TSC2 rare germline variants in non-tuberous sclerosis patients with neuroendocrine neoplasias

Asprino, Paula Fontes; Linck, Rudinei Diogo Marques; Cesar, Jonatas; Freitas, Florêncio P.; Koyama, Fernanda C.; Riechelmann, Rachel; Costa, Frederico; Hoff, Paulo M.; Galante, Pedro A. F.; Meyer, Diogo; Camargo, Anamaria A.; Sabbaga, Jorge

doi:10.1530/erc-17-0286

Cited by 6 publications

(4 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several case reports have described patients with germline pathogenic variants in TSC1 (79) and TSC2 (80), the genes causing the syndrome. In fact, the TSC2 germline variant was reported in a patient with PNETs and with no additional manifestations of TSC (80). Furthermore, mTOR inhibition was found efficacious for treating patients with a metastatic PNET with germline TSC2 mutations (81).…”

Section: Hereditary Syndromes With Low Pnet Penetrancementioning

confidence: 99%

Genetic and epigenetic alterations in pancreatic neuroendocrine tumors

Tirosh

Kebebew

2020

J Gastrointest Oncol

View full text Add to dashboard Cite

Neuroendocrine tumors (NETs) are a heterogenous group of tumors that originate from neuroendocrine cells, mainly in the pancreas and the gastrointestinal and bronchopulmonary tracts. There has been considerable progress in our understanding of the genetic and epigenetic changes associated with pancreatic NETs (PNETs). The main genetic alterations that drive PNETs include genetic alterations in MEN1, VHL and genes involved in the mTOR pathway, DAXX and/or ATRX mutations and their association with alternative telomere lengthening, and genes involved in DNA damage repair and chromatin modification. The epigenetic alterations in PNETs are also common based on genome-wide DNA methylation profiling studies, with a high rate of CpG hypermethylation in MEN1-associated PNETs compared to sporadic and VHL-associated PNETs. Moreover, the dysregulated DNA methylation status is associated with distinct gene expression profiles. This article reviews the commonly and recently discovered genetic and epigenetic changes that are associated with PNETs, inherited PNETs, and genotype-phenotype associations, and it discusses their clinical relevance.

show abstract

Section: Hereditary Syndromes With Low Pnet Penetrancementioning

confidence: 99%

Genetic and epigenetic alterations in pancreatic neuroendocrine tumors

Tirosh

Kebebew

2020

J Gastrointest Oncol

View full text Add to dashboard Cite

show abstract

“…They are typically sporadic but are known to occur with genetic syndromes such as multiple endocrine neoplasia type 1, von Hippel-Lindau disease, neurofibromatosis 1, and tuberous sclerosis complex (TSC) [2]. They are infrequent in the context of TSC compared with other genetic syndromes and have been reported almost exclusively in patients with the TSC2 variant [3, 4].…”

mentioning

confidence: 99%

Pancreatic Neuroendocrine Tumor in a Young Child With Tuberous Sclerosis Complex 1

Mehta

Rusyn

Ginsburg

et al. 2019

Journal of the Endocrine Society

View full text Add to dashboard Cite

Pancreatic neuroendocrine tumors (PNETs) occur in the context of tuberous sclerosis complex (TSC). To date, PNETs in association with TSC have been described almost exclusively in adults and in the context of TSC2. We present the evaluation of a PNET in a young child with TSC1. A 3-year, 6-month-old boy with TSC1 was found on surveillance to have a small pancreatic lesion measuring 0.4 cm on magnetic resonance imaging (MRI). The lesion showed interval enlargement to 1 cm on serial MRI studies during the ensuing 16 weeks. Endocrine laboratory tests did not reveal a functional tumor. The patient underwent enucleation of the pancreatic lesion. Microscopic examination defined a well-differentiated PNET, grade II/intermediate grade with a mitotic rate of two mitotic figures per 10 high-powered field and Ki-67 proliferation index of ∼15%. The tumor was positive for the TSC1 gene mutation. The patient was free of tumor recurrence at the 5-year follow-up examination, as determined by endocrine surveillance and annual MRI of the abdomen. In the reported data, PNET in patients with TSC has been primarily reported in association with TSC2. Our case demonstrates that patients with TSC1 can develop PNETs, even at an early age. The international TSC consensus group 2012 recommendation was to obtain MRI of the abdomen every 1 to 3 years for surveillance of renal angiomyolipomas and renal cystic disease. It might be beneficial to add a pancreatic protocol to the surveillance guidelines to evaluate for PNET.

show abstract

“…After 3 years of follow-up post NET diagnosis, the patient was enrolled in an investigational research protocol which started recruiting non-syndromic patients with gastroenteropancreatic NETs to be screened for germline mutations in genes associated with NET-predisposing syndromes. 1 The patients provided written informed consent for participation in the trial, data collection, and publication of clinical and molecular data. The study protocol was approved by the Ethics Committee of Hospital Sírio-Libanês (HSL2015-15), and the Instituto do Câncer do Estado de São Paulo (NP762/15).…”

Section: Case Reportmentioning

confidence: 99%

“… 2 Only variants with a predicted damaging impact on protein function determined by the SIFT web server 3 or by Polymorphism Phenotyping v2, PolyPhen-2, 4 and a minor allele frequency lower than 0.1% according to the gnomAD dataset 5 were used for further analysis. 1 …”

Section: Molecular Tumor Board Reviewmentioning

confidence: 99%

Suspected Germline TP53 Variants and Clonal Hematopoiesis of Indeterminate Potential: Lessons Learned From a Molecular Tumor Board

et al. 2023

Self Cite

View full text Add to dashboard Cite

Objective Li-Fraumeni syndrome (LFS) is a pan-cancer predisposition syndrome caused by germline pathogenic variants in the gene TP53. The interpretation of TP53 variants in clinical scenarios outside the classic LFS criteria may be challenging. Here, we report a patient affected by 2 primary cancers at later ages, who harbored a likely pathogenic TP53 at low allele frequency detected in a blood sample. Methods The Molecular Tumor Board committee at our institution revisited the case of a patient who was enrolled in a research protocol for the investigation of genetic conditions associated with neuroendocrine tumors. Clinical, familial, and molecular data were reviewed. The patient received germline testing using a next generation sequencing multi-gene panel and was incidentally found to harbor a TP53 likely pathogenic variant, with 22% of variant allele fraction. Additional samples, including a second blood sample, oral swab, and saliva, were collected for DNA analysis. A new TP53 sequencing round was performed with the attempt to distinguish between a true constitutional germline variant and a somatically acquired variant due to aberrant clonal expansion of bone marrow precursors. Results Patient’s personal and familial history of cancer did not meet classic nor Chompret LFS criteria. Environmental risk factors for cancer were identified, such as alcohol abuse and tobacco exposure. The TP53 variant initially found in the next-generation sequencing was confirmed by Sanger sequencing in the previous DNA sample extracted from blood for the first analysis and in a second blood sample collected 6 years later. The TP53 variant was not detected in the DNA extracted from the oral swab and saliva samples. Conclusion Considering the low TP53 variant allele fraction in blood, absence of variant detection in oral swab and saliva samples, the lack of LFS clinical criteria, and history of exposure to environmental risk factors for cancer, the main hypothesis for this case was aberrant clonal expansion due to clonal hematopoiesis. Oncologists should interpret TP53 findings during germline testing with caution.

show abstract

TSC2 rare germline variants in non-tuberous sclerosis patients with neuroendocrine neoplasias

Cited by 6 publications

References 10 publications

Genetic and epigenetic alterations in pancreatic neuroendocrine tumors

Genetic and epigenetic alterations in pancreatic neuroendocrine tumors

Pancreatic Neuroendocrine Tumor in a Young Child With Tuberous Sclerosis Complex 1

Suspected Germline TP53 Variants and Clonal Hematopoiesis of Indeterminate Potential: Lessons Learned From a Molecular Tumor Board

Contact Info

Product

Resources

About