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Journal of Steroid Biochemistry and Molecular Biology
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The Journal of Steroid Biochemistry & Molecular Biology
Clinical spectrum of Li-Fraumeni syndrome/Li-Fraumeni-like syndrome in Brazilian individuals with the TP53 p.R337H mutation
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Amanda Meneses Ferreiraª, Vania Balderrama Brondania, Vanessa Petry Helenab, Helaine Laiz Silva Charcharª, Maria Claudia Nogueira Zerbini“, Luiz Antonio Senna Leited, Ana Oliveira Hoffe, Ana Claudia Latronico, Berenice Bilharinho Mendonca”, Maria Del Pilar Estevez Dizª, Madson Queiroz de Almeida”, Maria Candida Barisson Villares Fragosof,*
a Unidade de Suprarrenal, Disciplina de Endocrinologia e Metabologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brasil
b Departamento de Oncologia, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil
· Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil
d Departmento de Oncologia, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
e Unidade de Endocrinologia Oncologica, Instituto do Câncer do Estado de São Paulo, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Unidade de Suprarrenal, Laboratorio de Hormonios e Genetica Molecular LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brasil
ARTICLE INFO
Keywords:
Pediatric adrenocortical tumor Li-Fraumeni syndrome TP53 gene
P.R337H mutation
ABSTRACT
Background: The TP53 p.R337H germline mutation is highly prevalent among children with adrenocortical tumors (ACTs) from South and Southeast Brazil. However, the prevalence of other tumors of the Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL) spectrum, the clinical outcomes and the potential tumor occurrence in relatives carrying this distinct TP53 mutation were not fully investigated.
Patients and Methods: We investigated tumor profile data and outcomes of individuals and their close relatives with the TP53 p.R337H germline mutation. A questionnaire and the Toronto protocol were used for evaluation of asymptomatic carriers of this TP53 mutation.
Results: The cohort of this study comprised 51 patients from 46 different families; 67% were female. All but one harbored the TP53 p.R337H mutation in heterozygous state; only one child was homozygous for this variant. Maternal allele inheritance occurred in 72% of the cases (p= 0,002). In pediatric group, ACT was the most common primary tumor at the diagnosis (55%; median age= 2 years). No patient of the pediatric group who initially presented with ACT developed a second primary tumor and 11% (n= 3) died due to complications related to the primary tumor (median follow-up time of 81.5 months, range = 3-378 months). In adult group, the main tumors at diagnosis were: adrenocortical carcinoma (ACC) (23%; median age= 29.5 years), breast cancer (12%; median age= 38.5 years), soft tissue sarcoma (8%; median age= 50.3 years) and choroid plexus carci- noma (CPC) (2%; median age= 18 years). Among adult patients who were diagnosed with ACC as the first primary tumor, all presented with aggressive disease as per histologic and clinical criteria at diagnosis, and 75% of patients died (median follow-up time of 19 months, range = 1-69 months). Five adult patients (22%) had a second primary tumor, including bronchoalveolar lung cancer (2 cases), ACC, uterine cervical carcinoma and fibrosarcoma. The diagnosis of these tumors was established from 8 to 36 months after the first primary tumor. Three families presented more than one case of ACT. Nine malignant neoplasms were diagnosed in asympto- matic carriers using Toronto protocol.
Conclusions: This study confirms a high frequency of TP53 p.R337H mutation in pediatric group with ACT. In addition, we observed the occurrence of other tumors of LFS/LFL spectrum and a difference in the aggressiveness of ACTs depending on the age group in which they were diagnosed. The predominance of maternal mutated allele inheritance was first demonstrated in the affected Brazilian’s families.
* Corresponding author.
E-mail address: maria.villares@hc.fm.usp.br (M.C.B.V. Fragoso).
1. Introduction
Li-Fraumeni syndrome (LFS), first described in 1969, is an auto- somal dominant cancer predisposition syndrome that results from germline mutations of the TP53 tumor suppressor gene [1-3]. LFS is characterized by a high lifetime cancer risk and early age onset. LFS includes a wide range of malignancies, such as soft tissue sarcomas, breast cancer, leukemia, choroid plexus carcinoma (CPC) and adreno- cortical tumors (ACTs) [1-4]. Li-Fraumeni-like syndrome (LFL) is a variant of LFS defined by less stringent criteria [5,6].
Clinical criteria based on cancer family history have been employed to identify high risk families to LFS/LFL, in which TP53 mutation testing should be performed (Table 1).
The TP53 tumor suppressor gene is located on chromosome 17p13.1 and encodes the tumor protein p53. Tumor protein p53 upregulates the transcription of target genes involved in cell cycle arrest, DNA repair, apoptosis, and senescence in response to DNA damage [7]. Approxi- mately 80% of individuals with cancer in LFS families carry pathogenic germline TP53 mutations in exons 5-8, which typically alter the p53 DNA-binding domains. Twenty percent of them present mutations outside the DNA-binding domains; tumor profile and penetrance among these mutation carriers are much less clear [8].
1.1. TP53 p.R337H mutation
The TP53 p.R337H is located outside the DNA-binding domains, in exon 10. The arginine residue at codon 337 is part of an alpha-helix motif involved in p53 oligomerization, and structural studies have shown that replacement of arginine by histidine disrupts oligomeriza- tion in a pH-dependent manner, making the domain unable to oligo- merize in conditions of slightly elevated pH [9,10].
In South and Southeast Brazil, the germline p.R337H mutation has been identified in up to 80% of children diagnosed with ACT [11]. Previous studies on this mutation stated that its main, if not exclusive, cancer-related risk in carriers was childhood ACTs [12]. This knowl- edge, however, was soon reconsidered by the demonstration of the occurrence of tumors of the LFS spectrum other than ACTs in TP53 p.R337H carriers [13-15].
Despite this, literature is still imprecise regarding the tumor types
that are also seen in patients with this mutation, the frequency at which they occur and the prevalence of more than one malignancy in these patients. The impact of a positive genetic evaluation and cancer burden in asymptomatic relatives are also poorly understood.
Unlike other cancer predisposition syndromes, effective risk man- agement approaches in carriers of TP53 mutations remains to be es- tablished. Safe, acceptable and effective risk management strategies are needed to reduce the morbidity and mortality associated with any in- herited genetic factor that predisposes to cancer. The first step in de- veloping an effective cancer risk management program for this in- herited cancer predisposition syndrome is defining the magnitude of the cancer risk in carriers of specific mutations [16].
The aim of the current study was to evaluate Brazilian TP53 p.R337H patients with LFS and LFL to determine the first primary malignancy diagnosed, the incidence of subsequent tumors, clinical outcome and cancer burden in relatives carrying this distinct mutation.
2. Patients and methods
An observational study of Brazilian LFS/LFL patients and their re- latives who carried the TP53 p.R337H mutation was conducted at HCFMUSP/ICESP between 1986 and 2018. While the data related to the first primary malignancy in the patients (index cases) were obtained retrospectively, the incidence of subsequent tumors, clinical outcome and cancer burden in relatives carrying this specific mutation were evaluated prospectively.
2.1. Patients
All patients with ACT/ACC were submitted to the genetic analysis of the TP53 gene after the informed consent. Patients with breast cancer, sarcoma or leukemia diagnosis who met the criteria for classical LFS, Birch’s LFL criteria or Eeles’s LFL were also submitted to the analysis of the TP53 gene. All individuals harboring the germline p.R337H muta- tion are referred as patients. The first-degree relatives were invited to be genotyped and were classified as asymptomatic carriers or non- carriers of the TP53 R337H mutation. The carriers who remained in follow-up constituted the population of interest to assess the occurrence of cancer over time
Table 1 Diagnostic Criteria for Li-Fraumeni Syndrome and Li-Fraumeni-like Syndrome.
Diagnostic Criteria for LFS/LFL
ClinicalCriteria for Classic Li-FraumeniSyndrome
I. Proband with sarcoma diagnosed before age 45 years AND
II. A first degree relative with cancer before age 45 years AND
III. A first- or second-degree relative with any cancer diagnosed during this age interval or sarcoma diagnosed at any age
Birch Li-Fraumeni-like Syndrome Criteria
I. Proband with any childhood cancer or a sarcoma, brain tumor or ACC with onset at < 45 years of age
AND
II. A first-degree or second-degree relative with a core LFS cancer (sarcoma, breast cancer, brain tumor, ACC or leukemia) with onset at any age AND
III. A first- or second-degree relative with any cancer with onset before the age of 60 years
Eeles Li-Fraumeni-like Syndrome Criteria
I. Two first-degree or second-degree relatives with core LFS malignancies [sarcoma, premenopausal breast cancer, brain tumor, ACC, leukemia or lung (bronchoalveolar) cancer] at any age
Chompret Criteria for Germline TP53 Mutation Screening
I. Proband with tumor belonging to LFS tumor spectrum (e.g., soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, ACC, leukemia, lung bronchoalveolar cancer) before age 46 years AND at least one first- or second-degree relative with LFS tumor (except breast cancer if proband has breast cancer) before age 56 years or with multiple tumors
OR
II. Proband with multiple tumors (except multiple breast tumors), two of which belong to LFS spectrum and first of which occurred before age 46 years OR
III. Patient with ACC or CPC, irrespective to family history.
2.2. Clinical data
Among patients, first primary malignancy and age at its diagnosis, occurrence of subsequent primary malignancies, inheritance pattern, clinical outcomes and time of follow-up were assessed. The history of cancer in familial asymptomatic carriers was obtained prospectively either through active questionnaire by one of the investigators (A.M.F.) or through the full-body magnetic resonance imaging (MRI) program in families under follow-up over the last decade (Toronto protocol) [17].
2.3. Genetic analysis
Exon 10 of TP53 gene was analyzed by standard Sanger sequencing in all patients. In the absence of p.R337H mutation, the remaining exons were subsequently studied.
2.4. Statistics
Evaluation of inheritance pattern was a specific goal and outcome of the study. It was statistically assessed using the exact binomial test (proportion test using a single sample). The associations were con- sidered statistically significant when the p-values were less than 0.05.
3. Results
3.1. Patients
TP53 gene was analyzed in 148 probands. As expected, the great majority due to the diagnosis of ACT or ACC [Chompret criteria (n = 122)] and a few for having fulfilled the criteria of Birch or Eeles (n = 26). No case had the genetic analysis motivated by fulfilling the criteria for classical LFS. The TP53 sequencing results are shown in Graphic 1. Fifty one patients harbored the p.R337H mutation. These patients belonged to 46 different and unrelated families. Two-thirds were female (67%).
In the entire population of the study, the median age at first ma- lignancy diagnosis was 3 years (range 0.25-60 years), and the median follow-up duration was 36 months (range 1-378 months). During this follow-up period, 15 patients (29%) had a lethal clinical outcome (Table 2).
3.2. First primary malignancies and age at diagnosis
ACT among pediatric patients was the most common primary tumor at the initial diagnosis (57%; median age at diagnosis = 2 years). In adult patients, the firsts primary tumors were: ACC (24%, median age at diagnosis = 29.5 years), breast cancer (10%, median age at diag- nosis = 41 years), soft tissue sarcoma (6%, median age at diag- nosis = 50.3 years) and one case with CPC (age at diagnosis = 18 years). No case of leukemia was observed as the first malignancy in this
Cases (n; %)
O
51; 34%
95; 64%
1; 1% 1; 1%
p.R337H =p.R273H p.R290H None Graphic 1. TP53 study results.
cohort. (Table 2 and Graphic 2 ).
3.3. Occurrence of multiple primary tumors
Multiple primary tumors (n = 2) were observed in only 10% (5/51) of study patients; in all of these cases the patients were adults and primary malignancies metachronous. No patient presented more than 2 malignancies so far. Nine patients (18%) had received radiotherapy for the treatment of the first primary tumor. Among them, three developed a second primary tumor. In only one case did the second primary tumor occur in the irradiated area.
3.4. Inheritance pattern (Maternal mutated allele inheritance x paternal mutated allele inheritance)
Genetic screening of parents was performed in 34 out of 51 patients (67%). Maternal allele inheritance was observed in 73% (n = 25) of cases, paternal inheritance in 25% (n = 8) and maternal and paternal inheritance in 3% (n = 1) of cases (Graphic 3). The maternal origin of the mutated allele was significantly higher than the paternal origin (95% CI, 0.6-1.0, p = 0.002).
The few patients who inherited the mutated allele from their fathers were mostly from the group that had ACT in infancy as the first primary malignancy (pediatric group: 8 cases of paternal inheritance, 15 cases of maternal inheritance and 1 case of maternal and paternal in- heritance). Regardless of whether the mutated allele was derived from the mother or the father, no difference was seen in the evolution of the first malignancy of these patients and occurrence of subsequent tumors.
Among the 51 cases with the p.R337H mutation, only one pediatric patient with ACT was homozygous. The benign evolution of this patient for a long period of clinical follow-up (228 months) suggested that TP53 p.R337H in homozygous state may not have a more severe disease phenotype than heterozygous carriers of the same mutation.
3.5. Adrenocortical tumors and adrenocortical carcinoma
Having adrenocortical carcinoma is, per se, a sufficient clinical condition to indicate the analysis of TP53 (Table 1, Chompret criteria). From 1986-2018, 121 individuals had the TP53 gene analyzed since they were diagnosed with either ACT (pediatric group) or ACC (adult group). Among these patients, 40 (33%) had the germline p.R337H mutation. Evaluating this prevalence in relation to age group at diag- nosis, 28/41 (68%) children with ACT (≤ 15 years of age) carried this mutation. Eighty adults (> 15 years of age) were diagnosed with ACC during this period, 15% (12/80) of them presented this distinct TP53 germline mutation (p.R337 H).
3.5.1. Pediatric group
In the pediatric group, 65% presented with virilizing syndrome as the initial clinical presentation; 35% presented with Cushing’s syn- drome and virilizing syndrome. No child presented isolated cortisol excess or nonfunctioning tumors.
Size of tumor ranged from 2 cm to 14.5 cm (median = 5 cm). The Wieneke score ranged from 0 to 5 with a median of 1 point. In addition, 48% of the children were in ENSAT stage I at diagnosis, 48% in ENSAT stage II and 4% in ENSAT stage IV.
Four children evolved with disease recurrence during follow-up; one of them had a fatal evolution with 10 months of overall survival (OS). Two other deaths in this group occurred - the child who was ENSAT stage IV at diagnosis (OS = 2 months) and a child due to severe and prolonged hypercortisolism before ACT diagnosis and surgical treat- ment (OS = 1 month).
3.5.2. Adult patients
The majority of adult patients with ACC (91%) presented with hy- percortisolism at initial clinical presentation. The size of the tumor
| Characteristic | First tumor diagnosed | All | ||||
|---|---|---|---|---|---|---|
| (51) | ||||||
| Pediatric ACT | Adult ACC | Breast Cancer | Sarcoma | Choroid Plexus Carcinoma | ||
| (28) | (12) | (6) | (4) | (1) | ||
| Age - yr | ||||||
| Median | 2 | 34.5 | 38.5 | 45.5 | 18 | 3 |
| Range | 0.8 - 12 | 15 - 44 | 32 - 53 | 44-60 | – | 0.8 - 60 |
| Sex - no. (%) | ||||||
| Male | 11 (39) | 3 (25) | 0 (0) | 2(50) | 1 (100) | 17 (33) |
| Female | 17 (61) | 9 (75) | 6 (100) | 2 (50) | 0 (0) | 34 (67) |
| Follow-up - months | ||||||
| Median | 82 | 19 | 28 | 22.5 | 5 | 36 |
| Range | 1 - 378 | 0.7 - 69 | 8- 228 | 14 - 52 | – | 1 - 378 |
| Death - no. (%) | 3 (11) | 9 (75) | 1 (0) | 2 (50) | 0 (0) | 15 (29) |
ACT: adrenocortical tumor; ACC: adrenocortical carcinoma.
30
25
20
15
10
5
0
Pediatric ACT
Adult ACC
Breast Cancer
Sarcoma
Choroid Plexus Carcinoma
First tumor diagnosed among p.R337H LFS/LFL patients
Inheritance Mutated Allele Pattern
3%
Maternal
24%
Paternal
73%
Maternal & Paternal
ranged from 6.5 cm to 20 cm with a median of 12 cm. The Weiss score ranged from 4 to 9 points with a median of 7 points. Twenty percent of the individuals diagnosed with ACC in adulthood were diagnosed in ENSAT stage II, while 60% were in the ENSAT stage III, and 20% were in ENSAT stage IV.
Mortality rate was 75% (median follow-up time of 19 months, range = 1-69 months).
The presence of more than one case of ACT was observed in 3 in- dependent families. In family XIII (Supplementary Table 1), the first case was a girl diagnosed with virilizing ACT when she was 2 years old. She had a benign evolution along 20 years of follow-up. Her oldest son was diagnosed with aggressive ACT at 3 years of age; tumor was 15 cm in greatest diameter and ENSAT stage 3 (T4N1M0) at diagnosis (Fig. 1). In family XXVII, the two cases occurred in second-degree cousins; one
I
WT/WT
WT/p.R337H
II
WT/WT
Adrenocortical Tumor Dx: 2 years
WT/WT
WT/WT
III
Adrenocortical Tumor Dx: 3 years
WT/p.R337H
5
presented with ACT during infancy and had an optimal evolution (overall survival = 378 months), while the other presented ACC in adulthood and had a poor outcome (overall survival = 6 months) (Fig. 2). In family XXXIII, the two cases were first-degree cousins. Both of them presented with ACC in adulthood and were ENSAT stage IV at diagnosis, with 15 and 7 months of overall survival respectively.
3.6. Cancer burden in familial asymptomatic carriers
From the 51 patients included in this study, it was possible to identify 85 related germline p.R337H mutation asymptomatic carriers. Cancer occurred only in 9 carriers, and thus far, none of them had developed more than one cancer. Among the 9 cases, 6 of them were tumors of the LFS/LFL spectrum [breast cancer [2], bronchoalveolar lung cancer [3] and leukemia (1)]. The remaining three cases were prostate, gastric and colorectal cancer. All these cancers were diagnosed after forty years of life.
4. Discussion
Since the initial discovery of TP53 p.R337H as a recurrent germline mutation in children with ACTs in Brazil, the tumor spectrum of pa- tients carrying this mutation has been controversial as well as on its relation with clinical outcomes and on its impact on predisposition to familial cancer. The findings of this study contribute to a better un- derstanding of these issues.
?
Gastric Cancer
Leukemia Dx <50 years
7
WT/p.R337H
WT/WT
WT/WT
Lung Cancer Dx <50 years
WT/p.R337H Breast and Lung Cancer Dx 1% tumor: 53 years Dx 2nd tumor: 54 years
WT/WT
Lung Cancer Dx <50 years
Adrenocortical Tumor Dx: 2 years
WT/p.R337H
WT/WT
Adrenocortical Cancer Dx: 25 years
WT/p.R337H
WT/p.R337H
WT/WT
WT/p.R337H
In concordance with the literature, we have not found any case of de novo p.R337H mutation, a fact that is in agreement with the demon- stration of a founder effect of this genetic event being responsible for the spreading of this mutation in the population of South and Southeast Brazil [18,19]. In addition, all patients except one were characterized as being heterozygous for the mutation. The tumor behavior and clin- ical outcome of the homozygous subjects for this mutation in relation to the heterozygotes are variable according to the few publications on this specific issue [20,21]. In our experience of only one homozygous case for the p.R337H mutation, it was observed that this case did not present a worse prognosis than did heterozygotes.
Germline TP53 mutations in general are estimated to occur in 7-14% of individuals meeting the Chompret criteria [22]. Since one sufficient criterion is the presence of ACC, we identified a mutation prevalence of 33% in our study population. This result draws attention to the applicability of the Chompret criteria and to the importance of offering TP53 gene analysis for all individuals presenting with ACT (pediatric group) and ACC (adults).
The development of multiple primary cancers in TP53 mutation carriers is another hallmark of classic LFS families. More than 40% of these individuals develop second tumors, usually within 10 years after the diagnosis of the primary tumor [23-25]. In this cohort, a few pa- tients presented multiple tumors - subsequent tumors following the first malignancy were observed in 10% of patients (n = 5). Considering the entire cohort, we had a follow-up longer than 10 years in 25% of pa- tients - the high lethality of ACC in adults should be seen as the main factor responsible for this low rate. When we analyzed only the group of patients with ACT in childhood as the first malignancy, 40% were fol- lowed for at least 10 years. No patients from this group developed a second cancer. This observation differs from the finding that the probability of additional cancers is inversely correlated with younger age at diagnosis of the first malignancy [26].
The higher prevalence of maternal inheritance of the mutated allele found in our cohort is the first reported for TP53 mutations. LFS/LFL is an autosomal dominant disease, and carrying mothers and fathers are expected to have the same potential to transmit the allelic variant. Whether this finding is a consistent characteristic of p.R337H variant or a specific characteristic of our study population needs to be assessed in different and larger cohorts.
The frequency of this germline variant in children with ACTs (68%) and in adults with ACCs (15%) was very similar to that published in a previous study by our group in 2001 (77.7% and 13.5%, respectively) [13]. All patients with ACC (adults) presented with aggressive disease at diagnosis and mostly had a poor outcome, which was not observed in the pediatric group (Graphic 4). With this study, we demonstrate once more that the association between the germline mutation p.R337H and the occurrence of ACT/ACC does not define a group of worse prognosis
Survival Distribution Function
1,0
Disease
Pediatric Adrenocortical Tumor Adrenocortical Carcinoma (Adults)
0,8
0,6
0,4
0,2
0,0
,00
100,00
200,00
,300,00
400,00
Months
in the pediatric age group, but it does so in the adult group [27].
The occurrence of malignancies in asymptomatic carriers occurred in 11%, being a much lower occurrence than what is observed with mutations that alter the DNA-binding domains. This finding, despite being slightly lower than that found by Mastellaro et al. recently [8], corroborates that p.R337H is a low-penetrance variant but does lead to a higher cancer risk in asymptomatic carriers in relation to noncarriers, even in adulthood.
This study confirms that the TP53 p.R337H mutation is associated with ACT in the pediatric group but also brings new insights such as the occurrence of other tumors of the LFS/LFL spectrum, the rare occur- rence of multiple tumors, the predominance of maternal allele in- heritance and, mostly, the difference in the aggressiveness of adreno- cortical tumors depending on the age group in which they were diagnosed.
Funding
This research was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), grant number 26345-5/2017, to AMF and MCBVF.
Acknowledgments
We thank Denise Aragão for technical work. We also thank the many pediatricians and physicians who referred patients.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.jsbmb.2019.04.011.
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