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1.
Nat Commun ; 10(1): 4717, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624251

RESUMO

Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. Here, we comprehensively profile the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families and discover recurrent mutations in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumors suggest that isoform-specific DNMT3A2 mutations are associated with dysregulated methylation. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumors. These findings contribute to existing paradigms of cutaneous tumorigenesis and metastasis.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Enzima Desubiquitinante CYLD/genética , Epigênese Genética , Mutação , Síndromes Neoplásicas Hereditárias/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Neoplasias Cutâneas/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Análise Mutacional de DNA , Enzima Desubiquitinante CYLD/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Síndromes Neoplásicas Hereditárias/metabolismo , Linhagem , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Estudos Retrospectivos , Neoplasias Cutâneas/metabolismo , Sequenciamento Completo do Exoma
2.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600923

RESUMO

Germline pathogenic variants in the CDH1 gene are a well-established cause of hereditary diffuse gastric cancer (HDGC) syndrome. The aim of this study was to characterize CDH1 mutations associated with HDGC from Chile, a country with one of the highest incidence and mortality rates in the world for gastric cancer (GC). Here, we prospectively include probands with family history/early onset of diffuse-type of GC. The whole coding sequence of the CDH1 gene was sequenced from genomic DNA in all patients, and a multidisciplinary team managed each family member with a pathogenic sequence variant. Thirty-six cases were included (median age 44 years/male 50%). Twenty-seven (75%) patients had diffuse-type GC at ≤50 years of age and 19 (53%) had first or second-degree family members with a history of HDGC. Two cases (5.5%) carried a non-synonymous germline sequence variant in the CDH1 gene: (a) The c.88C>A missense variant was found in a family with three diffuse-type GC cases; and (b) c.1531C>T a nonsense pathogenic variant was identified in a 22-year-old proband with no previous family history of HDGC. Of note, six family members carry the same nonsense pathogenic variant. Prophylactic gastrectomy in the proband's sister revealed stage I signet-ring cell carcinoma. The finding of 1531C>T pathogenic variant in the CDH1 in proband with no previous family history of HDGC warrants further study to uncover familial clustering of disease in CDH1 negative patients. This finding may be particularly relevant in high incidence countries, such as the case in this report.


Assuntos
Alelos , Antígenos CD/genética , Caderinas/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Gástricas/genética , Adulto , Feminino , Gastrectomia/métodos , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/prevenção & controle , Linhagem , Procedimentos Cirúrgicos Profiláticos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/prevenção & controle , Adulto Jovem
3.
Klin Onkol ; 32(Supplementum2): 14-23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409077

RESUMO

Expanded gene panel testing for hereditary cancer predispositions using massive parallel sequencing can identify heterozygous pathogenic variants of genes that cause autosomal recessive inherited cancer syndromes. There are no clinical guidelines regarding assessment of the risk of developing solid tumors or for developing appropriate surveillance strategies for heterozygotes for most of these genes, nor is there delineation with respect to the management for genetic testing of relatives and partners. Based on current knowledge, our aim was to create “Czech guidelines” for these cases. Here, we present an overview of the selected genes for autosomal recessive inherited tumor syndromes. The genes were divided into two groups: genes causing Fanconi anemia and genes causing other autosomal recessive inherited tumor syndromes. A summary table was created for each group. The table shows the population frequency of heterozygotes, the cancer risk for heterozygotes, the proposed surveillance strategy, and recommendations for family prediction and genetic testing of partners. Predictive testing should be performed in the case of heterozygotes that have an increased risk of cancer and/or as prerequisite to further reproduction of heterozygotes for a given gene with significant population frequency (this allows an estimation of the risk of autosomal recessive syndrome for children of heterozygote for mutation). These suggestions and recommendations are based on current knowledge and would need to be further corrected in the future based on increasing knowledge of existing or as-yet-unidentified genes. The authors thank to all the staff of the Molecular Genetic Laboratory of the GENNET Medical Genetics and Reproductive Medicine Center for their cooperation. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 21. 3. 2019 Accepted: 2. 5. 2019.


Assuntos
Anemia de Fanconi/genética , Predisposição Genética para Doença , Síndromes Neoplásicas Hereditárias/genética , Heterozigoto , Humanos , Guias de Prática Clínica como Assunto , Fatores de Risco
4.
Klin Onkol ; 32(Supplementum2): 79-91, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409083

RESUMO

BACKGROUND: Ovarian tumors in childhood and adolescence are distinguished from those that arise in adulthood by their histological subtype. These tumors may arise as the first manifestation of a cancer predisposition syndrome. Correct diagnosis of the syndrome may offer the possibility of surveillance for other members of the patients family. PURPOSE: To summarize current knowledge about paediatric ovarian tumors that may be associated with genetically defined cancer syndromes. Juvenile granulosa cell tumors occur in those with Ollier disease and Maffucci syndrome; they are caused by postzygotic IDH1 and IDH2 gene mutations. Sertoli-Leydig cell tumors usually arise in association with DICER1 syndrome, which is caused by germline DICER1 gene mutations. Sex cord tumors with annular tubules and Sertoli cell tumors may arise in patients with Peutz-Jeghers syndrome; this syndrome is caused by germline STK11 gene mutations. The majority of germ cell tumors develop in the context of gonadal dysgenesis. In XY gonadal dysgenesis, the presence of a Y chromosome material renders the patient at increased risk for developing gonadal malignancy. Characteristically, these patients develop gonadoblastoma, which has the potential to evolve into dysgerminoma and exhibit malignant behavior. Sex-chromosome aneuploidy syndromes or mutations in genes involved in gonadal development and differentiation may cause gonadal dysgenesis. Small cell carcinoma of the ovary of a hypercalcaemic type is usually caused by loss-of-function mutations in the SMARCA4 gene. CONCLUSION: Ovarian tumors are uncommon during childhood and adolescence. It is always necessary to consider gonadal dysgenesis or any of the inherited cancer syndromes. These patients require interdisciplinary care, careful noting of personal and family history, precise clinical examination, laboratory testing, and differential diagnosis by a clinician with a good knowledge of genetic syndromes. Expert pathological review may be required for correct diagnoses. This is necessary for appropriate management and to establish an association with hereditary cancer syndromes. The work was supported by the Ministry of Health of the Czech Republic - Conceptual Development of Research Organization, Faculty Hospital of Ostrava /2015. We thank to Lenka Foretová, M.D., Ph.D., (MMCI, Brno) and Radoslava Tomanová, M.D., (Institute of Pathology, University Hospital Ostrava) for rewarding advice, Mrs. Jana Němcová (Department of Medical Genetics, University Hospital Ostrava), Bc. Ludmila Stuchlá and Mrs. Lenka Zivčáková (Medical Library, University Hospital Ostrava) for help during manuscript preparation. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 10. 3. 2019 Accepted: 16. 4. 2019.


Assuntos
Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/genética , Adolescente , Criança , Feminino , Predisposição Genética para Doença , Humanos
5.
Klin Onkol ; 32(Supplementum2): 92-96, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409084

RESUMO

Gastrointestinal polyposes and Lynch syndrome are a group of heterogenous hereditary tumor syndromes associated with an increased risk of developing colorectal carcinoma and other malignancies. Typical early manifestations of gastrointestinal polyposes include multiple polyps in the gastrointestinal tract. Early recognition of these syndromes enables patients carrying a pathogenic mutation to undergo screening and to instigate precautions to minimize the risk of developing tumors. In some cases, gastrointestinal lesions could be an early indicator of tumor syndrome and histopathologic examination could lead to a recommendation for genetic testing of patients and their families. Supported by Ministry of Health, Czech Republic - Conceptual Development of Research Organization (MMCI, 00209805). The authors declare they have no potential conflicts of interest concerning drugs, products,or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 16. 4. 2019 Accepted: 6. 6. 2019.


Assuntos
Neoplasias Gastrointestinais , Síndromes Neoplásicas Hereditárias , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Humanos , Mutação , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia
6.
Klin Onkol ; 32(Supplementum2): 97-108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409085

RESUMO

BACKGROUND: It is estimated that 5-10% of colorectal cancers arise due to a known genetic syndrome. Individuals with these cancer syndromes are also at risk of extracolonic cancers. Polyposis and nonpolyposis hereditary syndromes are generally recognized. Inclusion of next-generation sequencing technology, especially multiple-gene panel testing, in routine laboratory practice has made identifying the causes of these diseases significantly easier. PURPOSE: To summarize current knowledge of the causes, clinical manifestations, diagnostic criteria, and recommendations for presymptomatic screening of individuals at risk of hereditary gastrointestinal polyposis and colorectal cancer syndromes. We dicuss currently defined syndromes detected by multiple-gene panel next-generation sequencing; these include constitutional mismatch repair deficiency (biallelic MLH1, MSH2, MSH6, PMS2 gene mutations), gastric adenocarcinoma and proximal polyposis of the stomach (APC gene), NTHL1-associated polyposis, polymerase proofreading-associated polyposis (POLD1, POLE genes), juvenile polyposis (SMAD4, BMPR1A genes), and serrated polyposis syndromes. Another aim is to summarize recent knowledge about well-known syndromes, including hereditary nonpolyposis colon cancer (Lynch syndrome), familial adenomatous polyposis, MUTYH-associated polyposis, and Peutz-Jeghers and Cowden/PTEN hamartoma tumor syndromes. CONCLUSION: Awareness of hereditary polyposis/colon cancer syndromes enables early diagnosis and prevention of cancer in affected individuals and their relatives. Genetic counseling, presymptomatic testing of at-risk individuals, and efficient screening may be beneficial for affected families. Thank to Lenka Foretová, M.D., PhD, (Masaryk Memorial Cancer Institute, Brno) for a critical review of the manuscript and valuable advices. The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 1. 3. 2019 Accepted: 6. 6. 2019.


Assuntos
Neoplasias Gastrointestinais , Síndromes Neoplásicas Hereditárias , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/prevenção & controle , Testes Genéticos , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/prevenção & controle
7.
Klin Onkol ; 32(Supplementum2): 109-117, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409086

RESUMO

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a rare variant of familial adenomatous polyposis. It is an autosomal-dominant cancer-predisposition syndrome with massive polyposis of the stomach and a significant risk of gastric adenocarcinoma. Li et al., 2016, described point mutations in the Ying Yang 1 binding site of the APC gene 1B promoter associated with GAPPS syndrome. The first GAPPS syndrome in a Czech family was described in 2016. At Masaryk Memorial Cancer Institute, GAPPS syndrome was diagnosed in eight families using Sanger sequencing. In all families, one mutation in promoter 1B of APC gene NM_001127511: c.-191T>C was detected. This mutation was not found in any patient with multiple colon polyposis without a detected classic mutation in the APC gene. In total, 24 carriers of this mutation in promoter 1B of the APC gene were detected. Out of those 24 carriers, 20 had massive gastric polyposis with more than 100 fundic glandular polyps diagnosed between the age of 22 and 65, 5 had already died of adenocarcinoma of the stomach (at the ages of 29, 40, 59, 60 and 64, respectively) and another woman was treated at the age of 29. Two female carriers do not yet have polyposis of the stomach at the ages of 31 and 65, respectively; one female carrier has incipient polyposis at the age of 58. A male carrier does not have any clinical symptoms, gastroscopy was not indicated because of his age. Prophylactic total gastrectomy with D2 lymphadenectomy has already been performed 6 times at Masaryk Memorial Cancer Institute, in 5 cases without adenocarcinoma at the ages of 27, 34, 44, 51 and 66, respectively; in one female carrier adenocarcinoma of the stomach was detected in a histology specimen. Two prophylactic gastrectomies with D1 lymphadenectomy were performed at University Hospital Brno at the ages of 42 and 50, respectively. In the Czech Republic point mutation c.-191T>C (rs879253783) in the 1B promoter of the APC gene is a frequent cause of gastric polyposis with a high risk of gastric adenocarcinoma, even at a young age. Positively tested individuals are recommended to high-risk oncology clinic. A necessary part of the discussion with the patient is information about a preventive gastrectomy.


Assuntos
Adenocarcinoma , Síndromes Neoplásicas Hereditárias , Neoplasias Gástricas , Adenocarcinoma/genética , Adenocarcinoma/prevenção & controle , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Institutos de Câncer , República Tcheca , Feminino , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/prevenção & controle , Procedimentos Cirúrgicos Profiláticos , Neoplasias Gástricas/genética , Neoplasias Gástricas/prevenção & controle , Adulto Jovem
8.
Klin Onkol ; 32(Supplementum2): 118-122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409087

RESUMO

BACKGROUND: BAP1 syndrome is an autosomal dominant hereditary cancer syndrome associated with increased risk of malignant mesothelioma; uveal and cutaneous melanoma; kidney cancer; lung adenocarcinoma; meningioma; basaliomas; and breast, ovarian, and prostate tumors. The BAP1 gene (BRCA1-associated protein 1) is a tumor suppressor gene involved in DNA repair via homologous recombination. BAP1 regulates the cell cycle, differentiation, DNA damage responses, and cell proliferation through deubiquitination. Somatic mutations in the BAP1 gene are common in many types of tumors. OBSERVATION: Two families harboring a germline mutation in the BAP1 gene were diagnosed at Masaryk Memorial Cancer Institute (MMCI). A 27-year-old index female from one family was followed-up for multiple nevi. Her mother and uncle had malignant mesothelioma, and her maternal grandmother had uveal melanoma. The index case tested positive for a BAP1 (NM_004656.2): c.217delG/p.Asp73Metfs*5 frame-shift mutation. The melanoma was removed at the age of 28 and 31. In the second family, an 11-year-old index female had two nevi removed from her head, and a spitzoid-type skin lesion was diagnosed at the age of 11. Her 34-year-old mother had multiple nevi, and a skin lesion of spitzoid-type was removed from the abdomen. Both patients harbored a BAP1 (NM_004656.2): c.123-1G>T acceptor splice site mutation (IARC [International Agency for Research on Cancer] class 4 [probably pathogenic]). Preventive measures for BAP1 syndrome should include known risks for cancer. Tumors occur early and repeatedly. At the MMCI, we recommend physical examination by an oncologist, eyes and skin examination, every 6 months; whole-body magnetic resonance imaging, including the central nervous system, every year (or low-dose computed tomography/chest and abdomen magnetic resonance imaging); annual abdominal ultrasound, breast ultrasound, or mammography; a gynecological ultrasound examination every 6 months; colonoscopy starting at the age of 45; and other suitable surveillances based on family history. CONCLUSION: BAP1 syndrome is a complex cancer syndrome with a high risk of rare malignant mesothelioma, malignant skin and uveal melanoma, spitzoid-type skin lesions, and other tumors. Detection of this syndrome is essential for the survival of high-risk individuals. Supported by the grant project MH CZ - RVO (MMCI, 00209805). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 21. 5. 2019 Accepted: 6. 6. 2019.


Assuntos
Síndromes Neoplásicas Hereditárias/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Adulto , Neoplasias da Mama/genética , Criança , Feminino , Mutação em Linhagem Germinativa , Humanos , Neoplasias Renais/genética , Neoplasias Pulmonares/genética , Masculino , Melanoma/genética , Mesotelioma/genética , Neoplasias Ovarianas/genética , Neoplasias da Próstata/genética , Neoplasias Cutâneas/genética , Neoplasias Uveais/genética
9.
Klin Onkol ; 32(Supplementum2): 123-127, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409088

RESUMO

DICER1 syndrome is an inherited disorder that increases the risk of different types of malignant and benign tumors. The syndrome is caused by mutations in the DICER1 gene, which is located on the long arm of chromosome 14, region q32.13. Patients with DICER1 syndrome commonly develop pleuropulmonary blastoma (PPB), multinodular goiter, ovarian Sertoli-Leydig cell tumors, and/or other types of tumors. In approximately 35% of families with children manifesting PPB, further (and rather rare) malignancies may be observed, including cystic nephroma, nodular dysplasia of the thyroid gland, medulloepithelioma of the iris, embryonal rhabdomyosarcoma botryoid type, nasal epithelial hamartoma, pituitary blastoma, and/or pineoblastoma. Large studies report a high variability of tumors associated with DICER1. DICER1 syndrome, which is associated with an inherited predisposition to tumors, is inherited in an autosomal dominant pattern. Symptoms of DICER1 syndrome may vary, even within families. Preventive screening of carriers with causative mutations is complicated. Follow-up is undertaken as recommended by the 2016 International PPB Register. This work was supported by grant of Ministry of Health of the Czech Republic AZV 16-3329A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 4. 6. 2019 Accepted: 6. 6. 2019.


Assuntos
RNA Helicases DEAD-box/genética , Síndromes Neoplásicas Hereditárias/genética , Ribonuclease III/genética , Predisposição Genética para Doença , Humanos , Mutação
10.
Dermatol Clin ; 37(4): 607-613, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31466598

RESUMO

Cutaneous findings that appear in childhood may be the first sign of a hereditary tumor syndrome. Early detection of genodermatoses allows the patient and at-risk family members to be screened for associated malignancies. This article provides a brief description of the pathogenesis and clinical manifestations of various inherited disorders with skin involvement, along with treatment updates. Advances in molecular-based therapy have spurred development of novel treatment methods for various genodermatoses such as xeroderma pigmentosum (XP) and Gorlin-Goltz syndrome. Further studies are needed to better assess the efficacy of many of these new treatment options.


Assuntos
Síndromes Neoplásicas Hereditárias/diagnóstico , Dermatopatias Genéticas/diagnóstico , Reparo do DNA/genética , Humanos , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Transdução de Sinais/genética , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia
12.
Med Oncol ; 36(9): 74, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332543

RESUMO

Hereditary renal cell carcinoma syndromes (HRCCS) are characterized by the presence of pathogenic germline variants that predispose patients to renal cell carcinomas as well as additional extra-renal manifestations. The importance of identifying HRCCS patients cannot be overemphasized, as patients and their families can begin surveillance for syndrome-associated manifestations once identified. The present study is a retrospective clinical and morphologic review of 60 hereditary renal tumors from 30 HRCCS patients treated at our institution with either Von Hippel-Lindau disease (VHL), Birt-Hogg-Dubé syndrome (BHD), tuberous sclerosis complex (TSC), hereditary leiomyomatosis and renal cell cancer syndrome, or succinate dehydrogenase (SDH) deficiency syndrome. Hereditary renal cell carcinoma syndromes kidney tumors often demonstrate specific morphologic features, characteristic background changes in renal parenchyma, and extra-renal manifestations, which, when recognized by the pathologist, can trigger genetic testing referral for specific familial cancer syndromes. Our study demonstrates the majority of tumors were consistent with the anticipated clinicopathologic profile of renal tumors found within HRCCS patients, although we found some unique characteristics within this cohort including a case of clear cell papillary renal cell carcinoma within a VHL patient, and a unique renal tumor with tubulopapillary features present in a patient with a germline SDHD mutation. Additionally, although the literature reports the presence of epithelioid angiomyolipoma (AML) as a common occurrence in TSC patients, our cohort of 3 patients with AMLs demonstrated only classic features. The findings we describe facilitate pathologist-based recognition of HRCCS and can prompt genetic evaluation for relevant patients.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Síndromes Neoplásicas Hereditárias/patologia , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/terapia , Criança , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Doenças Genéticas Inatas/terapia , Humanos , Rim/patologia , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Tecido Parenquimatoso/patologia , Estudos Retrospectivos , Succinato Desidrogenase/deficiência , Succinato Desidrogenase/genética , Centros de Atenção Terciária , Adulto Jovem
13.
Genes Chromosomes Cancer ; 58(11): 775-782, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31334572

RESUMO

Colorectal cancer (CRC), prostate cancer (PrC), and gastric cancer (GC) are common worldwide, and the incidence is to a certain extent dependent on genetics. We have recently shown that in families with more than one case of CRC, the risk of other malignancies is increased. We therefore suggested the presence of not yet described CRC syndromes. In this study, we have searched for genetic susceptibility loci for potential cancer syndromes involving CRC combined with PrC and/or GC. We have performed SNP (single-nucleotide polymorphism)-based linkage analyses in 45 families with CRC, PrC, and GC. In the regions with suggested linkage, we performed exome and association haplotype analyses. Five loci generated a high logarithm of odds (HLOD) score >2, suggestive of linkage, in chromosome bands 1q31-32, 1q24-25, 6q25-26, 18p11-q11, and Xp11. Exome analysis detected no potential pathogenic sequence variants. The haplotype association study showed that one of the top five haplotypes with the lowest P value in the chromosome band 6q25 interestingly was found in the family which contributed the most to the increased HLOD at that locus. This study supports a suggested hereditary cancer syndrome involving CRC and PrC and indicates a location at 6q25. The impact of this locus needs to be confirmed in additional studies.


Assuntos
Predisposição Genética para Doença/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Colorretais/genética , Família , Feminino , Ligação Genética/genética , Loci Gênicos , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla , Haplótipos/genética , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Fatores de Risco , Neoplasias Gástricas/genética , Sequenciamento Completo do Exoma/métodos
14.
J Surg Oncol ; 120(5): 864-872, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31355450

RESUMO

In the era of advanced cancer genomics, our recognition of hereditary cancer mutations continues to increase. Two of these conditions, which carry an increased risk of female cancers including endometrial, ovarian, breast, are hereditary breast and ovarian cancer syndrome and Lynch syndrome. Risk-reducing surgery, such as mastectomy, salpingo-oophorectomy, and hysterectomy may decrease cancer risk for mutation carriers. Background, indications, techniques, and consequences of these surgical procedures are reviewed.


Assuntos
Detecção Precoce de Câncer/métodos , Neoplasias do Endométrio/diagnóstico , Predisposição Genética para Doença , Síndromes Neoplásicas Hereditárias/diagnóstico , Neoplasias Ovarianas/diagnóstico , Procedimentos Cirúrgicos Operatórios/métodos , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Síndromes Neoplásicas Hereditárias/epidemiologia , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/cirurgia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/cirurgia , Prevalência , Fatores de Risco
15.
Pediatr Blood Cancer ; 66(11): e27916, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31342632

RESUMO

Approximately 10% of all children with cancer are affected by a monogenic cancer predisposition syndrome. This has important implications for both the child and her/his family. The assessment of hereditary cancer predisposition is a challenging task for clinicians and genetic counselors in daily routine. It includes consideration of tumor genetics, specific features of the patient, and the medical/family history. To keep up with the pace of this rapidly evolving and increasingly complex field of genetic susceptibility, we suggest a systematic approach for the evaluation of the child with cancer and her/his family by an interdisciplinary team specialized in hereditary cancer predisposition.


Assuntos
Aconselhamento Genético , Síndromes Neoplásicas Hereditárias , Adolescente , Idade de Início , Antineoplásicos/efeitos adversos , Criança , Tomada de Decisão Clínica , Feminino , Predisposição Genética para Doença , Testes Genéticos , Genótipo , Humanos , Comunicação Interdisciplinar , Masculino , Anamnese , Neoplasias Primárias Múltiplas/genética , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/psicologia , Equipe de Assistência ao Paciente , Linhagem , Psicologia , Medição de Risco
16.
Pediatr Blood Cancer ; 66(11): e27941, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31348592

RESUMO

Colorectal cancer (CRC) incidence is rising among adolescents and young adults (AYAs), with the greatest increase occurring in distal colon and rectal cancers. Reasons for this striking trend are not well understood. Genetically linked cases of CRC occur in the context of familial conditions such as Lynch Syndrome, but most AYA cases of CRC are sporadic. Unique biology is suggested, yet limited information is available regarding the molecular underpinnings of CRC in this age group. Young patients are more likely to experience delays in diagnosis and to present with advanced-stage disease; yet, prognosis by stage is comparable between younger and older adults. Treatment paradigms are based on evidence reflecting the older adult population. Given the concerning rise in CRC rates among AYAs, there is urgent need for further research into the role of screening from a younger age, biology of disease, and optimal therapies in this age group.


Assuntos
Adenocarcinoma/epidemiologia , Neoplasias Colorretais/epidemiologia , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adolescente , Adulto , Idade de Início , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Diagnóstico Tardio , Feminino , Preservação da Fertilidade , Mutação em Linhagem Germinativa , Humanos , Incidência , Masculino , Morbidade/tendências , Síndromes Neoplásicas Hereditárias/epidemiologia , Síndromes Neoplásicas Hereditárias/genética , Gravidez , Complicações Neoplásicas na Gravidez/epidemiologia , Prognóstico , Fatores de Risco , Programa de SEER , Estados Unidos/epidemiologia , Adulto Jovem
17.
Gynecol Obstet Fertil Senol ; 47(7-8): 582-590, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31255836

RESUMO

Extra-uterine leiomyomatosis is a rare pathology defined by the presence of benign smooth uterine muscle cells in unusual localizations, including different entities. It mainly affects premenopausal women with a medical history of uterine myoma with or without surgical treatment. Three main types are discribed: intraveinous leiomyomatosis, benign metastatisizing leiomyoma and leiomyomatosis peritonealis disseminata. The diagnosis may be complex with many differential diagnosis, and relies on histology. The treatment depends on multiple factors such as age, localization, size, symptoms and associated comorbidities. It is based on surgical resection and hormonal privation, surgical (adnexectomy) or medical (hormonotherapy). There is a high risk of recurrence. Some malignant evolutions have been reported, mostly leiomyosarcoma following peritoneal disseminated leiomyomatosis. Long term follow-up of these patients is mandatory. A particular manifestation of extra-uterine leiomyomatosis is the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. It is an autosomal dominant disorder which confers an increased risk of cutaneous and uterine leiomyomas and renal cell cancer, with a poor prognosis due to the urologic tumor.


Assuntos
Leiomiomatose/patologia , Feminino , Humanos , Leiomiomatose/tratamento farmacológico , Leiomiomatose/genética , Leiomiomatose/cirurgia , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Neoplasias Peritoneais/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Neoplasias Vasculares/patologia , Veias/patologia
18.
Eur J Med Genet ; 62(8): 103706, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31233827

RESUMO

Constitutional Mismatch Repair Deficiency (CMMRD) is a rare cancer predisposition syndrome, presenting in childhood, in which affected patients develop various malignancies such as hematological, gastrointestinal and central nervous system tumors. Although guidelines are being increasingly developed for surveillance and early detection of cancers in affected families, there are no clear recommendations regarding choice of therapy and very scarce information about tolerance to chemotherapy and radiation in these patients. We report the pedigree of a consanguineous family with four affected children. Although clinical and molecular tests confirm CMMRD, genetic testing revealed heterogeneous mutations. The index case developed severe toxicity from therapy for glioblastoma and T-cell leukemia and died from an infection while in complete remission. His sister developed a malignant brain tumor while undergoing surveillance for a low grade brain lesion and is still undergoing follow-up. This family illustrates the difficulties and opportunities with challenging diagnosis, surveillance and choice of therapy for children with CMMRD and the need for increased awareness and more information about this rare but important syndrome.


Assuntos
Neoplasias Encefálicas/terapia , Neoplasias Colorretais/terapia , Testes Genéticos , Neoplasias/terapia , Síndromes Neoplásicas Hereditárias/terapia , Lesões Pré-Cancerosas/terapia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Consanguinidade , Feminino , Humanos , Masculino , Mutação , Neoplasias/complicações , Neoplasias/genética , Neoplasias/patologia , Síndromes Neoplásicas Hereditárias/complicações , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Linhagem , Lesões Pré-Cancerosas/complicações , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia
19.
PLoS One ; 14(6): e0217521, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31242196

RESUMO

BACKGROUND: PPM1D (Protein phosphatase magnesium-dependent 1δ) is known as a damage response regulator, a part of the p53 negative feedback loop. Truncating mutations of PPM1D, resulting in overexpression, are frequently found in the blood of patients with breast or ovarian cancer. To identify whether the PPM1D mutation predisposes patients to such cancers or if it results from the cancer and therapy, somatic PPM1D mutations in association with previous cancer and chemotherapy need to be explored. METHODS: We performed next-generation sequencing (NGS) analysis of blood samples from patients suspected to have hereditary cancer. We grouped the patients according to their diagnoses and history of chemotherapy. For the patients with PPM1D mutations in blood, tumor tissue specimens were examined for the PPM1D mutation using conventional sequencing. RESULTS: A total of 1,195 patients, including 719 patients with breast cancer and 240 with ovarian cancer, were tested, and four (~0.3%) had the truncating mutation in PPM1D. All truncating mutations were in exon 6, in mosaic form, with a mean allele fraction of 11.15%. While 395 out of the 1,195 patients had undergone chemotherapy, the four with the truncating mutation had a history of cisplatin-based chemotherapy. No corresponding mutations were identified in the tumor tissues. CONCLUSIONS: We investigated the frequency of the somatic mosaic PPM1D mutation, in patients with breast or ovarian cancer, which is suggested to be low and related to a history of cisplatin-based chemotherapy. It may be a marker of previous exposure to selective pressure for cells with an impaired DNA damage response.


Assuntos
Neoplasias da Mama Masculina , Cisplatino/administração & dosagem , Mosaicismo , Proteínas de Neoplasias , Síndromes Neoplásicas Hereditárias , Neoplasias Ovarianas , Proteína Fosfatase 2C , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama Masculina/sangue , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama Masculina/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genética , Síndromes Neoplásicas Hereditárias/sangue , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Proteína Fosfatase 2C/sangue , Proteína Fosfatase 2C/genética
20.
Best Pract Res Clin Haematol ; 32(2): 163-176, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31203998

RESUMO

Myelodysplastic syndromes and acute myeloid leukemia are sporadic for the majority of cases affecting the elderly population. Inherited cases, however, do occur. Genetic predispositions to myeloid malignancies can be classified into three categories: familial cancer syndromes associated with increased risk of various malignancies including myelodysplasia and acute myeloid leukemia such as Li-Fraumeni syndrome and constitutional mismatch repair deficiency (CMMRD); germline mutations conferring a specific increased risk of myelodysplastic syndrome and acute myeloid leukemia such as mutations in ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes; and finally primarily pediatric inherited bone marrow failure syndromes such as Fanconi anemia, dyskeratosis congenita, severe congenital neutropenia, Shwachman-Diamond syndrome and Diamond Blackfan anemia. The recognition of these germline syndromes is essential in the management and follow-up of patients. Herein, we review the conditions associated with hereditary myeloid leukemia with a special clinical focus on management and monitoring.


Assuntos
Mutação em Linhagem Germinativa , Neoplasias Hematológicas , Transtornos Mieloproliferativos , Proteínas de Neoplasias , Síndromes Neoplásicas Hereditárias , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/terapia , Humanos , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/terapia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/metabolismo , Síndromes Neoplásicas Hereditárias/terapia
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