LFS is a rare autosomal dominant hereditary cancer susceptibility syndrome. In 1969, Li and Fraumeni conducted a retrospective study on four pediatric rhabdomyosarcoma pedigrees, providing the first report of this disease [12–14]. In 1990, germline pathogenic variants in the TP53 tumor suppressor gene were discovered, representing the sole known cause of LFS [15]. To date, approximately 1,000 families from 172 different countries worldwide have been affected by this syndrome [16]. Clinically, individuals carrying germline TP53 mutations exhibit an 80% penetrance of tumors by the age of 70. However, the penetrance of TP53 germline variants varies due to age, gender, and mutation type. Adrenal cortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma, and medulloblastoma are common tumors that occur between infancy and adolescence (between the ages of 0–15), accounting for 22% of all ages. Breast cancer, osteosarcoma, leukemia, gliomas, gastrointestinal cancer, lung cancer, and various sarcomas are common in young adults between the ages of 16 and 50, accounting for 51% of all ages. Lung and colorectal cancers occur frequently in middle-aged and elderly individuals (51–80 years old, 27%). Females are most likely to develop breast cancer, while males are more likely to develop brain tumors [17–20].
TP53 is a tumor suppressor gene, and the most common type of variant is missense mutations. The encoded p53 protein is a homotetrameric protein consisting of 393 amino acids, encompassing five major functional domains: two N-terminal transactivation domains (TADI, 1–42, and TADII, 43–62), a proline-rich domain (PRD, 64–92), a core DNA-binding domain (DBD, 102–292), an oligomerization domain (OD, 323–356), and a C-terminal regulatory domain (RD, 363–393). Mutations in different regions have varying effects on transcriptional function, leading to phenotypic differences among TP53 variant carriers. Boettcher et al. [8] used CRISPR-Cas9 technology to generate human leukemia cell lines with TP53 missense mutations in the DBD region. The loss of p53 protein function (LOF) was revealed through functional, DNA-binding, and transcriptional analyses. Moreover, mutational scanning of p53 single amino acid variants showed that missense mutations in the DBD region exhibit dominant negative effects (DNE), where the mutated protein not only lacks function but also hinders or interferes with the normal protein's physiological function. The mutations in families 2 and 3 described in this article are both missense mutations located in the DBD region and exhibit DNE. Research has shown that such mutations are associated with an earlier median age of onset compared to carriers of loss-of-function and rearrangement mutations (21.3 years vs. 28.5 years vs. 35.8 years; P < 0.05). In the pediatric population, they are the most prevalent mutation type and may have a poorer prognosis in specific cases [8, 21, 22]. Our research shows a statistically significant difference in the average age of tumor onset between families 1 and 2 (38.75 years vs. 18.5 years, P = 0.012), which consistent with previous research findings.
According to missense mutation allelic genes described by the International Agency for Research on Cancer (IARC) dataset and their ability to activate a set of human target sequences, the p53 missense variant forms can be classified into partially defective (PD) allelic genes, severely defective (SD) allelic genes and specific severe defects (O-SD) allelic genes [23]. In this article, both p53 p.R282W and p53 p.R248W belong to SD-type variants, while the p53 p.H214Qfs*7 frameshift mutation belongs to O-SD-type variants. Studies have indicated that p53 proteins with SD genotypes are more likely to exhibit DNE, while those with PD genotypes are less likely to show DNE [24]. Analysis of TP53 genotype and phenotype has revealed that patients with SD genotypes have an earlier median age of onset compared to those with O-SD genotypes (15 years vs. 25 years, P = 0.07) and a higher degree of cancer risk [24, 25], emphasizing the need for early attention and inclusion in clinical monitoring and management.
Currently, treatment options specifically targeting LFS are limited, with treatment mainly focused on symptomatic management of different cancers. During treatment, efforts should be made to avoid radiation exposure, radiotherapy, and alkylating agent therapy to prevent the development of second malignancies [26]. Studies have shown that radiotherapy and genotoxic chemotherapy increase the risk of tumor progression in LFS mouse models [26]. Yoon IN et al. [27] suggest minimizing radiotherapy whenever possible when alternative treatment options are available, and if radiation therapy is necessary, it can be adapted through proton therapy, image guidance, and minimizing the irradiated volume.
Furthermore, immunotherapy has emerged as a new treatment for malignant genetic heterogeneity. Hassin et al. [28] have proposed p53-related immunotherapy strategies involving the recognition and targeting of cancer cells carrying TP53 mutations by the immune system, enhancing the sensitivity of cancer cells to immune checkpoint inhibitors through the restoration of p53 function, among other treatment approaches. Yang et al. [29] demonstrated increased sensitivity of triple-negative breast cancer to PD-1 immunotherapy by restoring the activity of p53 protein carrying TP53 mutations. Megyesfalvi Z et al. [30] found widespread inactivation of the TP53 gene in small cell lung cancer, suggesting potential efficacy of immunotherapy in this context. Chen et al. [31] reported the first case of CAR-T cell therapy in an LFS patient with hematological malignancy, suggesting that CAR-T cell therapy may be an alternative option compared to traditional chemotherapy and allogeneic hematopoietic stem cell transplantation. In our research, the CPS of PD-L1 in the proband 1 was 70%, and the patient received radical resection, postoperative chemotherapy combination with immunotherapy. The progression-free survival (PFS) of the proband 1 is more than 3 years according to the recent follow-up. Due to the characteristic development of multiple tumors in LFS, early surgical intervention maybe result in better survival. Thus, screening, early diagnosis, and personalized treatment for TP53 variant carriers are crucial.
LFS patients and their relatives are advised to undergo regular cancer surveillance [32] and special screening for different cancer types and mutation types. To explore the importance of cancer surveillance, Villani et al [33, 34] conducted an 11-year follow-up study of LFS patients in the United States and Canada and found that the 5-year overall survival rate was higher in the surveillance group (88.8% vs 59.6%, P < 0.05). Studies have shown that exposure to radioactive substances should be avoided as much as possible during cancer screening [32]. Whole-body MRI should be performed instead of CT and X-ray examinations [32]. Adrenal cortical carcinoma should undergo abdominal ultrasound every 6 months, and if ultrasound does not provide sufficient imaging, cortisol levels can be measured. For patients who have received abdominal radiotherapy or have a family history of colorectal cancer, colonoscopy should be performed every 5 years from the age of 18. For female patients, annual breast MRI is recommended from the age of 20 to 65. For adults, annual brain MRI is recommended until the age of 50 [35]. The frequency of new TP53 mutations is approximately 7%-20%, and the average age of first cancer in these patients is 5–6 years, with 80% having multiple primary cancers. The accurate identification of new TP53 germline mutations is also of crucial clinical significance for the identification and screening of LFS patients. Even if there is no family history of tumors, patients with a history of early-onset multiple primary cancers should receive genetic counseling, cancer screening, and prevention as early as possible [36, 37].
In this study, the genetic characteristics of three families and the gene testing results of TP53 germline mutations were analyzed. TP53 p.H214Qfs*7 frameshift mutation was reported as the first case of a family inheritance mutation, providing more genetic pathogenic causes for LFS diagnosis and enriching the mutation spectrum of the TP53 gene. Differences in tumor occurrence time between individuals may be related to mutation types and the interaction of genetic and environmental factors. DNE missense mutations in the DBD region of the TP53 gene maybe associated with early-onset childhood tumors and poor prognosis; SD-type TP53 mutations may have an earlier age of onset, higher tumor risk and the p53 protein carrying SD mutations perhaps prone to DNE. These functionally impaired TP53 mutations can serve as potential biomarkers for LFS and may need more active monitoring and treatment.