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PLoS One 2019 18;14(4):e0215453. Epub 2019 Apr 18.

Department of Medicine III, University Hospital Munich, Ludwig-Maximilians-University Munich-Campus Großhadern, Munich, Germany.

Background And Objective: The revised World Health Organization classification of 2016 for myeloid neoplasms and acute leukemia added a section of myeloid neoplasms with germline predisposition. The main objective of our study was to evaluate the frequency of hematologic and solid malignancies in the family history of patients with acute myeloid leukemia (AML) by using a systemic pedigree interview. The family history was taken of 50 patients between 24 and 80 years. Read More

Hum Mutat 2019 Apr 18. Epub 2019 Apr 18.

Oncogenetics Unit, Oncology Center, Sírio-Libanês Hospital, São Paulo, Brazil.

Gastroenterology 2019 Apr 11. Epub 2019 Apr 11.

Clinical Genetics Branch, National Cancer Institute, Bethesda, Maryland.

Biosocieties 2018 Dec 28;13(4):761-779. Epub 2018 Sep 28.

Drawing on empirical ethnographic research in Brazil this paper examines how in the spaces between identifying genetic markers and conditional cancer risk, environments and diverse epigenetic logics are emerging and being negotiated among research and clinical communities, patients and their families. Focusing on an arena of research and medical intervention related to a gene variant known as R337h, thought to occur with high frequency in the south of Brazil and linked to the cancer syndrome Li-Fraumeni, it emphasises the relevance of examining epigenetics as an emic category but also its utility as an analytic category. It shows how in a context of not yet fully knowing how and in what ways R337h contributes to increased cancer, a range of different 'environments' are invoked that unevenly articulate an emerging and still inchoate and unfolding terrain of understanding. Read More

J Steroid Biochem Mol Biol 2019 Apr 8. Epub 2019 Apr 8.

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (FMUSP), Av Dr Eneas de Carvalho Aguiar, 155, 05.403-000, Sao Paulo, Brazil. Electronic address:

J AAPOS 2019 Apr 8. Epub 2019 Apr 8.

Department of Ophthalmology, Hospital for Sick Children, Toronto, Ontario.

J Genet Couns 2019 Apr 14;28(2):343-354. Epub 2018 Dec 14.

Department of Social Research, University of Helsinki, Unioninkatu 37, P.O. Box 54, 00014, Helsinki, Finland.

Genome-wide sequencing may generate secondary findings (SFs). It is recommended that validated, clinically actionable SFs are reported back to patients/research participants. To explore publics' perspectives on the best ways to do this, we performed a vignette study among Finnish adults. Read More

Cold Spring Harb Mol Case Stud 2019 Mar 18. Epub 2019 Mar 18.

St. Jude Children's Research Hospital, Memphis, TN;

Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome caused by heterozygous germline mutations in the TP53 gene. Although several missense and null TP53 mutations are well established as disease-causing, little is known about the pathogenicity and cancer risks associated with small in-frame deletions. This leads to challenges in variant classification and subsequent difficulty making a molecular diagnosis. Read More

Oxf Med Case Reports 2019 Feb 27;2019(2):omz006. Epub 2019 Feb 27.

General Medicine, Alexandra Health System Woodlands Health Campus, Singapore.

Adrenocortical carcinoma is a rare endocrine malignancy with poor prognosis. Adrenocortical carcinoma can be seen in familial syndromes such as multiple endocrine neoplasia 1(MEN-1), Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome and Carney complex (Kjellman, M, Roshani, L, The, BT . Genotyping of adrenocortical tumours: very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16. Read More

Hum Mutat 2019 Mar 6. Epub 2019 Mar 6.

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.

Germline pathogenic variants in the TP53 gene cause Li-Fraumeni syndrome, a condition that predisposes individuals to a wide range of cancer types. Identification of individuals carrying a TP53 pathogenic variant is linked to clinical management decisions, such as the avoidance of radiotherapy and use of high-intensity screening programs. The aim of this study was to develop an evidence-based quantitative model that integrates independent in silico data (Align-GVGD and BayesDel) and somatic to germline ratio (SGR), to assign pathogenicity to every possible missense variant in the TP53 gene. Read More

Australas J Dermatol 2019 Feb 26. Epub 2019 Feb 26.

Department of Dermatology, School of Medicine, Ankara University, Ankara, Turkey.

J Mol Biol 2019 Feb 21. Epub 2019 Feb 21.

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

Nearly one-third of non-synonymous single-nucleotide polymorphism (nsSNPs) are deleterious to human health, but recognition of the disease-associated mutations remains a significant unsolved problem. We proposed a new algorithm, DAMpred, to identify disease-causing nsSNPs through the coupling of evolutionary profiles with structure predictions of proteins and protein-protein interactions. The pipeline was trained by a novel Bayes-guided artificial neural network algorithm that incorporates posterior probabilities of distinct feature classifiers with the network training process. Read More

Oncotarget 2019 Jan 18;10(6):631-632. Epub 2019 Jan 18.

Cardiovascular Branch, DIR, NHLBI, National Institutes of Health, Bethesda, Maryland, USA.

Orv Hetil 2019 Feb;160(6):228-234

Sebészeti Klinika, Szegedi Tudományegyetem, Általános Orvostudományi Kar Szeged, Semmelweis u. 8., 6720.

Li-Fraumeni syndrome is a rare genetic disorder predisposing the individual to multiple different cancer types, caused by a germline mutation of the TP53 or CHEK2 genes inherited in an autosomal dominant manner. We hereby describe the case of a family with Li-Fraumeni syndrome. An asymptomatic 40-year-old female was diagnosed with primary lung leiomyosarcoma (T3N0), adenocarcinoma (T1aN0), and inflammatory myofibroblastic tumor, which were surgically removed without further treatment. Read More

Pediatr Blood Cancer 2019 May 4;66(5):e27629. Epub 2019 Feb 4.

Program in Personalized Health, University of Utah, Salt Lake City, Utah.

Introduction: Patients with germline TP53 pathogenic variants (Li-Fraumeni syndrome [LFS]) are at extremely high lifetime risk of developing cancer. Recent data suggest that tumor surveillance for patients with LFS may improve survival through early cancer detection. The objective of this study was to assess the cost-effectiveness of a cancer surveillance strategy for patients with LFS compared with those whose tumors present clinically. Read More

Cold Spring Harb Mol Case Stud 2019 Feb 1;5(1). Epub 2019 Feb 1.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA.

Li-Fraumeni syndrome (LFS) is an autosomal dominant condition associated with a high risk of a broad range of childhood- and adult-onset cancers. LFS is related to germline mutations of the tumor-suppressor gene The most common reported leukemia associated with LFS is hypodiploid acute lymphoblastic leukemia, but myeloid malignancies including acute myeloid leukemia (AML), chronic myeloid leukemia, and myelodysplastic syndrome (MDS) are also reported, often in the setting of therapy-related disease. We reviewed the clinicopathologic characteristics including cytogenetics and molecular analysis for seven adult patients with LFS and hematologic malignancies evaluated at the Hereditary Hematologic Malignancy Clinic (HHMC) at MD Anderson Cancer Center. Read More

Cir Esp 2019 Jan 29. Epub 2019 Jan 29.

Servicio de Cirugía General y Digestiva, Hospital Virgen de la Luz, Cuenca, España.

BMC Cancer 2019 Feb 1;19(1):118. Epub 2019 Feb 1.

Instituto Nacional de Cancerología, San Fernando Avenue #22, Zip Code 14080, Tlalpan, Mexico City, Mexico.

Background: Heterozygous germline TP53 gene mutations result in Li-Fraumeni Syndrome (LFS). Breast cancer (BC) is the most frequent tumor in young women with LFS. An important issue related to BC in the Mexican population is the average age at diagnosis, which is approximately 11 years younger than that of patients in the United States (U. Read More

Exp Hematol 2019 Mar 16;71:61-67. Epub 2019 Jan 16.

INSERM UMR-S 935 and ESTeam Paris Sud, Université Paris Sud, Villejuif, France; INGESTEM National iPSC Infrastructure, Villejuif, France.

Over the last decade, the possibility of reprogramming malignant cells to a pluripotent state has been achieved in several hematological malignancies, including myeloproliferative neoplasms, myelodysplastic syndromes, and chronic myeloid leukemia (CML). It has been shown that it is readily possible to generate induced pluripotent stem cells (iPSCs) from several types of primary CML cells and to generate progenitors and differentiated cells with variable efficiency. Although these experiments have brought some new insights in the understanding of CML pathophysiology, the ultimate goal of generating induced leukemic stem cells (LSCs) with long-term multilineage potential has not yet been demonstrated. Read More

Mol Clin Oncol 2019 Jan 26;10(1):153-158. Epub 2018 Oct 26.

Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.

The prognosis of childhood cancers has improved markedly, and the proportion of long-term survivors has increased in recent years. However, with the increase in the number of long-term survivors, the development of latent treatment-related adverse effects, such as secondary malignancies, has generated new problems. Secondary cancer is defined as a histologically distinct malignancy that develops at least 2 months after the completion of treatment for primary cancer. Read More

J Eur Acad Dermatol Venereol 2019 Apr 27;33(4):e174-e175. Epub 2019 Feb 27.

Department of Dermatology, College of Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Korea.

J Clin Oncol 2019 Feb 4;37(6):461-470. Epub 2019 Jan 4.

1 University of Toronto, Toronto, Ontario, Canada.

Purpose: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. Read More

Fam Cancer 2019 Apr;18(2):273-280

Department of Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB, Utrecht, The Netherlands.

Early-onset breast cancer may be due to Li-Fraumeni Syndrome (LFS). Current national and international guidelines recommend that TP53 genetic testing should be considered for women with breast cancer diagnosed before the age of 31 years. However, large studies investigating TP53 mutation prevalence in this population are scarce. Read More

J Psychosoc Oncol 2018 Dec 28:1-16. Epub 2018 Dec 28.

a Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics , National Cancer Institute , Rockville , Maryland , USA.

Purpose: Li-Fraumeni Syndrome (LFS) is an inherited tumor predisposition syndrome with lifetime cancer risks approaching 100% and evolving risk-management strategies. This study evaluated couples' coping with LFS-related burdens.

Research Approach: Constructivist grounded theory and anticipatory loss frameworks guided design and analysis. Read More

NPJ Genom Med 2018 19;3:35. Epub 2018 Dec 19.

2Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, 11525 Saudi Arabia.

Li-Fraumeni syndrome (LFS) is an inherited, autosomal-dominant condition that predisposes individuals to a wide-spectrum of tumors at an early age. Approximately 70% of families with classic LFS have pathogenic variants in the tumor suppressor gene that disrupt protein function or stability. While more than 70% of pathogenic variants in are missense variants, the vast majority occur very infrequently, and thus their clinical significance is uncertain or conflicting. Read More

Am J Pathol 2019 Jan;189(1):22-35

Yale Center for Pancreatic Diseases, Yale School of Medicine, New Haven, Connecticut; Yale Center for Pancreatic Diseases, Department of Digestive Diseases, Yale School of Public Health, New Haven, Connecticut. Electronic address:

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of only 8% and is estimated to be the second leading cause of cancer-related deaths by 2021. Prior convention held that screening for PDAC would not be beneficial; however, a deeper understanding of the carcinogenesis pathway supports a potential window of opportunity among the target population. Screening for PDAC is not a standard practice among the general population because of its low incidence. Read More

Cancer Genet 2018 12 23;228-229:1-4. Epub 2018 Jun 23.

Genetic Diagnostic Laboratory, Department of Clinical Analyses, Clinical University Hospital Virgen Arrixaca, Ctra Murcia-Cartagena s/n. El Palmar, 30120 Murcia, Spain.

Li-Fraumeni syndrome is an autosomal-dominant disorder caused by germline mutations in the tumour suppressor gene TP53. Here we report the case of a family whose index case was a woman diagnosed with bilateral breast cancer at the age of 18 and who had a non-informative result after BRCA1 and BRCA2 testing. After extending the study through multigene panel testing, two clinically relevant variants in the TP53 and BRIP1 genes, respectively, were found. Read More

Breast Cancer 2018 Dec 11. Epub 2018 Dec 11.

Universidade Federal de São João del Rei (UFSJ), 400 Sebastião Gonçalves Coelho Ave., Chanadour, Divinópolis, MG, 35501-296, Brazil.

Background: Few studies related to hereditary breast and ovarian cancer syndrome (HBOC) have been conducted in Brazil, and they are restricted to only small areas of the country. Here, we report the mutation profile of BRCA1/2, CHEK2 and TP53 genes in a cohort from Minas Gerais state.

Methods: These genes from 44 patients at high risk for HBOC were screened through high-resolution melting and/or sequencing. Read More

Curr Opin Pediatr 2019 Feb;31(1):41-47

Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.

Purpose Of Review: A significant proportion of pediatric cancer occurs in children with hereditary cancer predisposition syndromes. Their survival may be significantly improved and/or late effects diminished through screening for their greatly elevated cancer risks. Here, an overview of new developments in the field of pediatric cancer surveillance is provided. Read More

Rinsho Ketsueki 2018;59(11):2468-2474

Department of Pediatrics, St. Luke's International Hospital.

TP53 is a tumor-suppressor gene, and it is the most commonly mutated somatic gene in human cancer. Germline TP53 mutations correlate with a hereditary predisposition to cancer. Comprehensive genetic analysis revealed the role of germline and somatic TP53 gene mutations in hematological malignancies. Read More

Curr Opin Oncol 2019 Jan;31(1):52

Biostatistics 2018 Nov 14. Epub 2018 Nov 14.

Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Pressler St, TX, USA.

A common phenomenon in cancer syndromes is for an individual to have multiple primary cancers (MPC) at different sites during his/her lifetime. Patients with Li-Fraumeni syndrome (LFS), a rare pediatric cancer syndrome mainly caused by germline TP53 mutations, are known to have a higher probability of developing a second primary cancer than those with other cancer syndromes. In this context, it is desirable to model the development of MPC to enable better clinical management of LFS. Read More

Breast J 2019 Jan 9;25(1):16-19. Epub 2018 Nov 9.

Département de Médecine Oncologique, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Background: Invasive lobular carcinoma (ILC) of the breast has epidemiological, molecular and clinical specificities, and should likely be considered a unique entity. As for genetic susceptibility, CDH1 germline mutations predispose exclusively to ILC. Data are however scarce regarding ILC in women with BRCA1/2 (Hereditary Breast and Ovarian Cancer) and TP53 (Li-Fraumeni syndrome) germline mutations. Read More

Pathologe 2018 Dec;39(Suppl 2):306-310

Institut für Humangenetik, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625, Hannover, Deutschland.

Tackling the topic of genetic predisposition to childhood cancer requires close co-operation between pathologists, pediatric oncologists, and human geneticists. It is not just about the precise diagnosis and the most effective treatment of the cancer, but also to prevent further cancerous diseases for those affected and also their family members. On the basis of examples such as Li-Fraumeni syndrome, constitutional mismatch repair deficiency (CMMRD), medullo- and neuroblastoma, as well as hematological neoplasias, we will discuss the criteria for tumor predisposition genetic syndromes, the relationship between somatic and germline variants, and the immediate clinical consequences. Read More

Proc Natl Acad Sci U S A 2018 11 1;115(47):E11128-E11137. Epub 2018 Nov 1.

Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

Osteosarcoma (OS), the most common primary bone tumor, is highly metastatic with high chemotherapeutic resistance and poor survival rates. Using induced pluripotent stem cells (iPSCs) generated from Li-Fraumeni syndrome (LFS) patients, we investigate an oncogenic role of secreted frizzled-related protein 2 (SFRP2) in p53 mutation-associated OS development. Interestingly, we find that high SFRP2 expression in OS patient samples correlates with poor survival. Read More

Genes Chromosomes Cancer 2019 02 29;58(2):130-136. Epub 2018 Nov 29.

Cancer Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.

Sarcomas have a strong genetic etiology, and the study of families affected by sarcomas has informed much of what we now understand of modern cancer biology. The recent emergence of powerful genetic technologies has led to astonishing reductions in costs and increased throughput. In the clinic, these technologies are revealing a previously unappreciated and rich landscape of genetic cancer risk. Read More

Hum Mutat 2019 Jan 19;40(1):97-105. Epub 2018 Nov 19.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.

Reports of variable cancer penetrance in Li-Fraumeni syndrome (LFS) have raised questions regarding the prevalence of pathogenic germline TP53 variants. We previously reported higher-than-expected population prevalence estimates in sequencing databases composed of individuals unselected for cancer history. This study aimed to expand and further evaluate the prevalence of pathogenic and likely pathogenic germline TP53 variants in the gnomAD dataset (version r2. Read More

J Adv Pract Oncol 2017 Nov-Dec;8(7):742-746. Epub 2017 Nov 1.

Wellmont Cancer Institute, Kingsport, Tennessee.

Rinsho Ketsueki 2018;59(10):2290-2299

Division of Pediatrics, Department of Developmental and Urological-Reproductive Medicine, Faculty of Medicine, University of Miyazaki.

Recently, the modern technique of comprehensive genomic analysis has identified both somatic mutations originating from tumor cells and germline mutations as causative genes of inherited familial leukemias among which Fanconi anemia and Li-Fraumeni syndrome are well known. Pathogenic germline mutations occur in various pathways, affecting DNA repair, ribosome biogenesis, telomere biology, hematopoietic transcription factors, tumor suppressors, neutrophil development, and other critical cellular processes. The clinical manifestations of germline mutations present a wide phenotypic spectrum of patients displaying congenital anomalies, early-onset myelodysplastic syndrome, or no medical problems until the developing leukemia. Read More

J Pediatr Hematol Oncol 2018 Oct 9. Epub 2018 Oct 9.

Paediatric Oncology, Royal Hobart Hospital, Tas, Hobart.

Background: Osteosarcoma in children below the age of 5 is extremely rare.

Observation: We report on a previously well 14-month-old male infant, who presented with a reluctance to weight-bear on his right leg and had an associated limp. Plain imaging and a magnetic resonance imaging scan demonstrated a lytic lesion in the right distal femur. Read More

Fam Cancer 2019 Apr;18(2):281-284

Department of Human Genetics, Radboud University Medical Center, P.O. box 9101, 6500 HB, Nijmegen, The Netherlands.

Approximately 27-36 million patients in Europe have one of the ~ 5.000-8.000 known rare diseases. Read More

Lung Cancer 2018 Oct 28;124:279-282. Epub 2018 Aug 28.

Thoracic Oncology Unit and Laboratory of Personalized Medicine, Instituto Nacional de Cancerología (INCan), México City, Mexico.

Here we report a case of a young, never-smoker Hispanic woman with a hereditary familial overlap syndrome (Li-Fraumeni plus CDH1). The patient developed multiple synchronous primary lung adenocarcinomas related to Intra-Alveolar Tumor Spread (STAS) several years after the diagnosis of a locally advanced lower limb osteosarcoma. Comprehensive genomic profiling by next generation sequencing (NGS) was performed on 90 cancer-related genes over each lung lesion (including two nodules of acinar adenocarcinoma, one lepidic spread tumor and in the STAS area). Read More

Gastroenterology 2019 01 19;156(1):273-274. Epub 2018 Sep 19.

Division of Gastroenterology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Hum Mutat 2018 Dec 3;39(12):1764-1773. Epub 2018 Oct 3.

QIMR Berghofer Medical Research Institute, Herston, Brisbane, Australia.

Pathogenic germline variants in TP53 predispose carriers to the multi-cancer Li-Fraumeni syndrome (LFS). Widespread multigene panel testing is identifying TP53 pathogenic variants in breast cancer patients outside the strict clinical criteria recommended for LFS testing. We aimed to assess frequency and clinical implications of TP53 pathogenic variants in breast cancer cohorts ascertained outside LFS. Read More

Pediatr Hematol Oncol 2018 Apr 21;35(3):203-207. Epub 2018 Sep 21.

b School of Medicine , Renown Children's Hospital, University of Nevada, Reno , USA.

Li-Fraumeni syndrome is an autosomal dominant cancer syndrome characterized by pathogenic variants in the TP53 gene on chromosome 17. The most common cancers in Li-Fraumeni kindreds include sarcomas, breast cancer, brain tumors, and adrenocortical carcinoma. We report a 9-month-old male who was diagnosed with an adrenocortical tumor and later found to harbor a novel TP53 c. Read More

Fam Cancer 2019 Apr;18(2):231-239

Department of Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB, Utrecht, The Netherlands.

Germline TP53 mutations are associated with an increased risk of early-onset breast cancer. Traditionally, it was not standard practice to offer TP53 genetic testing due to the low mutation detection rate and limited options regarding preventive screening. Recent guidelines recommend that all women diagnosed with breast cancer before the age of 31, irrespective of family history, should be offered TP53 genetic testing. Read More

Hum Mutat 2018 Dec 3;39(12):2040-2046. Epub 2018 Oct 3.

Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.

The Li-Fraumeni cancer predisposition syndrome (LFS1) presents with a variety of tumor types and the TP53 gene is covered by most diagnostic cancer gene panels. We demonstrate that deleterious TP53 variants identified in blood-derived DNA of 523 patients with ovarian cancer (AGO-TR1 trial) were not causal for the patients' ovarian cancer in three out of six TP53-positive cases. In three out of six patients, deleterious TP53 mutations were identified with low variant fractions in blood-derived DNA but not in the tumor of the patient seeking advice. Read More

World Neurosurg 2018 Dec 6;120:125-128. Epub 2018 Sep 6.

Division of Neurosurgery, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan.

Background: Li-Fraumeni syndrome is a genetic disease that is caused by mutation of the tumor suppressor gene TP53. Patients with this syndrome may develop multiple malignant neoplasms including brain tumors. We herein report the first case of Li-Fraumeni syndrome in which development of supratentorial anaplastic ependymoma led to difficulty in terms of selecting the optimal postoperative therapeutic protocol. Read More