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In July 2023, the American Association for Cancer Research held the second Childhood Cancer Predisposition Workshop at which international experts in pediatric cancer predisposition met to update the previously published 2017 consensus statements on pediatric cancer predisposition syndromes. Since 2017, advances in tumor and germline genetic testing and increased understanding of cancer predisposition in pediatric cancer patients have led to significant changes in clinical care. Here, we provide an updated genetic counseling framework for pediatric oncology professionals. The framework includes: (1) referral indications and timing; (2) somatic and germline genetic testing options; (3) testing for adult-onset cancer predisposition syndromes in children with and without cancer; (4) evolving genetic counseling models to meet the increased demand for genetic testing; (5) barriers to cancer genetic testing and surveillance in children; and (6) psychosocial and equity considerations regarding cancer genetic testing and surveillance in children. Adaptable genetic counseling services are needed to provide support to pediatric oncology provider teams and diverse patients with pediatric cancer, cancer predisposition, and their families.
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Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood. The incidence of germline predisposition among children with brain tumors continues to grow as our knowledge on disease etiology increases. Some children with brain tumors may present with nonmalignant phenotypic features of specific syndromes (e.g., nevoid basal cell carcinoma syndrome, neurofibromatosis type 1 and type 2, DICER1 syndrome, and constitutional mismatch-repair deficiency), while others may present with a strong family history of cancer (e.g., Li-Fraumeni syndrome) or with a rare tumor commonly found in the context of germline predisposition (e.g., rhabdoid tumor predisposition syndrome). Approximately 50% of patients with a brain tumor may be the first in a family identified to have a predisposition. The past decade has witnessed a rapid expansion in our molecular understanding of CNS tumors. A significant proportion of CNS tumors are now well characterized and known to harbor specific genetic changes that can be found in the germline. Additional novel predisposition syndromes are also being described. Identification of these germline syndromes in individual patients has not only enabled cascade testing of family members and early tumor surveillance but also increasingly affected cancer management in those patients. Therefore, the AACR Cancer Predisposition Working Group chose to highlight these advances in CNS tumor predisposition and summarize and/or generate surveillance recommendations for established and more recently emerging pediatric brain tumor predisposition syndromes.
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Neoplasias Encefálicas , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Síndromes Neoplásicas Hereditárias , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/diagnóstico , Criança , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/epidemiologia , Testes Genéticos , Guias de Prática Clínica como AssuntoRESUMO
With the increasing use of comprehensive germline genetic testing of children and adolescents with cancer, it has become evident that pathogenic variants (PV) in adult-onset cancer predisposition genes (aoCPG) underlying adult-onset cancer predisposition syndromes, such as Lynch syndrome or hereditary breast and ovarian cancer, are enriched and reported in 1% to 2% of children and adolescents with cancer. However, the causal relationship between PVs in aoCPGs and childhood cancer is still under investigation. The best-studied examples include heterozygous PVs in mismatch repair genes associated with Lynch syndrome in children with mismatch repair deficient high-grade glioma, heterozygous PVs in BARD1 in childhood neuroblastoma, and heterozygous PVs in BRCA2 in children with rhabdomyosarcoma. The low penetrance for pediatric cancers is considered to result from a combination of the low baseline risk of cancer in childhood and the report of only a modest relative risk of disease in childhood. Therefore, we do not advise that healthy children empirically be tested for PVs in an aoCPG before adulthood outside a research study. However, germline panel testing is increasingly being performed in children and adolescents with cancer, and exome and genome sequencing may be offered more commonly in this population in the future. The precise pediatric cancer risks and spectra associated with PVs in aoCPGs, underlying cellular mechanisms and somatic mutational signatures, as well as treatment response, second neoplasm risks, and psycho-oncological aspects require further research.
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Predisposição Genética para Doença , Testes Genéticos , Mutação em Linhagem Germinativa , Adolescente , Adulto , Criança , Feminino , Humanos , Idade de Início , Testes Genéticos/métodos , Neoplasias/genética , Neoplasias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/diagnósticoRESUMO
PURPOSE: Molecular tumor profiling is becoming a routine part of clinical cancer care, typically involving tumor-only panel testing without matched germline. We hypothesized that integrated germline sequencing could improve clinical interpretation and enhance the identification of germline variants with significant hereditary risks. MATERIALS AND METHODS: Tumors from pediatric patients with high-risk, extracranial solid malignancies were sequenced with a targeted panel of cancer-associated genes. Later, germline DNA was analyzed for a subset of these genes. We performed a post hoc analysis to identify how an integrated analysis of tumor and germline data would improve clinical interpretation. RESULTS: One hundred sixty participants with both tumor-only and germline sequencing reports were eligible for this analysis. Germline sequencing identified 38 pathogenic or likely pathogenic variants among 35 (22%) patients. Twenty-five (66%) of these were included in the tumor sequencing report. The remaining germline pathogenic or likely pathogenic variants were single-nucleotide variants filtered out of tumor-only analysis because of population frequency or copy-number variation masked by additional copy-number changes in the tumor. In tumor-only sequencing, 308 of 434 (71%) single-nucleotide variants reported were present in the germline, including 31% with suggested clinical utility. Finally, we provide further evidence that the variant allele fraction from tumor-only sequencing is insufficient to differentiate somatic from germline events. CONCLUSION: A paired approach to analyzing tumor and germline sequencing data would be expected to improve the efficiency and accuracy of distinguishing somatic mutations and germline variants, thereby facilitating the process of variant curation and therapeutic interpretation for somatic reports, as well as the identification of variants associated with germline cancer predisposition.
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Neoplasias/genética , Sequenciamento Completo do Genoma/normas , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença/genética , Humanos , Lactente , Masculino , Medicina de Precisão/métodos , Medicina de Precisão/normas , Medicina de Precisão/tendências , Sequenciamento Completo do Genoma/métodos , Sequenciamento Completo do Genoma/estatística & dados numéricosRESUMO
The spectrum of neoplasms associated with DICER1 variants continues to expand, with the recent addition of primary "DICER1-associated central nervous system sarcoma" (DCS). DCS is a high-grade malignancy predominantly affecting pediatric patients. Six pediatric DCS were identified through a combination of clinical diagnostic studies, archival inquiry, and interinstitutional collaboration. Clinical, histologic, immunohistologic, and molecular features were examined. Genomic findings in the 6 DCS were compared with those in 14 additional DICER1-associated tumors sequenced with the same assay. The six patients presented at ages 3-15 years with CNS tumors located in the temporal (n = 2), parietal (n = 1), fronto-parietal (n = 1), and frontal (n = 2) lobes. All underwent surgical resection. Histologic examination demonstrated high-grade malignant spindle cell tumors with pleuropulmonary blastoma-like embryonic "organoid" features and focal rhabdomyoblastic differentiation; immature cartilage was seen in one case. Immunohistochemically, there was patchy desmin and myogenin staining, and patchy loss of H3K27me3, and within eosinophilic cytoplasmic globules, alfa-fetoprotein staining. Biallelic DICER1 variants were identified in all cases, with germline variants in two of five patients tested. DCS demonstrated genomic alterations enriched for Ras pathway activation and TP53 inactivation. Tumor mutational burden was significantly higher in the 6 DCS tumors than in 14 other DICER1-associated tumors examined (mean 12.9 vs. 6.8 mutations/Mb, p = 0.035). Postoperative care included radiation (n = 5) and chemotherapy (n = 3); at the last follow-up, three patients were alive without DCS, and three had died of disease. Our analysis expands the clinical, histologic, immunohistological, and molecular spectrum of DCS, identifying distinctive features that can aid in the diagnosis, multidisciplinary evaluation, and treatment of DCS.
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Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , RNA Helicases DEAD-box/genética , Ribonuclease III/genética , Sarcoma/genética , Sarcoma/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , MutaçãoRESUMO
Cancer genetic counseling practice is rapidly evolving, with services being provided in increasingly novel ways. Pretest counseling for cancer patients may be abbreviated from traditional models to cover the elements of informed consent in the broadest of strokes. Genetic testing may be ordered by a cancer genetics professional, oncology provider, or primary care provider. Increasingly, direct-to-consumer testing options are available and utilized by consumers anxious to take control of their genetic health. Finally, genetic information is being used to inform oncology care, from surgical decision-making to selection of chemotherapeutic agent. This review provides an overview of the current and evolving practice of cancer genetic counseling as well as opportunities and challenges for a wide variety of indications in both the adult and pediatric setting.
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Aconselhamento Genético , Testes Genéticos/métodos , Consentimento Livre e Esclarecido , Neoplasias/diagnóstico , Neoplasias/genética , Adulto , Criança , Predisposição Genética para Doença , Testes Genéticos/ética , Humanos , Modelos TeóricosRESUMO
It is estimated that at least 8% to 10% of children diagnosed with cancer have an inherited cancer predisposition syndrome. Pediatricians may be called upon to (1) identify children with symptoms suggestive of cancer that require further diagnostic testing, (2) identify children who should be referred to cancer genetics based on their personal and family histories, and (3) provide primary care to children who have an inherited cancer syndrome. This review article provides a list of clinical warning signs suggestive of childhood malignancy, discusses the personal and family history "red flags" suggestive of hereditary cancer, offers checklists to help identify patients who are candidates for cancer genetics evaluation, and describes features of the major pediatric cancer syndromes involving solid tumors and surveillance guidelines. This review aims to provide the pediatrician with the tools needed to recognize, refer, and help manage children at risk for pediatric cancer syndromes. [Pediatr Ann. 2018;47(5):e204-e216.].
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Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/terapia , Pediatria/métodos , Atenção Primária à Saúde/métodos , Criança , Testes Genéticos , Humanos , Imageamento por Ressonância Magnética , Anamnese , Síndromes Neoplásicas Hereditárias/genética , Exame Físico , Encaminhamento e ConsultaRESUMO
BACKGROUND: Pancreatic cancer (PancCa) is recognized as a component of many well-described hereditary cancer syndromes. Minimal research has focused on patient needs and experiences living with this risk. PURPOSE: To understand the meaning and experience of living with familial PancCa risk and to explore experiences related to screening and prevention of PancCa. METHODS: Participants underwent semi-structured, in-depth interviews. Adults without PancCa and who met familial or hereditary risk criteria were eligible. Thematic analysis was completed on the transcripts in order to identify patterns, consistencies, and differences. Narrative review of existing literature related to women living with hereditary breast and ovarian cancer (HBOC) risk was completed to explore similarities and differences between published findings and our current findings. RESULTS: Nineteen individuals (9 male, 10 female) participated. Major themes addressed participants' family experiences with PancCa and PancCa death and the associated grief from the experiences. Family experiences impacted how participants interpreted and approached their own cancer risk and participated in the cancer screening program. Participants wanted to control their cancer risk and sought information and resources to prevent PancCa or PancCa related death. Distress related to risk was not described as constant but occurred around salient time points. CONCLUSION & FUTURE IMPLICATIONS: Study results begin to describe the lived experience of individuals with PancCa risk. Through this research we have uncovered important variables to further understand, measure, and intervene upon in future research. Distress related to risk was not described as ongoing, but occurred around specific and salient time points that brought risk to the forefront. Individuals with familial PancCa risk may have a unique experience compared to other hereditary cancer syndromes due to the high mortality of the disease and uncertainty related to prevention and early detection outcomes.
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Tay-Sachs disease (TSD) is the prototype for ethnic-based carrier screening, with a carrier rate of â¼1/27 in Ashkenazi Jews and French Canadians. HexA enzyme analysis is the current gold standard for TSD carrier screening (detection rate â¼98%), but has technical limitations. We compared DNA analysis by next-generation DNA sequencing (NGS) plus an assay for the 7.6 kb deletion to enzyme analysis for TSD carrier screening using 74 samples collected from participants at a TSD family conference. Fifty-one of 74 participants had positive enzyme results (46 carriers, five late-onset Tay-Sachs [LOTS]), 16 had negative, and seven had inconclusive results. NGS + 7.6 kb del screening of HEXA found a pathogenic mutation, pseudoallele, or variant of unknown significance (VUS) in 100% of the enzyme-positive or obligate carrier/enzyme-inconclusive samples. NGS detected the B1 allele in two enzyme-negative obligate carriers. Our data indicate that NGS can be used as a TSD clinical carrier screening tool. We demonstrate that NGS can be superior in detecting TSD carriers compared to traditional enzyme and genotyping methodologies, which are limited by false-positive and false-negative results and ethnically focused, limited mutation panels, respectively, but is not ready for sole use due to lack of information regarding some VUS.
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Repair of mature skeletal muscle is mediated by adult muscle progenitors. Satellite cells have long been recognized as playing a major role in muscle repair, whereas side population (SP) cells have more recently been identified as contributing to this process. The developmental source of these two progenitor populations has been considerably debated. We explicitly tested and quantified the contribution of embryonic somitic cells to these progenitor populations. Chick somitic cells were labeled by using replication-defective retroviruses or quail/chick chimeras, and mouse cells were labeled by crossing somite-specific, Pax3-derived Cre driver lines with a Cre-dependent reporter line. We show that the majority of, if not all, limb muscle satellite cells arise from cells expressing Pax3 specifically in the hypaxial somite and their migratory derivatives. We also find that a significant number of, but not all, limb muscle SP cells are derived from the hypaxial somite. Notably, the heterogeneity in the developmental origin of SP cells is reflected in their functional heterogeneity; somitically derived SP cells are intrinsically more myogenic than nonsomitically derived ones. Thus, we show that the somites, which supply embryonic and fetal myoblasts, are also an important source of highly myogenic adult muscle progenitors.
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Células Musculares/citologia , Células Satélites de Músculo Esquelético/citologia , Células-Tronco/citologia , Animais , Linhagem da Célula , Movimento Celular , Células Cultivadas , Embrião de Galinha , Quimera , Embrião de Mamíferos/citologia , Embrião não Mamífero , Genes Reporter , Proteínas de Fluorescência Verde/metabolismo , Imuno-Histoquímica , Camundongos , Microscopia de Fluorescência , Músculos/citologia , Músculos/metabolismo , Fator de Transcrição PAX3 , Fatores de Transcrição Box Pareados/metabolismo , Codorniz , Retroviridae/genética , Somitos/citologia , Especificidade da EspécieRESUMO
To define factors in E. coli promoting survival to replication fork stress, we isolated insertion mutants sensitive to replication inhibitors. One insertion caused partial loss of the universally conserved GTPase, obgE/yhbZ gene. Although obgE is essential for growth, our insertion allele supported viability until challenged with various replication inhibitors. A mutation designed to negate the GTPase activity of the protein produced similar phenotypes, but was genetically dominant. Synergistic genetic interactions with recA and recB suggested that chromosome breaks and regressed forks accumulate in obgE mutants. Mutants in obgE also exhibited asynchronous overreplication during normal growth, as revealed by flow cytometry. ObgE overexpression caused SeqA foci, normally localized to replication forks, to spread extensively within the cell. We propose that ObgE defines a pathway analogous to the replication checkpoint response of eukaryotes and acts in a complementary way to the RecA-dependent SOS response to promote bacterial cell survival to replication fork arrest.
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Quebra Cromossômica , Replicação do DNA , Proteínas de Escherichia coli/genética , Escherichia coli/metabolismo , GTP Fosfo-Hidrolases/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Adenosina Trifosfatases/metabolismo , Sobrevivência Celular , Cromossomos Bacterianos/fisiologia , DNA Helicases/metabolismo , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Exodesoxirribonuclease V/metabolismo , Citometria de Fluxo , GTP Fosfo-Hidrolases/química , GTP Fosfo-Hidrolases/metabolismo , Genes Dominantes , Proteínas Monoméricas de Ligação ao GTP/química , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Mutagênese Insercional , Mutação , FenótipoRESUMO
Side population (SP) cells isolated from bone marrow, skeletal muscle, and skin have been shown to engraft in dystrophic muscle. However, there have been questions on the phenotypical heterogeneity, tissue of origin, and relationships among SP cell populations extracted from different tissues. Studies on bone marrow SP cells have followed a consistent protocol for their isolation and results obtained are concordant. In contrast, protocols for the isolation of muscle SP cells vary greatly, and consequently reports on their phenotype, differentiation potential and origin have been inconsistent. To address this controversy, we demonstrate that isolation parameters, such as tissue dissociation, cell counting, Hoechst concentration, and stringency in the selection of SP cells, have an effect on the yield, viability, and homogeneity of SP cells derived from bone marrow, skeletal muscle, and skin. In this paper, we demonstrate that SP cells isolated from the bone marrow are distinct from SP cells extracted from skeletal muscle and skin tissues. This study offers an explanation for the controversy surrounding muscle SP cells, provides a detailed standardized protocol for their isolation, and highlights basic guidelines for reproducible and reliable isolation of SP cells from any tissue.
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Transplante de Medula Óssea/métodos , Técnicas de Cultura de Células/métodos , Linhagem da Célula/genética , Separação Celular/métodos , Células Cultivadas/fisiologia , Células-Tronco/fisiologia , Animais , Benzimidazóis/farmacologia , Células da Medula Óssea/citologia , Células da Medula Óssea/fisiologia , Contagem de Células , Sobrevivência Celular/fisiologia , Células Cultivadas/citologia , Células Cultivadas/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/citologia , Músculo Esquelético/crescimento & desenvolvimento , Distrofias Musculares/terapia , Mioblastos/citologia , Mioblastos/fisiologia , Fenótipo , Pele/citologia , Pele/crescimento & desenvolvimento , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacosRESUMO
Cell-based therapy for Duchenne muscular dystrophy patients and mdx mice has proven to be a safe but ineffective form of treatment. Recently, a group of cells called muscle side population (SP) cells have been isolated based on their ability to efflux the DNA-binding dye Hoechst. To understand the potential of skeletal muscle SP cells to serve as precursors for muscle, SP cells from the two mice strains mdx(5cv) and C57BL/6N were isolated, transduced, and transplanted. Under coculture conditions with myogenic cells, some cells within the SP cell population can give rise to early Pax7-positive satellite cells and other later stage myogenic cells. Transduced SP cells were transplanted via the tail vein and were shown to successfully deliver enhanced GFP and human microdystrophin to the skeletal muscle of nonirradiated mdx(5cv) mice, thus demonstrating their ability to travel through the capillaries and enter into damaged muscle. These results demonstrate that i.v. delivery of genes via SP cells is possible and that these SP cells are capable of recapitulating the myogenic lineage. Because this approach shows definitive engraftment by using autologous transplantation of noninjured recipients, our data may have substantial implications for therapy of muscular dystrophy.