Report of 2 Pediatric Cases With Li-Fraumeni Syndrome Related Malignancy in a Family
Mami Takeoka, MD, Hidemi Toyoda, MD, PhD, Junya Hirayama, MD,
Naofumi Suzuki, MD, Ryo Hanaki, MD, Keishiro Amano, MD, PhD,
Shotaro Iwamoto, MD, PhD, and Masahiro Hirayama, MD, PhD
Summary: Li-Fraumeni syndrome (LFS) is a rare inherited disease characterized by a high and early-onset cancer risk. A cancer sur- veillance program is important to reduce cancer-related morbidity and mortality in individuals with LFS. We report 2 pediatric cases with LFS-related malignancy in a family. Eight-year-old elder brother was diagnosed with adrenocortical carcinoma and was found to have a heterozygous missense germline mutation c.736A >G: p.Met246Val in the TP53 gene. Cancer screening led to the diagnosis of rhabdo- myosarcoma at a curable stage in his 2-year-old younger brother. Comprehensive surveillance resulted in early tumor detection and improved survival.
Key Words: Li-Fraumeni syndrome, adrenocortical carcinoma, rhabdomyosarcoma
(J Pediatr Hematol Oncol 2021;43:e567-e570)
L i-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome. It was initially described in 1969 by Li and Fraumeni1 in 4 families. The original definition of the syndrome was established in 1988 as the result of an analysis of 24 families presenting with an autosomal dominant transmission of early-onset tumors including soft tissue sarco- mas, breast cancers, central nervous system tumors, leukemia and adrenocortical carcinomas (ACCs) before the age of 45 years.2 In 1990, germline TP53 mutations were identified in LFS families.3,4 Therefore, LFS can be defined as an inherited form of cancers caused by germline mutations of the TP53 gene.5 The identification of germline TP53 mutations in patients not fulfilling the original definition of LFS syndrome led to periodic updates of operational LFS criteria.6,7 These criteria, designated “the Chompret criteria,” take into account the 3 clinical situations suggestive of LFS: (1) familial pre- sentation (a proband with an LFS tumor [breast cancer, soft tissue sarcomas, osteosarcoma, central nervous system tumor, ACC, leukemia, bronchoalveolar lung cancer] under 46 y and one first-degree or second-degree relative with an LFS tumor under 56y or with multiple tumors), (2) multiple primary tumors (2 of which belong to the narrow LFS spectrum, the first being developed before 46 y), or (3) rare cancers (ACC or choroid plexus carcinoma irrespective of the family history).6-8 The sensitivity and specificity of these criteria have been esti- mated to be 82% to 95% and 47% to 58%, respectively.”
Germline TP53 testing is currently most commonly considered for individuals meeting original or Chompret criteria.
We report here 2 siblings with pediatric LFS; one of them presented with ACC and the other was diagnosed with rhabdomyosarcoma (RMS) detected during active surveil- lance. Comprehensive cancer surveillance led to the diag- nosis of RMS at a curable stage in second case.
CASES
A 8-year-old boy was referred for acne, moon face, increased appetite, and excessive weight gain. He had no past history of chronic diseases or medications. In his family medical history, paternal grandmother’s brother presented bone sarcoma at the age of 20 and paternal great-grand- parents had died of carcinomas. At the time of presentation, his height was 117 cm (2nd percentile) and weight was 27.8 kg (51st percentile). His weight had increased by 5 kg over the last 2 months. His blood pressure was elevated for age and sex (120/78 mm Hg, above the 95th percentile). On physical examination, the patient was noted to have hirsutism on trunk and extremities. He had moon face, central obesity and acne on face. His abdomen was flat and soft, and no mass was palpable. He did not have skin pigmentation, axillary hair, or pubic hair. Laboratory results revealed elevated cortisol levels (37.4 g/dL, normal range: 6 to 22 µg/dL) without circadian variation. Serum adrenocorticotropic hormone was sup- pressed (<0.1 pg/mL, normal range: 7.4 to 23 pg/mL). A large heterogenous tumor was detected in contact with the left adrenal gland on magnetic resonance imaging (MRI) (Fig. 1A). A solid, encapsulated, redbrown 13×9×6 cm tumor was resected. Histopathology showed a neoplastic process consisting of large polygonal cells with abundant granular eosinophilic cytoplasm. Nuclei were markedly variable in size, with some showing large intranuclear inclusions. Extensive zonal necrosis and invasion into the capsule was present. The nuclear grade was high (Fuhrmann grade IV). On the basis of a Weiss Score of 7 of 9 the final pathologic diagnosis was ACC (T2N0M0, stage 2). Although mitotane was initiated, it was difficult for him to take it orally. Four months following radical surgery, a local recurrence was diagnosed. Despite adjuvant chemotherapy (doxorubicin, etoposide, and cispla- tin) with mitotane, the relapsed tumor continued to increase in size and number, and disseminated to the lungs. The patient died of tumor progression 7 months after diagnosis. Since studies of children with what appears to be sporadic ACC reveal a 50% to 80% prevalence of germline TP53 mutations,9 germline DNA from leukocytes was sequenced. Figure 2 shows genomic DNA sequencing of nucleotides 726 to 746 in exon 7 of TP53. The A736G mutation, was revealed which resulted in the substitution of methionine 246 with valine in the TP53 protein (Fig. 2).
From the Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan.
Reprints: Hidemi Toyoda, MD, PhD, Department of Pediatrics, Mie University Graduate School of Medicine, 2-174 Edobashi Tsu, Mie 514-8507, Japan. E-mail: htoyoda@clin.medic.mie-u.ac.jp
A
B
Since the diagnosis of LFS was suspected based on the family history of cancer and confirmed by gene analysis, the other family members were screened genetically and clinically. The same germline mutation in TP53 gene was detected in the proband’s younger brother, the proband’s elder sister and the proband’s father. One week after the diagnosis of LFS was established, the proband’s younger brother, 2 years of age, was referred to our hospital due to a left temporal mass. It was noticed by physical examination that was performed because of the diagnosis of LFS. He had no past history of chronic dis- eases or medications. The mass was hard and 2×2 cm in size. There was no redness, heat or pain. Blood examination was normal including tumor makers. MRI showed a 1.8×3.3×3 cm heterogenous mass with hemorrhage in the left temporal region (Fig. 1B). An excisional biopsy was performed on day 14. Histology revealed a tumor composed of large round and spindle cells with an increase in the nucleocytoplasmic ratio. In addition, immunohistochemical analysis showed positive staining for desmin, myogenin, and p53. He was finally diag- nosed with embryonal RMS (T1N0M0, stage 1) and classified as low-risk subgroup A because of microresidual disease but no regional lymph node metastasis.10 He was treated with a Japan Rhabdomyosarcoma Study Group (JRSG) low-risk subgroup A protocol, consisting of 8 cycles of vincristine, actinomycin-D,
and cyclophosphamide 1.2 g/m2 (total dose 9.6 g/m2).10 Since he was found to have the same TP53 germline mutation, local radiotherapy was avoided. He remains in complete remission with no evidence of tumor recurrence 4 years after treatment. Their elder sister and their father carrying the same germline TP53 mutation are also under cancer surveillance and there is no evidence of tumor.
DISCUSSION
We report 2 siblings with pediatric LFS; one of them presented with ACC and the other was diagnosed with RMS detected during active surveillance. Both patients were found to have a heterozygous point mutation in exon 7 of the germline TP53 gene (c.736A > G: p.Met246Val). More than 250 different germline TP53 pathogenic variants have been reported.11,12 Missense mutations are the most common, occurring in ~70% of cases.11,12 Whether the c.736A>G germline mutation leads to loss of function of TP53 must be confirmed. This mutation in TP53 gene has been reported in a family affected with either breast or prostate cancer13 and in an individual affected with Wilms tumor, in whose mother- who had both cervical cancer and glioma-this variant had also been detected.14 TP53 pathogenic variants have been
A736G
our cases
wild type
reported within exons 5 to 8, which encode the core DNA- binding region of the gene15 and 8 hotspot codons (codons 175, 176, 220, 245, 248, 249, 273, and 282)12 represent ~30% of these mutations. A TP53 c.736A > G missense mutation is located within the hotspot codons. Monti et al16 showed that the Met246Val variant had severe deficiency to transactivate MDM2, BAX, and PUMA by using a luciferase-based yeast functional assay, when compared with the wild-type allele. In addition, Singerland and Benchimol17 reported that Met246Val variant in TP53 gene indicates reduced tumor suppressing ability when cotransfected with Ras in a study performed in rat embryo fibroblasts. Therefore, the c.736A > G mutation is likely to affect loss of function and dominant- negative effects of TP53.
The early detection of cancer has the potential to reduce morbidity and mortality in individuals with LFS. In our second case, comprehensive cancer surveillance performed soon after LFS diagnosis revealed a left temporal RMS at curable stage. To improve overall outcomes by enabling the early detection and treatment of tumors, the American Association of Cancer Research recommended that individuals with LFS (as defined by the identification of a pathologic TP53 germline mutation and/or by meeting the classic clinical LFS criteria) should be offered cancer surveillance as soon as the clinical or molecular LFS diagnosis is established.18 Physical examination in con- junction with frequent blood test and imaging studies are rec- ommended to monitor carriers of a germline TP53 mutation.9 In 2011, Villani et al19 reported the first prospective study of comprehensive clinical surveillance for individuals with LFS. It was reported that 40 asymptomatic tumors have been detected in 19 of 59 patients who underwent surveillance whereas among the 49 individuals who initially declined surveillance, 61 symptomatic tumors were diagnosed in 43 patients.20 Five-year overall survival was 88.8% in the surveillance group but 59.6% in the nonsurveillance group (P=0.0132).20 This data suggests that a comprehensive surveillance strategy is clinically relevant. The current guidelines recommended by the United States National Comprehensive Cancer Network include screening for breast cancer with annual breast MRI and/or mammog- raphy, based on age, annual rapid whole-body MRI with or without a separate brain MRI, colonoscopy every 2 to 5 years, annual dermatologic examination, and additional targeted surveillance based on family history of cancer.21 In our insti- tution, asymptomatic family members with TP53 germline mutation receive comprehensive screening based on the guideline including physical examination, blood testing, ultra- sonography, and MRI. However, it has been reported that non-MRI techniques, including baseline blood tests, abdominal ultrasonography in children, mammography, and colonoscopy, did not lead to a diagnosis of prevalent cancer.21 Therefore, identification of the optimal screening regimen is needed.
The tumors most closely associated LFS are called “core” cancers. Fifty percent to 80% of children with ACC have a germline TP53 mutation, even in the absence of an obvious family history.20 We started the investigation of LFS for the other family members because the first cancer case was an AAC. If the RMS case diagnosed first, the investigation protocol for LFS and the surveillance would not have been implemented. Furthermore, the proband’s father and paternal grandmother probably carrying the same pathogenic variant in TP53 had not experienced early-onset tumors, while the proband and his younger brother had experienced early-onset ACC and RMS, respectively. The potential causes of pheno- typic differences among members of the same family are not known. Therefore, in such cases, it is very important to look
carefully at the family history for clues that indicate a possible hereditary cancer.
The accurate diagnosis of LFS can improve the quality of life and long term survival in LFS families. Early diagnosis and management for cancers are important to reduce cancer- related morbidity and mortality in individuals with LFS, a rare, highly penetrant cancer predisposition syndrome.
CONCLUSIONS
In conclusion, we present 2 siblings with pediatric LFS; one of them presented with ACC and the other was diagnosed with RMS detected during comprehensive cancer surveillance. LFS is a well described disease and the tumors that our patients had are common in this condition. However due to its rarity it is important to have a high index of suspicion. The second case had successful outcome due to the early diagnosis. It suggests that rigorous and comprehensive surveillance of individuals and families with LFS could improve survival through early diagnosis of malignant tumors at curable stages.
ACKNOWLEDGMENT
The authors thank Dr Ataru Nakatani (Mie University Graduate School of Medicine) for performing the DNA sequencing.
REFERENCES
1. Li FP, Fraumeni JF Jr. Soft tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med. 1969;71:747-752.
2. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988;48:5358-5362.
3. Malkin D, Li FP, Strong LC, et al. Germline p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250:1233-1238.
4. Srivastava S, Zou ZQ, Pirollo K, et al. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li- Fraumeni syndrome. Nature. 1990;348:747-749.
5. McBride KA, Ballinger ML, Killick E, et al. Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nat Rev Clin Oncol. 2014;11:260-271.
6. Chompret A, Abel A, Stoppa-Lyonnet D, et al. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet. 2009;38:43-47.
7. Tinat J, Bougeard G, Baert-Desurmont S, et al. Version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol. 2009;27:e108-e109.
8. Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li- Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. 2015;33:2345-2352.
9. Valdez JM, Nichols KE, Kesserwan C. Li-Fraumeni syndrome: a paradigm for the understanding of hereditary cancer predisposition. Br J Haematol. 2017;176:539-552.
10. Hosoi H. Current status of treatment for pediatric rhabdomyo- sarcoma in the USA and Japan. Pediatr Int. 2016;58:81-87.
11. Wasserman JD, Novokmet A, Eichler-Jonsson C, et al. Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children’s oncology group study. J Clin Oncol. 2015;3:602-609.
12. Oliver M, Goldgar DE, Sodha N, et al. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and Tp53 genotype. Cancer Res. 2003;63:6643-6650.
13. Li J, Meeks H, Feng BJ, et al. Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families. J Med Genet. 2016;53:34 42.
14. Bardeesy N, Falkoff D, Petruzzi MJ, et al. Anaplastic Wilms’ tumor, a subtype displaying poor prognosis, harbours p53 gene mutations. Nat Genet. 1994;7:91-97.
15. Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, eds. Gene Revews® [Internet]. Seattle, WA: University of Washington, Seattle; 1999.
16. Monti P, Perfumo C, Bisio A, et al. Dominant-negative feutures of mutant p53 in germline carriers have limited impact on cancer outcomes. Mol Cancer Res. 2011;9:271-279.
17. Slingerland JM, Benchimol S. Transforming activity of mutant human p53 alleles. J Cell Physiol. 1991;148:391-395.
18. Kratz CP, Achatz MI, Brugières L, et al. Cancer screening recommendations for individuals with Li-Fraumeni syndrome. Clin Cancer Res. 2017;23:e38-e45.
19. Villani A, Tabori U, Schiffman J, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. 2011;12:559-567.
20. Villani A, Shore A, Wasserman JD, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016;17:1295-1305.
21. Mai PL, Khincha PP, Savage SA, et al. Prevalence of cancer at baseline screening in the national cancer institute Li-Fraumeni syndrome cohort. JAMA Oncol. 2017;3: 1640-1645.