Check for updates
Original Article
Clinical Features of Li-Fraumeni Syndrome in Korea
Ran Song (1, Sun-Young Kong(2, Wonyoung Choi3, Eun-Gyeong Lee1, Jaeyeon Woo1, Jai Hong Han1, Seeyoun Lee1, Han-Sung Kang1, So-Youn Jung İD
1Department of Surgery, Center of Breast Cancer, National Cancer Center, Goyang, 2Department of Laboratory Medicine, National Cancer Center, Goyang, 3Center of Rare Cancers, National Cancer Center, Goyang, Korea
Purpose Li-Fraumeni syndrome (LFS) is a hereditary disorder caused by germline mutation in TP53. Owing to the rarity of LFS, data on its clinical features are limited. This study aimed to evaluate the clinical characteristics and prognosis of Korean patients with LFS. Materials and Methods Patients who underwent genetic counseling and confirmed with germline TP53 mutation in the National Cancer Center in Korea between 2011 and 2022 were retrospectively reviewed. Data on family history with pedigree, types of muta- tion, clinical features, and prognosis were collected.
Results Fourteen patients with LFS were included in this study. The median age at diagnosis of the first tumor was 32 years. Mis- sense and nonsense mutations were observed in 13 and one patients, respectively. The repeated mutations were p.Arg273His, p.Ala138Val, and pPro190Leu. The sister with breast cancer harbored the same mutation of p.Ala138Val. Seven patients had multi- ple primary cancers. Breast cancer was most frequently observed, and other types of tumor included sarcoma, thyroid cancer, pan- creatic cancer, brain tumor, adrenocortical carcinoma, ovarian cancer, endometrial cancer, colon cancer, vaginal cancer, skin cancer, and leukemia. The median follow-up period was 51.5 months. Two and four patients showed local recurrence and distant metastasis, respectively. Two patients died of leukemia and pancreatic cancer 3 and 23 months after diagnosis, respectively.
Conclusion This study provides information on different characteristics of patients with LFS, including types of mutation, types of cancer, and prognostic outcomes. For more appropriate management of these patients, proper genetic screening and multidiscipli- nary discussion are required.
Key words Li-Fraumeni syndrome, TP53, Germ-line mutation, Hereditary disease
Introduction
Li-Fraumeni syndrome (LFS) is a rare autosomal domi- nant hereditary disorder caused by a germline mutation in TP53 [1,2]. TP53 gene is a tumor suppressor gene that pro- vides instruction for making a protein called p53 and plays a key role in apoptosis, cell cycle regulation, and DNA repair [3,4]. Therefore, LFS is associated with a high risk of early- onset malignancies, such as breast cancer, bone and soft tis- sue sarcoma, brain tumor, adrenocortical carcinoma, leuke- mia, gastric cancer, and colorectal cancer. Its lifetime risks of malignancy are ≥ 70% for male and ≥ 90% for female patients [1,5,6].
Owing to the high cancer risk of LFS, several efforts have been made to identify its phenotype and genotype. Although previous studies have reported the mutational characteris- tics of LFS based on locus-specific databases, including the International Agency for Research on Cancer (IARC) TP53
database (http://p53.iarc.fr/) [6,7] and Universal Mutation Database (UMD) (http://p53.fr/) [8], most of the data origi- nate from Western populations.
In Korea, studies have analyzed 14 patients with nine different types of TP53 mutations [9] and 12 patients with LFS with breast cancer [10]. Other case reports also have described patients with LFS with various types of malignan- cies [11-13].
However, because of the rarity of LFS, data on its types of mutation, clinical features, and treatment outcomes in Korean patients are limited. This study aimed to evaluate the clinical characteristics and prognosis of Korean patients with germline TP53 mutation.
Correspondence: Sun-Young Kong Department of Laboratory Medicine, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea
Tel: 82-31-920-1735 Fax: 82-31-920-1379 E-mail: ksy@ncc.re.kr
Co-correspondence: So-Youn Jung Department of Surgery, Center of Breast Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel: 82-31-920-1681 Fax: 82-31-920-1379 E-mail: goje1@ncc.re.kr
Materials and Methods
Patients who met the LFS criteria clinically, including the classic LFS criteria and Chompret criteria, or had a suspi- cious personal or family history underwent genetic coun- seling. All patients with confirmed germline TP53 mutation at the National Cancer Center, Korea, between 2011 and 2022 were included and retrospectively reviewed. Genetic test- ing was performed by direct sequencing of 11 exons of TP53 gene or by next-generation sequencing (NGS) of > 22 genes. Data on the age at diagnosis of the tumor, sex, personal his- tory, family history with pedigree (Fig. 1), types of mutation, clinical features, and prognosis were collected.
Results
Fourteen patients with germline TP53 mutation were inclu- ded in this study. Clinical and TP53 mutation data are sum- marized in Table 1.
1. Demographic data
Among the total patients, there was only one male pati- ent and the rest were female (male:female ratio, 0.1:1). The median age at diagnosis of the first tumor was 32 years (range, 1 to 67 years). A family history of primary cancer was observed in 12 patients, and family members of eight patients had LFS-related tumors, including osteosarcoma, breast cancer, brain tumor, and lung cancer. Three patients,
including two patients who were sisters, had a sibling diag- nosed with LFS.
2. Types of germline TP53 mutation
Half of the patients underwent genetic testing using direct sequencing, and the other half underwent multigene panel NGS. Eleven different types of mutation were identified in the 14 Korean patients. Missense and nonsense mutations were observed in 13 and one patients, respectively. The repeated mutations were located at codons 273 (p.Arg273His, n=2), 138 (p.Ala138Val, n=2), and 190 (p.Pro190Leu, n=2) (Fig. 2), and the sister with breast cancer harbored the same mutation of p.Ala138Val. All mutations were heterozygous, including one case of mosaicism (patient 10) with a variant allele frequency of 11.4%.
3. Clinical characteristics
Twelve patients had suspicious clinical features, two of whom met the classic LFS criteria and eight met the Chom- pret criteria. A patient with early-onset breast cancer and a negative BRCA test (patient 7) and a patient with multiple primary tumors (patient 12) also underwent genetic testing. Two patients diagnosed with pancreatic cancer did not have a significant family history in pedigrees, but TP53 mutations were found during screening.
Various primary malignancies were identified. “Core” cancers, including breast cancer, sarcoma, brain tumor, and adrenocortical carcinoma, were observed in 12 patients (85.7%). Breast cancer was most frequently observed (n=9),
A
B
I
I
32 Br (31)
80
80
II
62 Cvx (60)
65 Br (62)
61 Lun (58)
79 Mel (58)
58 Lun (55)
II
31 Br (31)
29
III
54
52 Br (43) Mel (52) Thy (52)
51
50 Ov (49) Cvx (49)
48
46
56
IV
23
26
29
33
Thy (27)
| Patient | Agea) (yr) | Sex | Indication | Testing method | Testing result | Nucleotide alteration | Amino acid alteration | Mutation type | Tumor type (age at diagnosis, yr) | Local/ systemic recurrence | Death | Follow- upb) (mo) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 1 | M | Classic LFS criteria | Direct sequencing | LPV | c.817C>T | p.Arg273Cys | Missense | Rhabdomyosarcoma (1) | Yes | No | 25 |
| 2 | 4 | F | Chompret criteria | Direct sequencing | LPV | c.569C>T | p.Pro190Leu | Missense | Adrenal cortical carcinoma (4), thyroid cancer (10), osteosarcoma (11), osteoblastoma (12) | Yes | No | 188 |
| 3 | 7 | F | Chompret criteria | Direct sequencing | PV | c.524G>A | p.Arg175His | Missense | Brain tumor (7), breast cancer (24, 35), dermatofibrosarcoma (35), leukemia (38) | Yes | Yes | 375 |
| 4 | 13 | F | Classic LFS criteria | Direct sequencing | PV | c.818G>A | p.Arg273His | Missense | Mesenchymal chondrosarcoma (13) | No | No | 11 |
| 5 | 28 | F | Chompret criteria | Multigene panel NGS | LPV | c.569C>T | p.Pro190Leu | Missense | Breast cancer (28), colon cancer (28) | No | No | 8 |
| 6c) | 29 | F | Chompret criteria | Direct sequencing | LPV | c.413C>T | p.Ala138Val | Missense | Breast cancer (29) | No | No | 134 |
| 7 | 31 | F | Young age breast cancer with negative BRCA gene test | Direct sequencing | PV | c.733G>A | p.Gly245Ser | Missense | Breast cancer (31, 34) | No | No | 110 |
| 8 | 33 | F | Chompret criteria | Multigene panel NGS | PV | c.844C>T | p.Arg282Trp | Missense | Breast cancer (33), sarcoma (35), basal cell carcinoma (35) | No | No | 26 |
| 9 | 38 | F | Chompret criteria | Multigene panel NGS | PV | c.742C>T | p.Arg248Trp | Missense | Breast cancer (38, 38), thyroid cancer (38), endometrial cancer (39) | No | No | 26 |
| 10c) | 40 | F | Chompret criteria | Direct sequencing | LPV | c.413C>T | p.Ala138Val | Missense | Breast cancer (40) | No | No | 57 |
| 11 | 43 | F | Chompret criteria | Multigene panel NGS | LPV | c.517G>T | p.Val173Leu | Missense | Breast cancer (43), vaginal melanoma (52), thyroid cancer (52) | Yes | No | 123 |
| 12 | 47 | F | Multiple primary tumors | Multigene panel NGS | PV | c.517G>A | p.Val173Met | Missense | Breast cancer (47), ovarian cancer (55) | Yes | No | 100 |
| 13 | 64 | F | N/A | Multigene panel NGS | PV | c.637C>T | p.Arg213* | Nonsense | Pancreatic cancer (64) | No | No | 17 |
| 14 | 67 | F | N/A | Multigene panel NGS | PV | c.818G>A | p.Arg273His | Missense | Pancreatic cancer (67) | Yes | Yes | 24 |
F, female; LFS, Li-Fraumeni syndrome; LPV, likely pathogenic variant; M, male; N/A, not applicable; NGS, next-generation sequencing; PV, pathogenic variant. a)Age at diagnosis of the first tumor, b)Follow-up periods after the diagnosis of the first tumor, “Patients in the same family.
[KR]-[STA]-K motif
Bipartite nuclear localization signal
DNA-binding domain
Nuclear export signal
2
A138V
P190L
R273H
Mutation type
Description
Frequency
. Missense mutation
· Nonsense mutation
1
TADI
TADII
0
0
50
100
150
200
250
300
350
Amino acid number
| Present study | Park et al. (2016) [9] | Alyami et al. (2021) [10] | |
|---|---|---|---|
| Patient selection | Patients with germline TP53 mutation (2011-2022) | Patients with germline TP53 mutation (2003-2015) | Patients with breast cancer with germline TP53 mutation (2005-2019) |
| No. of patients | 14 | 14 | 12 |
| F:M | 13:1 | 11:3 | 12:0 |
| Age at first diagnosis (yr), median (range) | 32 (1-67) | 25 | 33.5 (20-52) |
| Multiple primary cancer, n (%) | 7 (50.0) | 11 (78.6) | 9 (75.0) |
| Breast cancer | 9 (64.3) | 6 (42.9) | 12 (100) |
| Sarcoma | 5 (35.7) | 5 (35.7) | 1 (8.3) |
| Thyroid cancer | 3 (21.4) | 2 (14.3) | 2 (16.7) |
| Pancreatic cancer | 2 (14.3) | 0 | 1 (8.3) |
| Brain tumor | 1 (7.1) | 4 (28.6) | 0 |
| Adrenocortical carcinoma | 1 (7.1) | 1 (7.1) | 0 |
| Ovarian cancer | 1 (7.1) | 0 | 0 |
| Endometrial cancer | 1 (7.1) | 0 | 0 |
| Colon cancer | 1 (7.1) | 0 | 1 (8.3) |
| Vaginal cancer | 1 (7.1) | 0 | 0 |
| Skin cancer | 1 (7.1) | 2 (14.3) | 1 (8.3) |
| Leukemia | 1 (7.1) | 2 (14.3) | 0 |
| Lung cancer | 0 | 2 (14.3) | 4 (33.3) |
| Stomach cancer | 0 | 2 (14.3) | 1 (8.3) |
| Nasal cavity cancer | 0 | 1 (7.1) | 1 (8.3) |
| Lymphoma | 0 | 0 | 3 (25.0) |
F, female; M, male.
and other types of tumor included sarcoma (n=5), thyroid cancer (n=3), pancreatic cancer (n=2), brain tumor (n=1), adrenocortical carcinoma (n=1), ovarian cancer (n=1), endo- metrial cancer (n=1), colon cancer (n=1), vaginal cancer (n=1), skin cancer (n=1), and leukemia (n=1). Seven (50%) patients had multiple primary cancers (range, 2 to 4). Leu- kemia found in one patient was induced by treatment of the
preceding breast cancer (patient 3).
In some malignancies, biomarker testing was performed on cancer specimens for the selection of drug regimens. Except for patients without data, one BRAF-mutated thyroid cancer and one BRCA1-mutated ovarian cancer were identi- fied (S1 Table).
| Patient | Age (yr) | Side | Histological type | Grade | Stage | ER | PR | HER2 | Surgery | CTX | HTX | RTX | Anti- HER2 therapy |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 3 | 24 | Right | Unknown | Unknown | Unknown | Unknown | Unknown | Unknown | Mastectomy | Adjuvant | No | Yes | No |
| 35 | Left | IDC | 3 | cT2N2ª) | Neg | Neg | Pos | Mastectomy | Neoadjuvant | No | Yes | Yes | |
| 5 | 28 | Left | DCIS | 1 | pTisN0 | Pos | Pos | Neg | Mastectomy | No | Yes | No | No |
| 6 | 29 | Right | Mucinous carcinoma | 2 | pT1N0 | Pos | Pos | Neg | Mastectomy | Adjuvant | Yes | No | No |
| 7 | 31 | Right | IDC | 3 | cT2N3a) | Neg | Neg | Pos | BCS | Neoadjuvant | No | Yes | Yes |
| 34 | Left | IDC | 2 | pT1N0 | Pos | Pos | Neg | BCS | No | Yes | Yes | No | |
| 8 | 33 | Left | IDC | Unknown | cT1N1a) | Pos | Neg | Pos | Mastectomy | Neoadjuvant | Yes | No | Yes |
| 9 | 38 | Right | IDC | 3 | cT3N0a) | Pos | Neg | Pos | Mastectomy | Neoadjuvant | Yes | No | Yes |
| 38 | Left | IDC | 2 | cT2N0a) | Pos | Neg | Neg | Mastectomy | Neoadjuvant | Yes | No | Yes | |
| 10 | 40 | Right | DCIS | 3 | pTisN0 | Neg | Neg | Pos | Mastectomy | No | No | No | No |
| 11 | 43 | Left | IDC | Unknown | Unknown | Unknown | Unknown | Unknown | BCS | No | No | Yes | Unknown |
| 12 | 47 | Right | IDC | 3 | pT2N2 | Pos | Pos | Pos | Mastectomy | Adjuvant | Yes | Unknown | Unknown |
BCS, breast-conserving surgery; CTX, chemotherapy; DCIS, ductal carcinoma in situ; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HTX, hormone therapy; IDC, invasive ductal carcinoma; Neg, negative; Pos, positive; PR, progesterone receptor; RTX, radiation therapy. a)Clinical stage before neoadjuvant chemotherapy.
4. Prognostic outcomes
The median follow-up period from the diagnosis of the first tumor was 51.5 months (range, 6 to 188 months). After the diagnosis of LFS with genetic testing, one patient with breast cancer was diagnosed with colon cancer during the work-up for other malignancies (patient 5), and additional new-onset malignancies were found in three other patients during the follow-up. There were two and four cases of local recurrences and systemic recurrences, respectively. Two patients died of leukemia and pancreatic cancer 3 and 23 months after diagnosis, respectively.
Discussion
In this study, we reviewed Korean patients with LFS to evaluate their types of mutation and clinical features. There were 11 different types of mutation in 14 patients, and vari- ous spectra of malignancies were found.
Studies based on the IARC p53 database showed that most TP53 mutations were missense mutations, accounting for 74%, and nonsense and splice mutations accounted for approximately 9% and 8%, respectively [6,7]. Except for one patient with nonsense mutation, all patients in this study had missense mutation. Park et al. [9] investigated the muta- tions and tumor spectra of LFS in Korean patients and iden- tified two novel frameshift mutations in codons 98 and 27. Other studies on Korean patients have reported other types of mutation, such as frameshift or silent mutation (S2 Table)
[9-18]. Based on the IARC database, the most common hot- spot mutations were found in codons 175, 245, 248, 273, and 282 (http://p53.iarc.fr/). In this study, six different mutations were identified in these hotspots in seven unrelated patients. Other mutations were located in codons 138, 173, 190, and 213. Mutations in codons 173 (p.Val173Leu, p.Val173Met) and 213 (p.Arg213*) have not been reported in the Korean Reference Genome Database (KRGDB) or Genome Aggrega- tion database (gnomAD).
In addition to the types of mutation, the age at onset of the first tumor varied in this study. Studies have reported that age and sex are associated with cancer risk in patients with LFS. Cancer risk is highest after the age of 20 years in female patients, whereas it is higher in childhood and lat- er adulthood in male patients [5]. It is difficult to compare because there was only one male patient in the present study, but compared with the 1-year-old male patient, all female patients, except for two teenagers, were adults. A previous study reported a positive relationship between the age of onset of the first tumor and development of secondary tumors [19]. In this study, secondary malignancies were observed in two of four patients (50%), four of seven patients
(57.1%), and one of three patients (33.3%) aged 0-19, 20-44 years, and ≥ 45 years, respectively. This result is due to the relatively small number of patient aged 0-19 years, and two of them had short follow-up periods of 11 and 25 months.
Among the tumors identified in this study, core cancers, such as breast cancer and sarcoma, were frequently observed (85.7%), as reported previously [6,20,21]. Notably, two out of 14 patients were diagnosed with pancreatic cancer. According to the IARC database, the relative risk of pancre- atic cancer in patients with LFS is 7.3, with an incidence rate of 1.2% [22]. However, our study showed a higher incidence of pancreatic cancer, even compared to other Korean stud- ies (Table 2). This is because, in our institution, genetic test- ing was performed for screening all patients with any risk of hereditary pancreatic cancer syndrome. Another difference from previous studies is that no patients with gastric can- cer were included, although this study was conducted on Korean patients. A study reported that gastric cancer occur- red more frequently in Asian populations than in similar Caucasian cohorts [23]. Other Korean studies have reported the incidence of stomach cancer (Table 2).
As is already well known [20], breast cancer was most fre- quently identified in this study, with a rate of 64.3%. Three patients had bilateral breast cancer, two of whom had meta- chronous and one had synchronous breast cancer. In the 12 cases of breast cancer in 9 different patients, the median age at diagnosis was 33.5 years (range, 23 to 47 years). Except for two cases with no pathological information, seven (70%) were endocrine receptor (ER)-positive and six (60%), includ- ing three with ER co-expression, were human epidermal growth factor receptor 2 (HER2)-positive, showing a higher rate of HER2 expression than the general population [24]. Breast-conserving surgery with adjuvant radiation therapy was performed in three (25%) cases, and the other nine (75%) cases underwent mastectomy (Table 3).
These results are similar to those of previous studies inves- tigating the clinicopathological features of breast cancer in patients with LFS [25,26]. Breast cancer showed early onset with a median age of 32-34 years, and in immunohistochem- istry staining, the proportion of receptor expression was similar with 84%-90.5% ER positivity, 39.5%-63% HER2 posi- tivity, and 32.8%-53% ER and HER2 co-expression. However, a Korean study by Alyami et al. [10] showed differences in histological features and treatment outcomes. This study reported a lower rate of ER expression and a higher rate of triple-negative breast cancer. The recurrence rate was also higher than that in our study, which may be due to differ- ences in subtypes.
A patient (patient 3) of the present study diagnosed with bilateral breast cancer died of acute myeloid leukemia indu- ced by breast cancer treatment. Similar with this case, several
reports demonstrated that therapeutic interventions, such as chemotherapy and radiation therapy, caused therapy- induced secondary malignancies, including breast cancer [27,28], sarcoma [29], thyroid cancer [28,29], central nervous system tumor [28], and leukemia [9,28,30]. Despite clinical suspicion, there have been no large-scale comparative stud- ies supporting the tumorigenesis of therapeutic interven- tions. Further multicenter studies with larger populations are required to evaluate which treatments can increase the risk of malignancy or which tissues are particularly vulner- able. Clinicians should be aware of the possibility of second- ary cancer and should be careful when making treatment decisions.
This study is one of the largest case series performed in Korean patients with LFS and includes prognostic data. However, this study has some limitations. This was a ret- rospective study, and the data were obtained from medical records. Therefore, clinical information, such as indications for genetic testing or environmental factors, including life- style, was insufficient. In addition, this study was conducted in a single institution, and the number of included patients was small; therefore, it is difficult to define the characteristics and prognosis of patients with the disease. Finally, because this study included patients lost to follow-up or recently diagnosed patients, the prognostic outcomes were inaccu- rate.
This study provides information regarding the mutation- al features and clinical characteristics of patients with LFS in South Korea. Similar to other countries, several Korean patients with LFS also have early onset and multiple primary tumors. The clinical features and prognosis vary according to the type of mutation, type of cancer, and time of diagnosis.
This study emphasizes that genetic counseling and screen- ing are required not only for patients but also for their fam- ily members. And for proper management, clinicians should assess genetic testing results and conduct multidisciplinary discussion before making treatment decisions. Further mul- ticenter, large-cohort studies are required for the proper screening and management of Korean patients with LFS.
Electronic Supplementary Material
Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).
Ethical Statement
This study was approved by the Institutional Review Board of the National Cancer Center, Korea (IRB No. NCC2022-0268). The requi- rement for informed consent was waived owing to the retrospec- tive nature of this study.
Author Contributions
Conceived and designed the analysis: Song R, Kong SY, Jung SY.
Collected the data: Song R.
Contributed data or analysis tools: Song R.
Performed the analysis: Song R.
Wrote the paper: Song R.
Interpretation of data, critical revision of manuscript, final approv-
al of the version: Song R, Kong SY, Choi W, Jung SY.
Interpretation of data: Lee EG, Woo J, Han JH, Lee S, Kang HS.
ORCID iDs
Ran Song D: https://orcid.org/0000-0001-6373-7411
Sun-Young KongD: https://orcid.org/0000-0003-0620-4058 So-Youn Jung ®: https://orcid.org/0000-0002-4508-4522
Conflicts of Interest
Conflict of interest relevant to this article was not reported.
Acknowledgments
This work was supported by a National Cancer Center Grant (No. NCC 2110181-3).
References
1. Schneider K, Zelley K, Nichols KE, Garber J. Li-Fraumeni syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, et al., editors. GeneReviews. Seattle, WA: University of Washington; 1993.
2. Malkin D. Li-fraumeni syndrome. Genes Cancer. 2011;2:475- 84.
3. Harris CC. Structure and function of the p53 tumor suppres- sor gene: clues for rational cancer therapeutic strategies. J Natl Cancer Inst. 1996;88:1442-55.
4. Aubrey BJ, Strasser A, Kelly GL. Tumor-suppressor functions of the TP53 pathway. Cold Spring Harb Perspect Med. 2016;6: a026062.
5. Mai PL, Best AF, Peters JA, DeCastro RM, Khincha PP, Loud JT, et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Frau- meni syndrome cohort. Cancer. 2016;122:3673-81.
6. Guha T, Malkin D. Inherited TP53 mutations and the Li-Frau- meni syndrome. Cold Spring Harb Perspect Med. 2017;7: a026187.
7. Bouaoun L, Sonkin D, Ardin M, Hollstein M, Byrnes G, Zavadil J, et al. TP53 variations in human cancers: new les- sons from the IARC TP53 Database and Genomics Data. Hum Mutat. 2016;37:865-76.
8. Leroy B, Anderson M, Soussi T. TP53 mutations in human cancer: database reassessment and prospects for the next dec- ade. Hum Mutat. 2014;35:672-88.
9. Park KJ, Choi HJ, Suh SP, Ki CS, Kim JW. Germline TP53 mutation and clinical characteristics of Korean patients with Li-Fraumeni syndrome. Ann Lab Med. 2016;36:463-8.
10. Alyami H, Yoo TK, Cheun JH, Lee HB, Jung SM, Ryu JM, et al. Clinical features of breast cancer in South Korean patients with germline TP53 gene mutations. J Breast Cancer. 2021;24:175-82.
11. Bang YJ, Kang SH, Kim TY, Jung CW, Oh SM, Choe KJ, et al. The first documentation of Li-Fraumeni syndrome in Korea. J Korean Med Sci. 1995;10:205-10.
12. Kim IJ, Kang HC, Shin Y, Yoo BC, Yang HK, Park JG. Famil- ial gastric cancers with Li-Fraumeni syndrome: a case repast. World J Gastroenterol. 2005;11:4124-6.
13. Baek YS, Seo JY, Song JY, Lee SY, Kim A, Jeon J. Li-Fraumeni syndrome presenting as cutaneous melanoma in a child: case report and review of literature. J Eur Acad Dermatol Venereol. 2019;33:e174-5.
14. Hwang SM, Lee ES, Shin SH, Kong SY. Genetic counseling can influence the course of a suspected familial cancer syndrome patient: from a case of Li-Fraumeni like syndrome with a ger- mline mutation in the TP53 gene. Korean J Lab Med. 2008;28: 493-7.
15. Shin HJ, Kwon YJ, Lim YJ, Park BK, Ghim TT, Shin SH, et al. Family of Li-Fraumeni syndrome with a germline mutation in the p53 gene. Clin Pediatr Hematol Oncol. 2009;16:38-42.
16. Cho Y, Kim J, Kim Y, Jeong J, Lee KA. A case of late-onset Li-Fraumeni-like syndrome with unilateral breast cancer. Ann Lab Med. 2013;33:212-6.
17. Oh CS, Lee JH, Jung ST, Na BR. Osteosarcoma with adeno- carcinoma of lung in Li-Fraumeni syndrome: a case report. J Korean Bone Joint Tumor Soc. 2014;20:99-103.
18. Ku I, Park JU. Dermatofibrosarcoma in Li-Fraumeni syn- drome with early-onset multiple primary tumors. J Dermatol. 2020;47:e333-5.
19. Hisada M, Garber JE, Fung CY, Fraumeni JF Jr, Li FP. Multi- ple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst. 1998;90:606-11.
20. Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. 2015;33:2345-52.
21. Nichols KE, Malkin D, Garber JE, Fraumeni JF Jr, Li FP. Germ- line p53 mutations predispose to a wide spectrum of early- onset cancers. Cancer Epidemiol Biomarkers Prev. 2001;10: 83-7.
22. Kasuga A, Okamoto T, Udagawa S, Mori C, Mie T, Furu- kawa T, et al. Molecular features and clinical management of hereditary pancreatic cancer syndromes and familial pancre- atic cancer. Int J Mol Sci. 2022;23:1205.
23. Ariffin H, Chan AS, Oh L, Abd-Ghafar S, Ong GB, Mohamed M, et al. Frequent occurrence of gastric cancer in Asian kin- dreds with Li-Fraumeni syndrome. Clin Genet. 2015;88:450-5.
24. Acheampong T, Kehm RD, Terry MB, Argov EL, Tehranifar P.
Incidence trends of breast cancer molecular subtypes by age and race/ethnicity in the US from 2010 to 2016. JAMA Netw Open. 2020;3:e2013226.
25. Masciari S, Dillon DA, Rath M, Robson M, Weitzel JN, Bal- mana J, et al. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat. 2012;133:1125-30.
26. Sandoval RL, Polidorio N, Leite AC, Cartaxo M, Pisani JP, Quirino CV, et al. Breast cancer phenotype associated with Li-Fraumeni syndrome: a Brazilian cohort enriched by TP53 p.R337H carriers. Front Oncol. 2022;12:836937.
27. Yoon IN, Cha ES, Kim JH, Lee JE, Chung J. Breast cancer after radiation therapy in a patient with Li-Fraumeni syndrome: a
case report. Taehan Yongsang Uihakhoe Chi. 2022;83:246-51.
28. Braunstein S, Nakamura JL. Radiotherapy-induced malignan- cies: review of clinical features, pathobiology, and evolving approaches for mitigating risk. Front Oncol. 2013;3:73.
29. Le AN, Harton J, Desai H, Powers J, Zelley K, Bradbury AR, et al. Frequency of radiation-induced malignancies post- adjuvant radiotherapy for breast cancer in patients with Li- Fraumeni syndrome. Breast Cancer Res Treat. 2020;181:181-8.
30. Talwalkar SS, Yin CC, Naeem RC, Hicks MJ, Strong LC, Abru- zzo LV. Myelodysplastic syndromes arising in patients with germline TP53 mutation and Li-Fraumeni syndrome. Arch Pathol Lab Med. 2010;134:1010-5.