ORIGINAL ARTICLE
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Description of six cases of melanoma in 512 patients with germline pathogenic variants in the TP53 gene
Elisabeth de A. C. Callegaro1(D . Janina Pontes Pisani1 . Vanessa Monteleone1 . Maria Isabel Achatz1
Received: 25 September 2025 / Accepted: 28 November 2025 @ The Author(s), under exclusive licence to Springer Nature B.V. 2025
Abstract
Li-Fraumeni Syndrome (LFS) is an autosomal dominant condition associated with germline pathogenic variants in the tumor suppressor gene TP53. Carriers have a higher risk of developing multiple primary tumors and a broad spectrum of cancers. The main tumors include premenopausal breast cancer, sarcomas, adrenocortical carcinoma and central nervous system tumors. Melanoma is a recognized but uncommon manifestation of LFS, with few reports in the literature linking the syndrome to this malignancy. The main objective of this study is to evaluate the occurrence of melanoma in patients carrying the germline pathogenic variant in the TP53 gene, registered in the Brazilian Li-Fraumeni Syndrome Study (BLISS) database from 2018 to 2023. From our database, six out of 512 patients developed melanoma, with melanoma representing the sole clinical manifestation of LFS in half of these patients. Of the 512 patients with LFS, 417 were car- riers of the R337H variant, and among them, three patients developed melanoma. Three melanomas were detected during routine surveillance with total-body photography and digital dermoscopy. This study shows that melanoma is one of the manifestations of LFS, highlighting the importance of its screening within the Toronto protocol. It is essential for health- care professionals who manage patients with LFS to recognize this risk in order to enable early diagnosis and identification of precursor lesions.
Keywords Li Fraumeni syndrome . TP53 gene . Melanoma . Total-body photography and digital dermoscopy
Introduction
Li-Fraumeni syndrome (LFS) is an autosomal dominant condition associated with germline pathogenic variants in the tumor suppressor gene TP53, which encodes a transcrip- tion factor that regulates cell proliferation, apoptosis, and genomic stability [1]. These variants confer an increased predisposition to early-onset cancer [2].
Melanoma is part of the tumor spectrum of LFS; how- ever, it is diagnosed less frequently than the core cancers of this syndrome, which include premenopausal breast cancer, sarcomas, adrenocortical carcinoma and central nervous system tumors [3].
Annual dermatological examination starting at age 18 is recommended for LFS patients [1]. Guidelines suggest that
dermoscopy, digital dermoscopy and total-body mapping should be performed in individuals at high risk for mela- noma, as these tools enable early tumor detection [4]. Thus, LFS patients may benefit from these screening exams.
In Brazil, a high prevalence of LFS is observed due to a founder mutation in the TP53 gene c.1010G >A; (p.Arg337His) (R337H), identified in approximately 0.3% of the population from the south and southeast regions [5]. Despite this high prevalence of patients with LFS, no stud- ies to date have systematically described the occurrence of melanoma in these patients. Therefore, this study aimed to evaluate the occurrence of melanoma in patients with germ- line pathogenic variants in the TP53 gene, registered in the Brazilian Li-Fraumeni Syndrome Study (BLISS) database from 2018 to 2023. BLISS is a system organized in Excel since 2018, where patient data are entered into the Prog- eny software, allowing for the organization and analysis of familial cancer cases through the construction of pedigrees.
☒ Elisabeth de A. C. Callegaro ecallegaro@yahoo.com
1 Oncology Center, Department of Oncogenetics, Hospital Sírio-Libanês, São Paulo, Brazil
Methods
After approval by the Ethics and Research Committee of Hospital Sírio-Libanês, São Paulo, Brazil, we analyzed the medical records of 512 patients with germline pathogenic variants in the TP53 gene, registered in the Brazilian Li- Fraumeni Syndrome Study (BLISS) database between 2018 and 2023.
All patients with LFS were consecutively registered in the BLISS database between 2018 and 2023. For this study, we included all melanoma cases among these patients. Most patients undergo annual follow-up in the Cancer Genetics clinic, during which personal and family cancer histories are updated.
Demographic and clinical data were collected in the patients with melanoma, including sex, age, age at LFS diagnosis, type of germline pathogenic variant, personal history of cancer (type and age at diagnosis), age at mela- noma diagnosis and histopathological description of mela- noma. Additional factors were assessed including previous total-body mapping and digital dermoscopy exams, history of sunburn during childhood or adolescence, and habitual use of sunscreen. Additionally, pedigrees of patients and their relatives were also reviewed.
Results
Of the 512 patients registered in the BLISS database, six were diagnosed with melanoma. The average age at mela- noma diagnosis was 39.8 years, ranging from 30 to 50 years, with an equal proportion of male and female patients. Of the 512 patients, 417 carried the R337H variant, and three of these patients were diagnosed with melanoma. Among the 95 patients with non-R337H variants, three patients also had melanoma (Fig. 1).
Of the six patients with melanoma, half had other tumors preceding melanoma. One patient had breast cancer eight years before the melanoma diagnosis, another had thyroid cancer five years prior, and the third had two cancers: a
myelin sheath tumor eleven years earlier and a squamous cell carcinoma of the neck in the same year as the melanoma diagnosis.
Of the six patients with melanoma, three were under reg- ular follow-up with total-body mapping and digital dermos- copy exams, with melanoma being diagnosed during this monitoring.
Below is a description of the six cases of melanoma.
Case 1: Male, 32 years old, diagnosed with LFS at 28 years of age, carrying mutation in the TP53 gene c.375G>A; (p.Thr125Thr). Genetic testing was performed for the fam- ily variant, previously known in the family. No history of other tumors. During follow-up with total-body mapping and digital dermoscopy, a change in a mole on his back was observed, which was removed and diagnosed as superficial spreading melanoma with a Breslow depth of 0.4 mm, as shown in Fig. 2. He is a phototype 3 patient with a personal history of more than three episodes of sunburn during child- hood and adolescence and the use sunscreen for any outdoor activity. No family history of skin cancer.
Case 2: Male, 44 years old, diagnosed with LFS at 28 years of age, carrying mutation in the TP53 gene c.589G>A; (p.Val197Met). Genetic testing was performed with the panel of 83 genes. During follow-up with total-body map- ping and digital dermoscopy, two melanoma lesions were identified. One lesion on his right thigh was diagnosed as melanoma in situ (Fig. 3) and another lesion on his back was also diagnosed as melanoma in situ.
This patient also underwent excision of three atypical moles and five basal cell carcinoma lesions in sun-exposed areas. He is a phototype 2, with light-colored eyes, and has a personal history of more than three episodes of sunburn dur- ing childhood and adolescence. He uses sunscreen for any outdoor activity. No family history of skin cancer.
Case 3: Female, 40 years old, diagnosed with LFS at 35 years of age, carrying mutation in the TP53 gene c.811 C>T; (p.Arg271Cys), with this case likely being a mosaic. Genetic testing was performed using a panel of 83 genes. She has a personal history of thyroid tumor at 29 years old and mela- noma in situ on her back at 34 years old. The variant was
512 patients
417 patients with R337H variant (81%)
95 patients with non-R337H variants (19%)
1
1
3 cases of melanoma
3 cases of melanoma (3/95 - 3,1%)
(3/417 -0,7%)
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tested in two other tissues, with negative results. However, as the patient is young and has already developed two pri- mary tumors, and presents clinical features compatible with LFS, we included this patient in the sample, even though the final diagnosis of the syndrome has not been definitively confirmed.
Case 4: Female, 70 years old, with the age of LFS diag- nosis not reported, carrying the R337H variant. The type of genetic testing performed was not available. Personal his- tory includes five tumors: a myelin sheath tumor at 39 years of age, melanoma in situ at 50 years, squamous cell carci- noma of the neck at 50 years, leiomyosarcoma at 56 years and breast cancer at 59 years. The patient does not undergo follow-up with total-body mapping and digital dermoscopy.
Case 5: Female, 61 years old, diagnosed with LFS at 58 years of age, carrying the R337H variant. Genetic testing was performed for the family variant, previously known in the family. She developed breast cancer at 42 years old and melanoma on her back at 50 years old. The histological type was superficial spreading melanoma, measuring less than
0.5 mm in Breslow depth. The patient does not undergo follow-up with total-body mapping and digital dermoscopy.
Case 6: Male, 40 years old, diagnosed with LFS at 35 years of age, carrying the R337H variant. Genetic testing was performed for the family variant, previously known in the family. Patient has no history of other tumors. During follow-up with total-body mapping and digital dermoscopy, a change was observed in a mole on his right arm, which was diagnosed as Superficial spreading melanoma with a Breslow depth of 0.2 mm, as shown in Fig. 4. He is a pho- totype 3 patient with a personal history of more than three episodes of sunburn during childhood and adolescence and the use of sunscreen for any outdoor activity. No family his- tory of skin cancer.
Based on the results obtained, there is a predominance of melanoma cases in non-R337H variants (3/95 vs. 3/417) and a younger age of onset (30-35 vs. 39-50 years) compared to the R337H variant. However, due to the small number of melanoma cases, no statistical association can be made, and long-term follow-up of these patients may allow for the identification of potential associations.
| Case | Gender | Age (Years) | Melanoma location (Age) | Pathogenic vari- ant in the TP53 gene Genetic test performed | Histopathological results | Other tumors (Age) | Skin phototype | Previous sunburn history | Total-body photography and digital dermoscopy |
|---|---|---|---|---|---|---|---|---|---|
| 01 | M | 32 | Back (30) | p.Thr125Thr Family variant | Superficial spreading melanoma Breslow 0,4 mm | No | 3 | Yes | Yes |
| 02 | M | 44 | Right thigh and back (36) | p. Val197Met Panel of 83 genes | Superficial spreading melanoma in situ (2) | No | 2 | Yes | Yes |
| 03 | F | 40 | Back (34) | p.Arg271Cys Panel of 83 genes | NA | Thyroid (29) | NA | NA | NA |
| 04 | F | 70 | NA (50) | p.Arg337His NA | NA | Myelin sheath tumor (39) Neck SCC (50) | NA | NA | NA |
| Sarcoma (56) Breast (59) | |||||||||
| 05 | F | 61 | Back (50) | p.Arg337His Family variant | Superficial spreading melanoma - Breslow less than 0.5 mm | Breast (42) | 3 | Yes | No |
| 06 | M | 40 | Right arm (39) | p.Arg337His Family variant | Superficial spreading melanoma Breslow 0.2 mm. | No | 3 | Yes | Yes |
F: Female, M: Male; NA: Not available
Additionally, it was observed that half of the melanoma cases were diagnosed during follow-up with total-body mapping and digital dermoscopy exams. None of the six melanoma cases had a Breslow depth greater than 1 mm, indicating that all melanomas were diagnosed at early stages. Table 1 summarizes the six melanoma cases found in our database.
Discussion
Li-Fraumeni syndrome (LFS) confers a high risk of cancer development to its carriers. Some cases of melanoma have been described in individuals with pathogenic TP53 vari- ants; however, there are few studies in the literature specifi- cally describing malignant cutaneous lesions [3]. In Brazil, due to a founder effect in the oligomerization domain of the
TP53 gene (R337H), we have the world’s largest population of LFS carriers.
Considering our sample of 512 patients registered in the BLISS database, six cases of melanoma were identified, with a mean age at diagnosis of 39.8 years, similar to the study by Hatton which reported a mean age of 42 years. In our study, melanoma was the primary tumor in half of the cases, a finding also observed by Hatton where 41% of mel- anoma cases were the primary tumor in LFS patients [6]. The prevalence of melanoma in our cohort was 1.1%, which is lower than the 6.2% reported by Hatton [6]. This discrep- ancy may be attributed to underdiagnosed melanoma cases in our population and the higher incidence of melanoma in the United States compared to Brazil. Arnold et al. reported a melanoma incidence five times higher in North America than in South America in 2020 [7].
In our cohort, there were no patients with mucosal mela- noma. In the literature, studies by Hajkova et al., Klein et
al., and Song et al. reported cases of mucosal melanoma in ocular, oral, and vaginal sites, respectively [8-10].
None of the melanoma cases in our database occurred in children or adolescents. Baek et al. reported a case of a 16-year-old LFS patient with the p.Arg181His variant diag- nosed with melanoma in situ on the lateral thigh [11]. In our pediatric and adolescent LFS cases, the tumors found were those expected for this age group, such as adrenocortical carcinoma and choroid plexus carcinoma with no cases of melanoma observed.
Multiple melanomas in LFS patients are very rare, with only two reports in the literature describing patients with multiple lesions. Akay et al. described a 41-year-old male patient with multiple primary melanomas and LFS carrying the Leu111Phefs variant [12]. Curiel-Lewandowski et al. (2011) reported a 32-year-old female patient diagnosed with five melanomas during dermatological examination after a mandibular sarcoma diagnosis at age 28 [13]. In our study, we identified one patient with two melanomas at 36 years of age. These cases highlight the importance of regular follow- up for LFS patients, as these young individuals may develop additional melanoma lesions over the years.
In terms of the number of melanomas registered in the BLISS database, the prevalence of melanoma in our cohort was 1.1% (6/512), approximating that of the general popu- lation. It is important to contextualize that population data consider lifetime melanoma occurrence, while our study represents a cross-sectional assessment of LFS patients. However, it is noteworthy that LFS carriers develop mel- anoma at a younger age compared to individuals without pathogenic variants. In hereditary cancer syndromes related to skin cancer, patients tend to develop melanoma 10-15 years earlier than the general population and may present with other tumors in addition to melanoma [14]. These data support our study’s findings, where most melanoma patients were diagnosed at a young age, with a mean age of 39 years, along with the presence of other associated tumors in half of the patients.
From our 512 patients registered in the BLISS database, the majority, 81.4% (417/512), have the R337H variant. Among these patients, three developed melanoma (0.7%), while three of the 95 patients with non-R337H variants developed melanoma (3.1%). Patients with non-R337H variants were diagnosed at younger ages (30, 34, and 35 years) compared to R337H patients (39 and 50 years). This raises the question of whether the R337H variant is less associated with melanoma or presents melanoma at an age similar to the general population. Further follow-up is needed to address these questions.
Although melanoma is not a common tumor in LFS, it is part of its spectrum, and therefore, dermatologists should maintain heightened vigilance for melanoma in LFS
patients. It is interesting to note that three patients with mel- anoma enrolled in our BLISS registry were able to make the melanoma diagnosis during follow-up through total-body photography and digital dermoscopy in the context of the annual screening of the Toronto protocol. However, despite not being part of the Toronto protocol, this examination was the one that allowed for the early diagnosis of melanoma. In the original Toronto protocol, the guideline recommends annual dermatological evaluation for individuals over 18 years of age. Thus, we recommend incorporating total-body photography and digital dermoscopy into routine surveil- lance for TP53 variant carriers, which is the best method for early diagnosis, reducing morbidity and mortality in these patients.
Another important finding is that two of the three patients with melanoma diagnosed during the mapping examina- tion had melanomas with small diameters. Small-diameter melanomas can raise diagnostic doubts, as they may not yet have dermoscopic characteristics specific to melanoma. It is important to emphasize that, despite their small size, up to 70% of these melanomas can already be invasive [15]. Thus, total-body photography and digital dermoscopy are essential for detecting these lesions, as evidenced by the diagnosis in our two cases of small-diameter melanoma and thin invasive melanomas with Breslow thicknesses of 0.2 mm and 0.4 mm [15].
In addition to dermatological examination and total-body photography with digital dermoscopy, it is important to raise awareness in patients with the syndrome about the signifi- cance of self-skin exams and the recommendation to seek a dermatologist if they notice a new lesion and/or a change in the clinical pattern. The study by Brady evaluated 471 melanoma lesions, showing that the majority, 57%, were diagnosed by the patients themselves, with women being the most likely to perform self-diagnosis, as well as diag- nosing melanoma in their husbands [16].
Among the limitations of our study, we have the small number of melanomas in our database, which did not allow for the conduct of statistical tests. Furthermore, of the six patients with melanoma, only two underwent the complete panel of 83 genes, and three only underwent testing for the familial variant, which prevented us from correlating mel- anoma with other pathogenic variants. In one patient, the type of genetic test performed was not identified,
Thus, we conclude that melanoma is a manifestation of LFS, although it is not part of the central spectrum of the syndrome. A comparatively lower number of melanoma cases was observed in association with the R337H variant compared to other variants in the TP53 gene. In the cases diagnosed during the screening of patients in this study, none were thick (Breslow> 1 mm) or metastatic.
Based on this study, it can be suggested that cutaneous melanomas are more prevalent in LFS than in the general population, particularly in carriers of non-R337H variants. Studies with larger populations and long-term follow-up will help confirm this association.
Author contributions Elisabeth Callegaro conceived and designed the study, collected and analyzed the data, and drafted the manuscript. Janina Pisani and Vanessa Monteleone contributed to data collection, preparation of tables, and assisted with data analysis.Maria Isabel Achatz supervised the project, provided methodological guidance, and critically revised the manuscript.
Funding This research received no external funding.
Data availability No datasets were generated or analysed during the current study.
Declarations
Conflict of interest The authors declare no competing interests.
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