The Iceberg Map of germline mutations in childhood cancer: focus on primary immunodeficiencies

Kindler, Oliver; Quehenberger, Franz; Benesch, Martin; Seidel, Markus G.

doi:10.1097/mop.0000000000000680

Cited by 18 publications

(17 citation statements)

References 32 publications

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“…115 Among patients surviving cellular therapy for IEIs, an increased risk of cancer might exist because of (1) the specific gene defect (eg, DNA instability); (2) long-term effects of the conditioning regimen; or (3) potentially, insertional oncogenesis (GT). 116,117 Genetic counseling and sterility treatment. Survivors of cellular therapy for IEIs require genetic counseling to assess the risk of transmitting the disease to their offspring.…”

Section: Common Clinical Hallmarks In the Transitional Care For Patients Having Undergone Hsct Or Gt In Childhoodmentioning

confidence: 99%

Consensus of the Italian Primary Immunodeficiency Network on transition management from pediatric to adult care in patients affected with childhood-onset inborn errors of immunity

Cirillo

Giardino

Ricci

et al. 2020

Journal of Allergy and Clinical Immunology

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Section: Common Clinical Hallmarks In the Transitional Care For Patients Having Undergone Hsct Or Gt In Childhoodmentioning

confidence: 99%

Consensus of the Italian Primary Immunodeficiency Network on transition management from pediatric to adult care in patients affected with childhood-onset inborn errors of immunity

Cirillo

Giardino

Ricci

et al. 2020

Journal of Allergy and Clinical Immunology

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“…Despite intensive research, gaps remain in our understanding of the genetic landscape of pediatric cancer susceptibility. It is assumed that germline mutations in cancer-predisposing genes (CPGs) in children and adolescents are rare events [2][3][4]. However, the genetic predisposition to childhood cancer is most likely underidentified.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the genetic architecture of hepatoblastoma risk: birth defects and increased burden of germline damaging variants in gastrointestinal/renal cancer predisposition and DNA repair genes

Aguiar

Teixeira

Scliar

et al. 2021

Preprint

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The ultrarare hepatoblastoma is the most common pediatric liver cancer. HB risk is related to a few rare syndromes, and the molecular bases remain elusive for most cases. We investigated the burden of rare damaging germline variants in 30 Brazilian patients with HB. A high frequency of prematurity (20%) and birth defects (37%), especially craniofacial (17%, including craniosynostosis) and kidney (7%) anomalies, was observed. Pathogenic or likely pathogenic variants mapped to 10 cancer predisposition genes (APC, CHEK2, DROSHA, ERCC5, FAH, MSH2, MUTYH, RPS19, TGFBR2 and VHL,) were detected in 33% of the patients, only 40% of them with a family history of cancer. These findings showed a predominance of CPGs with a known link to gastrointestinal/colorectal and renal cancer risk. A remarkable feature was an enrichment of rare damaging variants affecting different classes of DNA repair genes, particularly those known as Fanconi anemia genes. Moreover, several damaging rare variants mapped to genes impacting liver functions were observed. To our knowledge, this is the first comprehensive assessment of rare germline variants in HB patients, contributing to elucidating the genetic architecture of HB risk.

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“…Moreover, it is interesting to note the distinctive distribution of cancer subtypes affecting patients with a PID. Indeed, lymphoid malignancies represent more than half of the cancers seen among subjects with a PID, followed by skin cancers and, to a lesser extent, solid tumors such as gastric cancers or tumors of the central nervous system [ 3 , 4 , 5 ]. Among lymphoid malignancies, non-Hodgkin lymphomas (NHLs) are more common than Hodgkin’s lymphomas and leukaemia, and diffuse large B cell lymphomas represent the largest subset of NHLs [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

The Possibilities of Immunotherapy for Children with Primary Immunodeficiencies Associated with Cancers

2020

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Many primary immunodeficiencies (PIDs) are recognised as being associated with malignancies, particularly lymphoid malignancies, which represent the highest proportion of cancers occurring in conjunction with this underlying condition. When patients present with genetic errors of immunity, clinicians must often reflect on whether to manage antitumoral treatment conventionally or to take a more personalised approach, considering possible existing comorbidities and the underlying status of immunodeficiency. Recent advances in antitumoral immunotherapies, such as monoclonal antibodies, antigen-specific adoptive cell therapies or compounds with targeted effects, potentially offer significant opportunities for optimising treatment for those patients, especially with lymphoid malignancies. In cases involving PIDs, variable oncogenic mechanisms exist, and opportunities for antitumoral immunotherapies can be considered accordingly. In cases involving a DNA repair defect or genetic instability, monoclonal antibodies can be proposed instead of chemotherapy to avoid severe toxicity. Malignancies secondary to uncontrolled virus-driven proliferation or the loss of antitumoral immunosurveillance may benefit from antivirus cell therapies or allogeneic stem cell transplantation in order to restore the immune antitumoral caretaker function. A subset of PIDs is caused by gene defects affecting targetable signalling pathways directly involved in the oncogenic process, such as the constitutive activation of phosphoinositol 3-kinase/protein kinase B (PI3K/AKT) in activated phosphoinositide 3-kinase delta syndrome (APDS), which can be settled with PI3K/AKT inhibitors. Therefore, immunotherapy provides clinicians with interesting antitumoral therapeutic weapons to treat malignancies when there is an underlying PID.

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The Iceberg Map of germline mutations in childhood cancer: focus on primary immunodeficiencies

Cited by 18 publications

References 32 publications

Consensus of the Italian Primary Immunodeficiency Network on transition management from pediatric to adult care in patients affected with childhood-onset inborn errors of immunity

Consensus of the Italian Primary Immunodeficiency Network on transition management from pediatric to adult care in patients affected with childhood-onset inborn errors of immunity

Unraveling the genetic architecture of hepatoblastoma risk: birth defects and increased burden of germline damaging variants in gastrointestinal/renal cancer predisposition and DNA repair genes

The Possibilities of Immunotherapy for Children with Primary Immunodeficiencies Associated with Cancers

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