Li-Fraumeni Syndrome and p53 in 2015: Celebrating their Silver Anniversary

In a typical morning in the Cancer Genetics Clinic at The Hospital for Sick Children in Toronto, the following array of patients and families might be seen: a family of three children, all harbouring a mutation of the succinyl dehydrogenase C gene inherited from their father who had had extensive surgery several years ago for a secreting paraganglioma; three families with Li-Fraumeni syndrome, each with at least one child harbouring a TP53 gene mutation conferring a lifetime risk of cancer approaching 100% and currently undergoing surveillance for early tumour detection; two children with Li-Fraumeni syndrome undergoing treatment for cancer – one having had three cancer diagnoses before 19 months of age and the other just completing therapy for metastatic adrenocortical carcinoma at age 3; two children with von Hippel-Lindau disease being monitored for persistent pancreatic neuroendocrine tumors and cerebellar hemangioblastomas, respectively; and one child with Beckwith-Wiedeman syndrome and Wilms tumor and another child completing therapy for a pleuropulmonary blastoma (PPB).

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Neuroradiology Manifestations of Li-Fraumeni Syndrome: Epidemiology, Genetics, Imaging Findings, and Management

Neurographics ◽

10.3174/ng.2000003 ◽

2020 ◽

Vol 10 (4) ◽

pp. 228-235

Author(s):

S. Naganawa ◽

T. Donohue ◽

A. Capizzano ◽

Y. Ota ◽

J. Kim ◽

...

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Soft Tissue Sarcomas ◽

Suppressor Gene ◽

Imaging Findings ◽

Li Fraumeni Syndrome ◽

Increased Risk ◽

Li Fraumeni ◽

Risk Of Cancer

Li-Fraumeni syndrome is a familial cancer predisposition syndrome associated with germline mutation of the tumor suppressor gene 53, which encodes the tumor suppressor p53 protein. Affected patients are predisposed to an increased risk of cancer development, including soft-tissue sarcomas, breast cancer, brain tumors, and adrenocortical carcinoma, among other malignancies. The tumor suppressor gene TP53 plays an important, complex role in regulating the cell cycle, collaborating with transcription factors and other proteins. The disruption of appropriate cell cycle regulation by mutated TP53 is considered to be the cause of tumorigenesis in Li-Fraumeni syndrome. Appropriate surveillance, predominantly by using MR imaging, is used for early malignancy screening in an effort to improve the survival rate among individuals who are affected. Patients with Li-Fraumeni syndrome are also at increased risk for neoplasm development after radiation exposure, and, therefore, avoiding unnecessary radiation in both the diagnostic and therapeutic settings is paramount. Here, we review the epidemiology, genetics, imaging findings, and the current standard surveillance protocol for Li-Fraumeni syndrome from the National Comprehensive Cancer Network as well as potential treatment options.Learning Objective: Describe the cause of second primary malignancy among patients with Li-Fraumeni syndrome.

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The TP53 gene promoter is not methylated in families suggestive of Li-Fraumeni syndrome with no germline TP53 mutations

Cancer Genetics and Cytogenetics ◽

10.1016/j.cancergencyto.2009.04.014 ◽

2009 ◽

Vol 193 (1) ◽

pp. 63-66 ◽

Cited By ~ 2

Author(s):

Alena Finkova ◽

Alzbeta Vazna ◽

Ondrej Hrachovina ◽

Sarka Bendova ◽

Kamila Prochazkova ◽

...

Keyword(s):

Gene Promoter ◽

Tp53 Gene ◽

Tp53 Mutations ◽

Li Fraumeni Syndrome ◽

Li Fraumeni

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Identification and characterization of TP53 gene Allele Dropout in Li-Fraumeni syndrome and Oral cancer cohorts

Scientific Reports ◽

10.1038/s41598-018-30238-7 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 1

Author(s):

Mohammed Moquitul Haque ◽

Pradnya Kowtal ◽

Rajiv Sarin

Keyword(s):

Oral Cancer ◽

Tp53 Gene ◽

Li Fraumeni Syndrome ◽

Allele Dropout ◽

Li Fraumeni ◽

Identification And Characterization

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Evaluation of TP53 Variants Detected on Peripheral Blood or Saliva Testing: Discerning Germline From Somatic TP53 Variants

JCO Precision Oncology ◽

10.1200/po.21.00278 ◽

2021 ◽

pp. 1677-1686

Author(s):

Alison N. Schwartz ◽

Sophie R. Hyman ◽

Samantha M. Stokes ◽

Danielle Castillo ◽

Nadine M. Tung ◽

...

Keyword(s):

Peripheral Blood ◽

Cancer Genetics ◽

Hematologic Malignancy ◽

Clonal Expansion ◽

Somatic Tissue ◽

Ancillary Data ◽

Germline Variants ◽

Li Fraumeni Syndrome ◽

Panel Testing ◽

Li Fraumeni

PURPOSE Multigene panel testing (MGPT) identifies TP53 pathogenic or likely pathogenic (P/LP) variants in patients with diverse phenotypes, of which only one is classic Li-Fraumeni syndrome. Low variant allelic fraction (VAF) in TP53 found on germline testing may suggest aberrant clonal expansion or constitutional mosaicism. We evaluated TP53-positive probands seen in a cancer genetics program to determine germline versus somatic status. METHODS We reviewed TP53-positive probands from 2012 to 2019 identified by MGPT on blood or saliva (N = 84). Available VAFs were collected. Probands with a familial variant, who met Li-Fraumeni syndrome testing criteria or who carried a founder variant, were considered germline. For those with uncertain germline status, TP53 variants were further examined using ancillary data of family members and somatic tissue. RESULTS Of the 84 probands, 54.7% had germline variants with 33.3% meeting criteria for germline status and 21.4% confirmed through ancillary testing. Aberrant clonal expansion comprised 13.1% with clonal hematopoiesis of indeterminate potential and 2.4% with a hematologic malignancy. Constitutional mosaicism was confirmed in 8.3% probands. Definitive status could not be determined in 3.6% despite ancillary assessment, and 17.9% did not have ancillary testing. CONCLUSION A TP53 P/LP variant found on peripheral blood or saliva MGPT does not always originate in the germline. In a clinical cancer genetics cohort, approximately half of the patients had TP53 P/LP germline variants; these patients plus those with constitutional mosaicism require intensified surveillance. A framework of multiple strategies enables discernment of germline from constitutional mosaic and acquired variants, which is essential for appropriate management.

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Nearly half of TP53 variants are misattributed to Li-Fraumeni syndrome: A clinical evaluation of individuals with TP53 variants detected by hereditary cancer panel assays on blood or saliva.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10501 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10501-10501

Author(s):

Alison Schwartz ◽

Sophie Hyman ◽

Samantha Stokes ◽

Danielle Castillo ◽

Jeffrey N. Weitzel ◽

...

Keyword(s):

Cancer Genetics ◽

Hematologic Malignancy ◽

Tissue Samples ◽

Cultured Fibroblasts ◽

Li Fraumeni Syndrome ◽

Panel Testing ◽

Cultured Skin ◽

Somatic Status ◽

Li Fraumeni ◽

Status Data

10501 Background: Multigene panel testing (MGPT) has identified TP53 pathogenic or likely pathogenic (P/LP) variants in patients with diverse phenotypes from no cancer to classic Li-Fraumeni syndrome (LFS). There is increasing recognition of variants at low allelic fraction (VAF) for TP53 in particular, which can be suggestive of post-zygotic mosaicism or aberrant clonal expansion (ACE), comprising clonal hematopoiesis of indeterminate potential (CHIP) or occult hematologic neoplasia. Distinguishing among these categories is essential because of widely different cancer risk and management implications for patients and their relatives. We report an evaluation of TP53 positive probands to determine germline versus somatic status from a cancer genetics clinic. Methods: We reviewed probands with TP53 P/LP variants by MGPT on blood (N = 83) or saliva (N = 1) samples from 2012-2019. Available VAFs were collected from commercial testing laboratories. Probands positive for a known familial variant, who met LFS testing criteria without indication of low VAF, or who carried the Brazil founder p.R337H variant were considered germline. For those with uncertain germline status, data was obtained from ancillary testing of family members, cultured skin fibroblasts, and other somatic benign or tumor tissues. TP53 variants were further categorized based on all available data. Results: Of the 84 probands, 28 (33%) had germline TP53 P/LP variants determined by above initial criteria; 18 (21%) were confirmed germline through ancillary testing. Seven (8%) individuals were classified as having constitutional mosaicism. In eleven (13%) individuals, the TP53 variants were consistent with ACE, in 9 (11%) with CHIP and in 2 (2%) with a hematologic malignancy (1 CLL, 1 NHL). Five (6%) cases could not be categorized despite ancillary testing. Fifteen (18%) probands declined any further workup. Conclusions: A TP53 P/LP variant found on peripheral blood or saliva MGPT does not always originate in the germline. In a clinical cancer genetics cohort, only 54% of patients had TP53 P/LP germline variants; these patients plus those with constitutional mosaicism (8%) require intensified surveillance. Assessment of VAF, family member testing, and analysis of TP53 in cultured fibroblasts or other tissue samples may distinguish germline and constitutional mosaic variants from the ACE spectrum. Expanding use of MGPT will increase this clinical challenge, which may motivate the modification of lab reports to include VAF and possible non-germline explanations. The findings of this study support a framework of multiple strategies to discern true constitutional status of a TP53 P/LP variant.

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Efficacy of oral metformin in a patient with metastatic adrenocortical carcinoma: Examination of mechanisms and therapeutic implications

Rare Tumors ◽

10.1177/2036361317749645 ◽

2018 ◽

Vol 10 ◽

pp. 203636131774964 ◽

Cited By ~ 2

Author(s):

RD Peixoto ◽

LM Gomes ◽

TT Sousa ◽

DJ Racy ◽

M Shigenaga ◽

...

Keyword(s):

Adrenocortical Carcinoma ◽

Tp53 Mutation ◽

Germ Line ◽

Objective Response ◽

Tp53 Gene ◽

Li Fraumeni Syndrome ◽

Therapeutic Implications ◽

Treatment Regimens ◽

First Line Therapy ◽

Li Fraumeni

Although rare, adrenocortical carcinoma is among the most common tumors found in children with Li-Fraumeni syndrome and Li-Fraumeni-like syndrome, associated with germ-line mutations in the TP53 gene. In southern Brazil, one form of Li-Fraumeni syndrome, associated with childhood adrenocortical carcinoma, is caused by a mutation in the R337H TP53 tetramerisation domain and is attributed to a familial founder effect. Adrenocortical carcinoma is considered an aggressive neoplasm, usually of poor prognosis and is generally unresponsive to systemic chemotherapy. Optimal treatment regimens remain to be established. We report the case of a young woman with metastatic adrenocortical carcinoma, who achieved stable disease with mitotane, cisplatin, doxorubicin, and etoposide as first-line therapy, but then had an objective response to oral metformin that lasted 9 months. The presence of the R337H TP53 mutation suggests a mechanism for the observed response to metformin.

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Wilms tumor and von Hippel Lindau disease

Onco-Nephrology ◽

10.1016/b978-0-323-54945-5.00035-7 ◽

2020 ◽

pp. 244-250.e2

Author(s):

JOSHUA A. SAMUELS

Keyword(s):

Wilms Tumor ◽

Von Hippel Lindau ◽

Von Hippel Lindau Disease

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Recurrent Pleomorphic Myxoid Liposarcoma in a Patient With Li-Fraumeni Syndrome

International Journal of Surgical Pathology ◽

10.1177/1066896919878804 ◽

2019 ◽

Vol 28 (2) ◽

pp. 225-228 ◽

Cited By ~ 3

Author(s):

Somaye Y. Zare ◽

Mariah Leivo ◽

Oluwole Fadare

Keyword(s):

Young Patients ◽

B Cell Lymphoma ◽

Myxoid Liposarcoma ◽

Tp53 Gene ◽

Anterior Chest Wall ◽

Second Primary ◽

Mdm2 Gene ◽

Li Fraumeni Syndrome ◽

First Case ◽

Li Fraumeni

Pleomorphic myxoid liposarcoma is an extremely rare, clinically aggressive subtype of liposarcoma that has been primarily reported in young patients. In this article, we report a case of a pleomorphic myxoid liposarcoma that presented as a second primary neoplasm in a 34-year-old man with history of primary mediastinal large B-cell lymphoma. During the clinical workup, the patient was diagnosed with a germline TP53 gene mutation and Li-Fraumeni syndrome. The tumor, a 2.9 × 2.3 × 2.0 cm well-demarcated and solid mass, was centered in the anterior chest wall soft tissue. Histologically, most of the tumor displayed abundantly myxoid stroma, low cellularity of mostly bland spindle cells, delicate branching capillaries, and lipoblasts; these areas transitioned to small areas whose features were reminiscent of pleomorphic liposarcoma. As assessed by fluorescence in situ hybridization, the tumor showed no DDIT3 ( CHOP) (12q13) rearrangements or MDM2 gene amplification. Clinically, the tumor progressed with multiple recurrences and metastasis to the humerus bone. To our knowledge, this is the first case of pleomorphic myxoid liposarcoma diagnosed in an adult with Li-Fraumeni syndrome.

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