scholarly journals A pedigree-based prediction model identifies carriers of deleterious de novo mutations in families with Li-Fraumeni syndrome

2020 ◽  
Author(s):  
Fan Gao ◽  
Xuedong Pan ◽  
Elissa B. Dodd-Eaton ◽  
Carlos Vera Recio ◽  
Matthew D. Montierth ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
De Novo ◽  
Cancer Genetics ◽  
De Novo Mutations ◽  
Cancer Syndrome ◽  
Li Fraumeni Syndrome ◽  
Inherited Cancer ◽  
Li Fraumeni ◽  
Validation Set ◽  
Hotspot Mutation

ABSTRACTDe novo mutations (DNMs) are increasingly recognized as rare disease causal factors. Identifying DNM carriers will allow researchers to study the likely distinct molecular mechanisms of DNMs. We developed Famdenovo to predict DNM status (DNM or familial mutation (FM)) of deleterious autosomal dominant germline mutations for any syndrome. We introduce Famdenovo.TP53 for Li-Fraumeni syndrome (LFS) and analyze 324 LFS family pedigrees from four US cohorts: a validation set of 186 pedigrees and a discovery set of 138 pedigrees. The concordance index for Famdenovo.TP53 prediction was 0.95 (95% CI: [0.92, 0.98]). Forty individuals (95% CI: [30, 50]) were predicted as DNM carriers, increasing the total number from 42 to 82. We compared clinical and biological features of FM versus DNM carriers: 1) cancer and mutation spectra along with parental ages were similarly distributed; 2) ascertainment criteria like early-onset breast cancer (age 20 to 35 years) provides a condition for an unbiased estimate of the DNM rate: 48% (23 DNMs versus 25 FMs); 3) hotspot mutation R248W was not observed in DNMs, although it was as prevalent as hotspot mutation R248Q in FMs. Furthermore, we introduce Famdenovo.BRCA for hereditary breast and ovarian cancer syndrome, and apply it to a small set of family data from the Cancer Genetics Network. In summary, we introduce a novel statistical approach to systematically evaluate deleterious DNMs in inherited cancer syndromes. Our approach may serve as a foundation for future studies evaluating how new deleterious mutations can be established in the germline, such as those in TP53.

Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome

2017 ◽  
Vol 55 (3) ◽  
pp. 173-180 ◽  
Author(s):  
Mariette Renaux-Petel ◽  
Françoise Charbonnier ◽  
Jean-Christophe Théry ◽  
Pierre Fermey ◽  
Gwendoline Lienard ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
De Novo ◽  
Multiple Primary Cancers ◽  
Breast Cancers ◽  
De Novo Mutations ◽  
Li Fraumeni Syndrome ◽  
Medical Laboratories ◽  
Li Fraumeni ◽  
Adrenocortical Carcinomas ◽  
Generation Sequencing

BackgroundDevelopment of tumours such as adrenocortical carcinomas (ACC), choroid plexus tumours (CPT) or female breast cancers before age 31 or multiple primary cancers belonging to the Li-Fraumeni (LFS) spectrum is, independently of the familial history, highly suggestive of a germline TP53 mutation. The aim of this study was to determine the contribution of de novo and mosaic mutations to LFS.Methods and resultsAmong 328 unrelated patients harbouring a germline TP53 mutation identified by Sanger sequencing and/or QMPSF, we could show that the mutations had occurred de novo in 40 cases, without detectable parental age effect. Sanger sequencing revealed two mosaic mutations in a child with ACC and in an unaffected father of a child with medulloblastoma. Re-analysis of blood DNA by next-generation sequencing, performed at a depth above 500X, from 108 patients suggestive of LFS without detectable TP53 mutations, allowed us to identify 6 additional cases of mosaic TP53 mutations, in 2/49 children with ACC, 2/21 children with CPT, in 1/31 women with breast cancer before age 31 and in a patient who developed an osteosarcoma at age 12, a breast carcinoma and a breast sarcoma at age 35.ConclusionsThis study performed on a large series of TP53 mutation carriers allows estimating the contribution to LFS of de novo mutations to at least 14% (48/336) and suggests that approximately one-fifth of these de novo mutations occur during embryonic development. Considering the medical impact of TP53 mutation identification, medical laboratories in charge of TP53 testing should ensure the detection of mosaic mutations.

scholarly journals A pedigree-based prediction model identifies carriers of deleterious de novo mutations in families with Li-Fraumeni syndrome

2020 ◽  
Vol 30 (8) ◽  
pp. 1170-1180
Author(s):  
Fan Gao ◽  
Xuedong Pan ◽  
Elissa B. Dodd-Eaton ◽  
Carlos Vera Recio ◽  
Matthew D. Montierth ◽  
...  
Keyword(s):  
Prediction Model ◽  
De Novo ◽  
De Novo Mutations ◽  
Li Fraumeni Syndrome ◽  
Li Fraumeni

High frequency of de novo mutations in Li-Fraumeni syndrome

2009 ◽  
Vol 46 (10) ◽  
pp. 689-693 ◽  
Author(s):  
K D Gonzalez ◽  
C H Buzin ◽  
K A Noltner ◽  
D Gu ◽  
W Li ◽  
...  
Keyword(s):  
High Frequency ◽  
De Novo ◽  
De Novo Mutations ◽  
Li Fraumeni Syndrome ◽  
Li Fraumeni

Identification and characterization of de novo TP53 mutation carriers in Li-Fraumeni syndrome families: A single institution experience.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10538-10538
Author(s):  
Carlos Christian Vera Recio ◽  
Jessica Corredor ◽  
Elissa Dodd-Eaton ◽  
Angelica M. Gutierrez-Barrera ◽  
Najat C. Daw ◽  
...  
Keyword(s):  
Tp53 Mutation ◽  
De Novo ◽  
De Novo Mutation ◽  
Brier Score ◽  
Li Fraumeni Syndrome ◽  
Mutation Carriers ◽  
Cancer Types ◽  
Li Fraumeni ◽  
Identification And Characterization

10538 Background: Li-Fraumeni syndrome (LFS) is an inherited cancer syndrome mainly caused by a deleterious mutation in TP53. An estimated 48% of LFS patients present due to a deleterious de novo mutation (DNM) in TP53. The knowledge of DNM status, DNM or familial mutation (FM), of an LFS patient requires genetic testing of both parents which is often inaccessible, making de novo LFS patients an understudied population. Famdenovo.TP53 is a Mendelian Risk prediction model used to predict DNM status of TP53 mutation carriers based on the cancer-family history and several input genetic parameters, including disease-gene penetrance. The good predictive performance of Famdenovo.TP53 was demonstrated using data collected from four historical US cohorts. We hypothesize that by incorporating penetrance estimates that are specific for different types of cancers diagnosed in family members, we can develop a model with further improved calibration, accuracy and prediction. Methods: We present Famdenovo.CS, which uses cancer-specific penetrance estimates that were derived previously using a Bayesian semi-parametric competing risk model, to calculate the DNM probability. We use our model to analyze 101 families recently collected from the Clinical Cancer Genetic program at MD Anderson Cancer Center (CCG-TP53) that includes 20 families with known DNM status and 81 families with unknown DNM status. We used the concordance index (AUC), observed:expected ratios (OE) and Brier score (BS) to measure our model’s discrimination, calibration and accuracy, respectively. We estimate the proportion of probands that present a DNM and compare DNM to FM carriers in several areas including: cancer types diagnosed, age at diagnosis, number of primary cancers diagnosed, sex, amino acid change caused by mutation in TP53. Results: Famdenovo.CS showed equally good discrimination and calibration performance to Famdenovo.TP53, while improving the overall accuracy, demonstrated by a decrease in the Brier score of -0.09 (95% CI: [-0.02, -0.19]). Of the 101 probands in the CCG-TP53 cohort, we predict 39 to be DNMs and 62 to be FMs. The cancer types and ages of diagnosis observed in FMs and DNMs are similarly distributed. Conclusions: Famdenovo.CS shows improved model accuracy in the CCG cohort. DNMs in TP53 are a prevalent cause of LFS and we did not find differences in the clinical characteristics of DNM and FM carriers. Our model allows for a systematic identification and characterization of TP53 DNM carriers.

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

2016 ◽  
Vol 39 (1) ◽  
pp. 37 ◽  
Author(s):  
David Malkin
Keyword(s):  
Wilms Tumor ◽  
Cancer Genetics ◽  
Tp53 Gene ◽  
Pleuropulmonary Blastoma ◽  
Li Fraumeni Syndrome ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Li Fraumeni ◽  
Sick Children ◽  
Risk Of Cancer

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).

Predisposing Genes in Breast and Ovarian Cancer: An Overview

1993 ◽  
Vol 79 (5) ◽  
pp. 291-296 ◽  
Author(s):  
Simon A. Smith ◽  
Bruce A.J. Ponder
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
At Risk ◽  
Chromosome 17 ◽  
Cancer Syndrome ◽  
Breast And Ovarian Cancer ◽  
Li Fraumeni Syndrome ◽  
Predisposing Genes ◽  
Li Fraumeni ◽  
Cancer Syndromes

The isolation of genes that predispose to familial disease is an important goal in cancer research. The identification of such genes « opens up » the possibility of genetic diagnosis in families so that individuals who are at risk of cancer through inheriting a predisposing mutation can be Identified. Genes that are involved in familial cancer syndromes may also be important in the pathogenesis of sporadic forms of the disease, which are often more common. In the search for genes that predispose to familial breast and ovarian cancer much recent progress has been made. A locus on the long arm of chromosome 17, in the interval 17q12-21, has been identified by genetic linkage, and appears to be responsible for disease in approximately 40 % of breast cancer families and most families that contain breast and ovarian cancer. The region containing this locus, which has been called BRCA1, has been narrowed to a 3-4 cM interval defined by THRA1, the thyroid hormone receptor locus alpha, and D17S183, an anonymous microsatellite polymorphism. Loci other than BRCA1 that have been identified appear not only to predispose to breast and/or ovarian tumors, but to tumors at other sites too. A new locus has been identified on chromosome 2 which is linked to hereditary non-polyposis colorectal cancer (HNPCC). Families with HNPCC are also at risk of endometrial cancer and tumors of the ovary, amongst other cancer sites. Finally, mutations in the p53 gene are inherited in families with Li-Fraumeni syndrome, a rare cancer syndrome predisposing to breast tumors, sarcomas, leukemia and other cancers. Li-Fraumeni syndrome is also the only inherited cancer syndrome that predisposes at least in part to breast cancer where the actual predisposing gene is known. For the other cancer syndromes, the cloning of the predisposing genes is eagerly awaited.

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

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.

scholarly journals Pre- and Post-Zygotic TP53 De Novo Mutations in SHH-Medulloblastoma

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2503
Author(s):  
Jacopo Azzollini ◽  
Elisabetta Schiavello ◽  
Francesca Romana Buttarelli ◽  
Carlo Alfredo Clerici ◽  
Laura Tizzoni ◽  
...  
Keyword(s):  
Family History ◽  
De Novo ◽  
Wide Spectrum ◽  
De Novo Mutations ◽  
Autosomal Dominant Disorder ◽  
P53 Overexpression ◽  
Tp53 Mutations ◽  
Li Fraumeni Syndrome ◽  
First Case ◽  
Germline Testing

Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder caused by mutations in the TP53 gene, predisposing to a wide spectrum of early-onset cancers, including brain tumors. In medulloblastoma patients, the role of TP53 has been extensively investigated, though the prevalence of de novo mutations has not been addressed. We characterized TP53 mutations in a monocentric cohort of consecutive Sonic Hedgehog (SHH)-activated medulloblastoma patients. Germline testing was offered based on tumor p53 immunostaining positivity. Among 24 patients, three (12.5%) showed tumor p53 overexpression, of whom two consented to undergo germline testing and resulted as carriers of TP53 mutations. In the first case, family history was uneventful and the mutation was not found in either of the parents. The second patient, with a family history suggestive of LFS, unexpectedly resulted as a carrier of the mosaic mutation c.742=/C>T p.(Arg248=/Trp). The allele frequency was 26% in normal tissues and 42–77% in tumor specimens. Loss of heterozygosity (LOH) in the tumor was also confirmed. Notably, the mosaic case has been in complete remission for more than one year, while the first patient, as most TP53-mutated medulloblastoma cases from other cohorts, showed a severe and rapidly progressive disease. Our study reported the first TP53 mosaic mutation in medulloblastoma patients and confirmed the importance of germline testing in p53 overexpressed SHH-medulloblastoma, regardless of family history.

Sign in / Sign up

Export Citation Format

Share Document