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1.
Nucleic Acids Res ; 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31799629

RESUMO

Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5'UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5'UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5'UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts.

2.
Genet Med ; 21(12): 2723-2733, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31239556

RESUMO

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

3.
J Natl Cancer Inst ; 2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31076742

RESUMO

BACKGROUND: Women with epithelial ovarian cancer (OC) have a higher chance to benefit from PARP inhibitor (PARPi) therapy if their tumor has a somatic or hereditary BRCA1/2 pathogenic variant. Current guidelines advise BRCA1/2 genetic predisposition testing for all OC patients, though this does not detect somatic variants. We assessed the feasibility of a workflow for universal tumor DNA BRCA1/2 testing of all newly diagnosed OC patients as prescreen for PARPi treatment and cancer predisposition testing. METHODS: Formalin fixed paraffin embedded (FFPE) tissue was obtained from OC patients in seven hospitals, immediately after diagnosis or primary surgery. DNA was extracted and universal tumor BRCA1/2 testing was then performed in a single site. Diagnostic yield, uptake, referral rates for genetic predisposition testing, and experiences of patients and gynecologists were evaluated. RESULTS: Tumor BRCA1/2 testing was performed for 315 (77.6%) of the 406 eligible OC samples, of which 305 (96.8%) were successful. In 51 of these patients pathogenic variants were detected (16.7%). Most patients (88.2%) went on to have a genetic predisposition test. BRCA1/2 pathogenic variants were shown to be hereditary in 56.8% and somatic in 43.2% patients. Participating gynecologists and patients were overwhelmingly positive about the workflow. CONCLUSIONS: Universal tumor BRCA1/2 testing in all newly diagnosed OC patients is feasible, effective and appreciated by patients and gynecologists. Because many variants cannot be detected in DNA from blood, testing tumor DNA as the first step can double the identification rate of patients who stand to benefit most from PARP inhibitors.

4.
Am J Hum Genet ; 104(4): 758-766, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929739

RESUMO

By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.

5.
JAMA Oncol ; 5(5): 671-680, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30920605

RESUMO

Importance: Survivors of childhood cancer (CCSs) face risk of developing subsequent tumors. Solid benign tumors may be cancer precursors; benign tumors and cancers may share etiologic factors. However, comprehensive data on the risk for solid benign tumors are lacking. Objective: To quantify the incidence of and treatment-related risk factors for histologically confirmed solid nonskin benign tumors among CCSs. Design, Setting, and Participants: This record linkage study involves the Dutch Childhood Oncology Group-Long-Term Effects After Childhood Cancer (DCOG-LATER) cohort of 6165 individuals diagnosed with childhood cancer at younger than 18 years from January 1, 1963, through December 31, 2001, in 7 Dutch pediatric centers and who survived at least 5 years after the diagnosis. Study groups eligible for record linkage from 1990 onward included 5843 CCSs (94.8%) and 883 siblings. Benign tumors were identified from the population-based Dutch histopathology and cytopathology registry (PALGA). Follow-up was completed on May 1, 2015. Data were analyzed from January 1, 1990, through May 1, 2015. Main Outcomes and Measures: Cumulative incidence of any subsequent benign tumor for cohort strata and multivariable Cox proportional hazards regression models (hazard ratios [HRs]) were used to evaluate potential risk factors for 8 major benign tumor subtypes. Results: Of the 5843 eligible CCSs (55.9% male), 542 (9.3%) developed a histologically confirmed subsequent benign tumor after a median follow-up of 22.7 years (range, 5.0-52.2 years). Among women, abdominopelvic radiotherapy inferred dose-dependent increased risks for uterine leiomyoma (n = 43) for doses of less than 20 Gy (HR, 1.9; 95% CI, 0.5-7.0), 20 to less than 30 Gy (HR, 3.4; 95% CI, 1.1-10.4), and at least 30 Gy (HR, 5.4; 95% CI, 2.4-12.4) compared with no abdominopelvic radiotherapy (P = .002 for trend). High-dose radiotherapy to the trunk was not associated with breast fibroadenoma (n = 45). Of 23 osseous and/or chondromatous neoplasms, 16 occurred among leukemia survivors, including 11 after total body irradiation (HR, 37.4; 95% CI, 14.8-94.7). Nerve sheath tumors (n = 55) were associated with radiotherapy (HR at 31 years of age, 2.9; 95% CI, 1.5-5.5) and a crude indicator of neurofibromatosis type 1 or 2 status (HR, 5.6; 95% CI, 2.3-13.7). Subsequent risk for benign tumors was higher than the risks for subsequent nonskin solid malignant neoplasms and for benign tumors among siblings. Conclusions and Relevance: This record linkage study uses a unique resource for valid and complete outcome assessment and shows that CCSs have an approximately 2-fold risk of developing subsequent benign tumors compared with siblings. Site-specific new findings, including for uterine leiomyoma, osteochondroma, and nervous system tumors, are important to enable early diagnosis; this information will be the first step for future surveillance guidelines that include some benign tumors in CCSs and will provide leads for in-depth etiologic studies.

6.
Cancer Cell ; 35(2): 256-266.e5, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30753826

RESUMO

Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.

7.
Int J Cancer ; 145(4): 941-951, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30694527

RESUMO

Two percent of patients with Wilms tumors have a positive family history. In many of these cases the genetic cause remains unresolved. By applying germline exome sequencing in two families with two affected individuals with Wilms tumors, we identified truncating mutations in TRIM28. Subsequent mutational screening of germline and tumor DNA of 269 children affected by Wilms tumor was performed, and revealed seven additional individuals with germline truncating mutations, and one individual with a somatic truncating mutation in TRIM28. TRIM28 encodes a complex scaffold protein involved in many different processes, including gene silencing, DNA repair and maintenance of genomic integrity. Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss-of-function effect of the mutations identified. The tumors showed an epithelial-type histology that stained negative for TRIM28 by immunohistochemistry. The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests. Exome sequencing on eight tumor DNA samples from six individuals showed loss-of-heterozygosity (LOH) of the TRIM28-locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development. Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis. In conclusion, we identified heterozygous germline truncating mutations in TRIM28 in 11 children with mainly epithelial-type Wilms tumors, which become homozygous in tumor tissue. These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH.


Assuntos
Haploinsuficiência/genética , Proteína 28 com Motivo Tripartido/genética , Tumor de Wilms/genética , Carcinogênese/genética , Pré-Escolar , DNA de Neoplasias/genética , Feminino , Genes do Tumor de Wilms/fisiologia , Predisposição Genética para Doença/genética , Genótipo , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Lactente , Neoplasias Renais/genética , Mutação com Perda de Função/genética , Perda de Heterozigosidade/genética , Masculino , Sequenciamento Completo do Exoma/métodos
8.
Haemophilia ; 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30431218

RESUMO

INTRODUCTION: Bleeding assessment tools and laboratory phenotyping often remain inconclusive in patients with a haemorrhagic diathesis. AIM: To describe the phenotype and genetic profile of patients with a bleeding tendency. METHODS: Whole exome sequencing (WES) was incorporated in the routine diagnostic pathway of patients with thrombocytopenia (n = 17), platelet function disorders (n = 19) and an unexplained bleeding tendency (n = 51). The analysis of a panel of 126 OMIM (Online Mendelian Inheritance in Man) genes involved in thrombosis and haemostasis was conducted, and if negative, further exome-wide analysis was performed if informed consent given. RESULTS: Eighteen variants were detected in 15 patients from a total of 87 patients (17%). Causative variants were observed in MYH9 (two cases), SLFN14, P2RY12 and GP9. In addition, one case was considered solved due to combined carriership of F7 and F13A1 variants and one with combined carriership of F2, F8 and VWF, all variants related to secondary haemostasis protein aberrations. Two variants of uncertain significance (VUS) were found in two primary haemostasis genes: GFI1B and VWF. Eight patients were carriers of autosomal recessive disorders. Exome-wide analysis was performed in 54 cases and identified three variants in candidate genes. CONCLUSION: Based on our findings, we conclude that performing WES at the end of the diagnostic trajectory can be of additive value to explain the complete bleeding phenotype in patients without a definite diagnosis after conventional laboratory tests. Discovery of combinations of (novel) genes that predispose to bleeding will increase the diagnostic yield in patients with an unexplained bleeding diathesis.

9.
Artigo em Inglês | MEDLINE | ID: mdl-30260442

RESUMO

Context: The DICER1 syndrome is a rare, autosomal dominant inherited disorder that predisposes to a variety of cancerous and noncancerous tumors of mostly pediatric- and adolescent-onset, including differentiated thyroid carcinoma (DTC). DICER1-related DTC has been hypothesized to arise secondary to the increased prevalence of pre-malignant lesions, i.e. thyroid hyperplastic nodules. Objective: To determine somatic alterations in DICER1-associated differentiated thyroid cancer and to study patient outcomes. Design: Retrospective series. Setting: Tertiary referral centers. Patients: Ten patients with germline pathogenic DICER1 variants and early-onset DTC. Investigation: Somatic DICER1 mutation analysis and extensive somatic DNA variant and gene fusion analyses on all tumors. Results: Median age at DTC diagnosis was 13.5 years and no patients developed recurrent or metastatic disease (median follow-up 8 years). All thyroid specimens showed diffuse nodular hyperplasia with at least one focus suspect for DTC, but without infiltrative growth, extra-thyroidal extension, vascular invasion, or lymph node metastasis. Distinct somatic DICER1 RNase IIIb domain variants were identified in most presumed-malignant (and benign) nodules tested from each patient's tumor, suggestive of multiple distinct poly-clonal tumors. Furthermore, 9 of 10 DICER1-related DTC lacked well known oncogenic driver DNA variants and gene rearrangements. Conclusions: On the basis of our clinical, histological and molecular data, we consider that the majority of DICER1-related DTCs form a low-risk subgroup. As these tumors may arise from one of many benign polyclonal nodules, hemi- or more likely total thyroidectomy may be often required, but radioiodine treatment may be unnecessary, given the patients age and their low propensity for metastases.

11.
J Clin Sleep Med ; 14(8): 1427-1430, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30092902

RESUMO

ABSTRACT: We report an unusual case of an adult patient carrying a germline PHOX2B frameshift mutation and hence was diagnosed with congenital central hypoventilation syndrome. He came to medical attention after the mutation was identified in his daughter who presented with hypoventilation and a neuroblastoma. Although PHOX2B mutations are usually associated with a phenotype of congenital hypoventilation, severe autonomic dysfunction and neural crest tumors, our patient had no complaints at the time of presentation. At polysomnography we found severe positional hypercapnic central sleep apnea, partly responsive to positional therapy. Eventually, he was titrated to noninvasive ventilation with resolution of the central breathing events and, in hindsight, a more refreshing sleep than before. Clinicians working in sleep medicine need to be aware of the variable expression of this rare condition to prevent late cardiorespiratory and neurocognitive complications.

12.
J Natl Cancer Inst ; 110(7): 758-767, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29986097

RESUMO

Background: Although colorectal adenomas serve as prime target for colorectal cancer (CRC) surveillance in other high-risk groups, data on adenoma risk after childhood cancer are lacking. We evaluated the risk of histologically confirmed colorectal adenomas among childhood cancer survivors. A secondary aim was to assess CRC risk. Methods: The DCOG-LATER cohort study includes five-year Dutch childhood cancer survivors and a sibling comparison group (n = 883). Colorectal tumors were identified from the population-based Dutch Pathology Registry (PALGA). We calculated cumulative incidences of adenomas/CRCs for survivors and siblings. For adenomas, multivariable Cox regression models were used to evaluate potential risk factors. All statistical tests were two-sided. Results: Among 5843 five-year survivors (median follow-up = 24.9 years), 78 individuals developed an adenoma. Cumulative incidence by age 45 years was 3.6% (95% confidence interval [CI] = 2.2% to 5.6%) after abdominopelvic radiotherapy (AP-RT; 49 cases) vs 2.0% (95% CI = 1.3% to 2.8%) among survivors without AP-RT (28 cases; Pdifference = .07) and vs 1.0% (95% CI = 0.3% to 2.6%) among siblings (6 cases) (Pdifference = .03). Factors associated with adenoma risk were AP-RT (hazard ratio [HR] = 2.12, 95% CI = 1.24 to 3.60), total body irradiation (TBI; HR = 10.55, 95% CI = 5.20 to 21.42), cisplatin (HR = 2.13; 95% CI = 0.74 to 6.07 for <480 mg/m²; HR = 3.85, 95% CI = 1.45 to 10.26 for ≥480 mg/m²; Ptrend = .62), a hepatoblastoma diagnosis (HR = 27.12, 95% CI = 8.80 to 83.58), and family history of early-onset CRC (HR = 20.46, 95% CI = 8.10 to 51.70). Procarbazine was statistically significantly associated among survivors without AP-RT/TBI (HR = 2.71, 95% CI = 1.28 to 5.74). Thirteen CRCs occurred. Conclusion: We provide evidence for excess risk of colorectal adenomas and CRCs among childhood cancer survivors. Adenoma risk factors include AP-RT, TBI, cisplatin, and procarbazine. Hepatoblastoma (familial adenomatous polyposis-associated) and family history of early-onset CRC were confirmed as strong risk factors. A full benefit-vs-harm evaluation of CRC screening among high-risk childhood cancer survivors warrants consideration.

13.
Eur J Hum Genet ; 26(10): 1417-1423, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29904176

RESUMO

Constitutional MisMatch Repair Deficiency (CMMRD) is caused by homozygous or compound heterozygous germline variants in one of the mismatch repair (MMR) genes (MSH2, MSH6, PMS2, MLH1). This syndrome results in early onset colorectal cancer, leukemia and lymphoma, brain tumors and other malignancies. Children with CMMRD are at high risk of developing multiple cancers and cancer surveillance does not guarantee detection of cancer at a curable stage. The development of a preventive treatment strategy would be a major step forward. Long-term daily use of acetylsalicylic acid (ASA) has been shown to reduce cancer risk in individuals with Lynch syndrome (LS). LS is caused by heterozygous germline variants of MSH2, MSH6, PMS2 and MLH1 and characterized by an increased risk of developing colorectal and endometrial cancer at adult age. Here we discuss the potential use of ASA for cancer prevention in patients with CMMRD.

14.
Genet Med ; 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907796

RESUMO

PURPOSE: SMARCB1 encodes a subunit of the SWI/SNF complex involved in chromatin remodeling. Pathogenic variants (PV) in this gene can give rise to three conditions. Heterozygous loss-of-function germline PV cause rhabdoid tumor predisposition syndrome and schwannomatosis. Missense PV and small in-frame deletions in exons 8 and 9 result in Coffin-Siris syndrome, which is characterized by intellectual disability (ID), coarse facial features, and fifth digit anomalies. METHODS: By a gene matching approach, individuals with a similar SMARCB1 PV were identified. Informed consent was obtained and patient data were collected to further establish genotype-phenotype relationship. RESULTS: A recurrent de novo missense PV (c.110G>A;p.Arg37His) in exon 2 of SMARCB1, encoding the DNA-binding domain, was identified in four individuals from different genetic centers. They shared a distinct phenotype consisting of profound ID and hydrocephalus due to choroid plexus hyperplasia. Other shared features include severe neonatal feeding difficulties; congenital heart, kidney, and eye anomalies; obstructive sleep apnea; and anemia. CONCLUSION: The p.Arg37His PV in the DNA-binding domain of SMARCB1 causes a distinctive syndrome, likely through a gain-of-function or dominant-negative effect, which is characterized by severe ID and hydrocephalus resulting from choroid plexus hyperplasia. This report broadens the phenotypic spectrum associated with PV in SMARCB1.

15.
Clin Cancer Res ; 24(7): 1594-1603, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29351919

RESUMO

Purpose: In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer.Experimental Design: To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer, or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer-predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome.Results: Four patients carried causative mutations in a known cancer-predisposing gene: TP53 and DICER1 (n = 3). In another 4 patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy (EP300-based Rubinstein-Taybi syndrome, ARID1A-based Coffin-Siris syndrome, ACTB-based Baraitser-Winter syndrome, and EZH2-based Weaver syndrome). In addition, we identified two genes, KDM3B and TYK2, which are possibly involved in genetic cancer predisposition.Conclusions: In our selected cohort of patients, pathogenic germline mutations causative or likely causative of the cancer phenotype were found in 8 patients, and two possible novel cancer-predisposing genes were identified. Therewith, our study shows the added value of sequencing beyond a cancer gene panel in selected patients, to recognize childhood cancer predisposition. Clin Cancer Res; 24(7); 1594-603. ©2018 AACR.

16.
J Clin Endocrinol Metab ; 102(12): 4534-4540, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29040582

RESUMO

Context: Heterozygous pathogenic germline variants in CDC73 predispose to the development of primary hyperparathyroidism (pHPT) and, less frequently, ossifying fibroma of the jaw and renal and uterine tumors. Clinical information on CDC73-related disorders has so far been limited to small case series. Objective: To assess the clinical manifestations and penetrance in CDC73-related disorders and to improve case detection in pHPT. Design: Nationwide retrospective Dutch cohort study. Setting: Tertiary referral center. Patients: We studied 89 patients with pHPT referred for germline CDC73 analysis and 43 subsequently tested relatives who proved to be mutation carriers. Investigation: Germline CDC73 mutation analysis. Mean Outcome: CDC73 mutation detection yield, referral rate, and CDC73-related disease penetrance. Results: Pathogenic germline CDC73 variants were identified in 11 of the 89 referred pHPT patients (12.4%), with (suspected) hyperparathyroidism-jaw tumor (HPT-JT) syndrome (n = 3), familial isolated pHPT (n = 5), apparently sporadic parathyroid carcinoma (n = 2), and apparently sporadic parathyroid adenoma (n = 1). The estimated penetrance of CDC73-related disorders was 65% at age 50 years (95% confidence interval, 48% to 82%) in 43 nonindex mutation carriers. Conclusions: Germline CDC73 analysis is recommended in individuals with (suspected) HPT-JT syndrome, familial isolated pHPT, atypical or malignant parathyroid histology, and young individuals with pHPT. These criteria would increase germline CDC73 mutation detection, enabling optimal clinical management of pHPT as well as genetic counseling and surveillance for family members at risk for developing CDC73-related disorders.


Assuntos
Hiperparatireoidismo Primário/genética , Hiperparatireoidismo Primário/fisiopatologia , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Feminino , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Hiperparatireoidismo Primário/patologia , Neoplasias Maxilomandibulares/genética , Neoplasias Maxilomandibulares/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Países Baixos , Neoplasias das Paratireoides/genética , Neoplasias das Paratireoides/patologia , Penetrância , Estudos Retrospectivos , Adulto Jovem
17.
Cancer Lett ; 403: 159-164, 2017 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-28645564

RESUMO

Monoallelic germline mutations in one of the DNA mismatch repair (MMR) genes cause Lynch syndrome, with a high lifetime risks of colorectal and endometrial cancer at adult age. Less well known, is the constitutional mismatch repair deficiency (CMMRD) syndrome caused by biallelic germline mutations in MMR genes. This syndrome is characterized by the development of childhood cancer. Patients with CMMRD are at extremely high risk of developing multiple cancers including hematological, brain and intestinal tumors. Mutations in MMR genes impair DNA repair and therefore most tumors of patients with CMMRD are hypermutated. These mutations lead to changes in the translational reading frame, which consequently result in neoantigen formation. Neoantigens are recognized as foreign by the immune system and can induce specific immune responses. The growing evidence on the clinical efficacy of immunotherapies, such as immune checkpoint inhibitors, offers the prospect for treatment of patients with CMMRD. Combining neoantigen-based vaccination strategies and immune checkpoint inhibitors could be an effective way to conquer CMMRD-related tumors. Neoantigen-based vaccines might also be a preventive treatment option in healthy biallelic MMR mutation carriers. Future studies need to reveal the safety and efficacy of immunotherapies for patients with CMMRD.


Assuntos
Anticorpos/uso terapêutico , Antígenos de Neoplasias , Neoplasias Encefálicas/terapia , Vacinas Anticâncer/uso terapêutico , Neoplasias Colorretais/terapia , Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA , Imunoterapia/métodos , Mutação , Síndromes Neoplásicas Hereditárias/terapia , Animais , Anticorpos/efeitos adversos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/mortalidade , Vacinas Anticâncer/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Reparo de Erro de Pareamento de DNA/genética , Reparo de Erro de Pareamento de DNA/imunologia , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/imunologia , Predisposição Genética para Doença , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/mortalidade , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/imunologia , Síndromes Neoplásicas Hereditárias/mortalidade , Fenótipo
18.
Eur J Cancer ; 80: 48-54, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28544908

RESUMO

INTRODUCTION: Recognising a tumour predisposition syndrome (TPS) in childhood cancer patients is of major clinical relevance. The presence of a TPS may be suggested by the type of tumour in the child. We present an overview of 23 childhood tumours that in themselves should be a reason to refer a child for genetic consultation. METHODS: We performed a PubMed search to review the incidence of TPSs in children for 85 tumour types listed in the International Classification of Childhood Cancer third edition (ICCC-3). The results were discussed during a national consensus meeting with representative clinical geneticists from all six academic paediatric oncology centres in The Netherlands. A TPS incidence of 5% or more was considered a high probability and therefore in itself a reason for referral to a clinical geneticist. RESULTS: The literature search resulted in data on the incidence of a TPS in 26 tumours. For 23/26 tumour types, a TPS incidence of 5% or higher was reported. In addition, during the consensus meeting the experts agreed that children with any carcinoma should always be referred for clinical genetic consultation as well, as it may point to a TPS. CONCLUSION: We present an overview of 23 paediatric tumours with a high probability of a TPS; this will facilitate paediatric oncologists to decide which patients should be referred for genetic consultation merely based on type of tumour.


Assuntos
Aconselhamento Genético , Predisposição Genética para Doença , Síndromes Neoplásicas Hereditárias/epidemiologia , Criança , Humanos , Incidência , Encaminhamento e Consulta
20.
Pediatr Blood Cancer ; 64(3)2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27667142

RESUMO

Transient myeloproliferative disorder (TMD) is a leukemia type that occurs typically in newborns. In Down syndrome, TMD is referred to as transient abnormal myelopoiesis (TAM).32 Recently, transientness has also been reported in acute myeloid leukemia patients with germline trisomy 21 mosaicism, and even in cases with somatic trisomy 21, with or without GATA1 mutations. TMD cases without trisomy 21 are rare, and recurrent genetic aberrations that aid in clinical decision-making are scarcely described. We describe here a TMD patient without trisomy 21 or GATA1 mutation in whom single-nucleotide polymorphism analysis of leukemic blasts revealed a novel combined submicroscopic deletion (5q31.1-5q31.3 and 8q23.2q24).


Assuntos
Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 8/genética , Síndrome de Down/genética , Fator de Transcrição GATA1/genética , Leucemia Megacarioblástica Aguda/genética , Polimorfismo de Nucleotídeo Único/genética , Síndrome de Down/patologia , Humanos , Recém-Nascido , Leucemia Megacarioblástica Aguda/patologia , Prognóstico
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