFT to predict pathogenesis and found that none of the different prediction methods had a score value, which may be related to the mutation being a synonymous mutation.

Fig. 7

A diagram for TP53 protein with all known domains, and where the mutation is located

The most common cancers associated with LFS include osteosarcoma, ACC, CNS neoplasm and soft tissue sarcoma, with incidence rates of 30%, 27%, 26% and 23% respectively [10]. Both of our cases are brain tumors. The first one, CPC, is a rare pediatric brain neoplasm accounts for less than 1% of the total number of CNS tumors [11]. But with LFS, CPC are the classic brain tumor, glioma and medulloblastoma are also relevant to LFS [12]. In addition, A review study about Characteristics of LFS in Japan pointed out that Children with CPC of the brain and ACC were reported to have a high likelihood of carrying a TP53 germline variant, even in the absence of any family history [13]. Because in the early stage of the disease, the family members of the child denied the relevant family history of the tumor. For this reason We did not perform genetic testing for the first patient immediately, so we ignored their relevance and missed the opportunity to discover this LFS family earlier. Therefore, the report of this case also reminds clinicians to pay more attention to CPC, even when there is no family history of tumors, TP53 gene testing should be performed in time for children with CPC to be alert to the existence of LFS.

Thus, the diagnosis of LFS and the detection of TP53 mutation are very necessary. A large-sample clinical trial of Bougeard et al. included 1,730 patients with LFS in France, the results showed that the average age of first tumor was 24.9 years old, and 41% of the patients were clearly diagnosed as tumors before the age of 18 [10]. Another study had shown that the risk of primary cancer is 50% for women at the age of 31 and 50% for men at the age of 46 [14]. By analyzing the TP53 database of the international agency for research on cancer, the incidence rate of cancer in patients with TP53 mutation is estimated at 80% at 70 years old, while the risk of women is close to 100% due to the high incidence of breast cancer [15]. Therefore, we should be more sensitive to what kind of patients need genetic testing in clinical work, so that they and their families can be monitored for cancer earlier. The latest diagnostic criteria updated in 2009 by Chompret et al. defines conditions to select individuals who carry germline mutations in TP53 independent of family history [6, 16]. According to the current knowledge of TP53 gene, the following characteristics can be adopted as screening indicators for TP53 mutant genes in children: (1) various types of childhood tumors with at least one first/second-degree relative diagnosed with LFS-related tumors (premenopausal breast cancer, soft tissue sarcoma and ACC for example) at any age (2) At least one of all primary tumors in patients with multiple tumors in childhood belongs to the type of LFS-related tumors; (3) Once certain special types of tumors are diagnosed, TP53 gene detection should be performed for any of the following: breast cancer, ACC, CPC, papilloma, soft tissue sarcoma and osteosarcoma .

LFS patients with TP53 mutations have significantly higher rates of secondary tumors than those with normal TP53 [17]. Compared with adult patients, children may have a longer tumor development process because of their early-onset age. In order to manage related patients properly, once TP53 gene mutation is found positive with them, clinical monitoring should be carried out for early tumor detection and control of cancer and treatment-related morbidity and mortality [18]. Some scholars have found that the 5-year survival rate of LFS patients with TP53 mutation can be significantly improved through clinical monitoring [19]. Annual brain MRI and whole-body MRI were suggested for these children patients. Blood tests should be done regularly to check indicators like complete blood count, erythrocyte sedimentation rate, lactate dehydrogenase, testosterone, androstenedione and dehydroepiandrosterone sulfate. Abdominal and pelvic ultrasonography should be conducted. It is also important to have a complete physical examination for blood pressure, growth curve, Cushingoid appearance, male physical signs and comprehensive neurological assessment, with focus on rapid weight and height growth. Once LFS is diagnosed, family members should also be screened for related genetics and have a high probability of developing malignant neoplasm [20,21,22,23]. Early disease surveillance of TP53 mutation carried in family members of LFS patients since childhood can identify a wide range of early diagnosable diseases, including breast cancer, soft tissue sarcoma, brain tumor, osteosarcoma, ACC, bladder cancer, colorectal cancer, gastric cancer, nephroblastoma, liver cancer, lung cancer, melanoma and pancreatic cancer [24]. In our case, if we find that this is a LFS family at the first time, and carry out tumor surveillance on his family earlier, maybe we can find the sister’s glioblastoma sooner. The genes of the two children and their family members had already been tested since we realized this point. We followed up their father and another brother who carried the same mutant gene. Up to now, there were no signs of growing tumors. Furthermore, there are also recent literature reports that germ cell mosaicism as the cause of recurrence of LFS in siblings [25], so when the genetic test of the parent who was suspected of having a TP53 mutation, Even if the result is negative, we still cannot relax our vigilance against the siblings of the proband.

To develop mature treatment plans for LFS related patients, further exploration is also demanded to learn about the clinical characteristics of LFS patients with Tp53 mutation. The current study suggests that patients with TP53 gene mutation are very sensitive to radioactivity factors [12], Radiotherapy-induced cancer is more common in LFS patients [10]. Therefore, radiological examination and treatment should be avoided as much as possible in the process of diagnosis and treatment for such patients. But in our cases, both children received focal irradiation following gross total resection. In our opinion, prognostic benefits of postoperative radiotherapy must be weighed against the risk of long-term secondary cancer if the tumor is highly malignant. In addition, the results of Hendrickson et al. who studied 40 patients with LFS on radiotherapy and secondary malignant tumors were different from before, their data provide preliminary evidence to suggest RT should not be withheld in patients with LFS [26]. Recently, a strong link between TP53 mutations and hypermethylation at the promoter of the p53-associated microRNA miR-34A, which was found as a potential putative novel therapeutic target and a marker for clinical prognostication [27].

In conclusion, the germline mutation of the TP53 gene is the only known pathogenic gene of LFS. Timely identification and discovery of this mutation can effectively help clinicians to manage treatment and obtain the best therapeutic effect, especially for children. In such cases, aggressive preventive surveillance and treatment may bring optimistic outcome for patients and their family members who also carry this mutation.

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