Note: Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders
Note: Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders
doi: 10.1158/1078-0432.CCR-17-0465
DNA repair syndromes
Defective in DNA replication
Defective in DNA damage response
Majority of DNA repair syndrome
Inherited - autosomal-recessive manner
Minor of DNA repair syndrome
Autosomal dominant
X-linked recessive
Clinical features
Highly varied depending on underlying genetic cause
Higher risk in cancer
Can be found in childhood
No clear evidence-based approaches
This paper
Want to develop guidelines for children with cancer-prone disorder
Focus more common rare DNA repair disorders
ataxia telangiectasia,
Bloom syndrome,
Fanconi anemia,
dyskeratosis congenita,
Nijmegen breakage syndrome,
Rothmund–Thomson syndrome,
Xeroderma pigmentosum.
Conclusion
Recommended -- centralized centers of excellence in caring patients with heritable DNA repair
Observation
Defect in DNA repair disorders
Diagnosed in childhood
Aberrant telomere
Manifest later in life
Focus -- Pediatric cancer surveillance guidelines for children hereditary risk of cancer
Ataxia Telangiectasia (AT)
Autosomal recessive
Biallelic pathogenic variants in ATM (ataxia-telangiectasia mutated)
Cell cycle checkpoint kinase regulator of multiple proteins
Pathogenic variants
Decreases in expression
Decrease in function
Patients with this defect ~ 1-4 years
Progressive cerebellar ataxia
Oculomotor apraxia
Choreoathetosis
Immunodeficiency
Aberrant DNA repair -- causing neuronal cell death
Up to 40% of patients -- malignancy developed -- usually
non-Hodgkin lymphoma
Acute lymphoid leukemia
Cancer screening/surveillance/management protocols for AT
Diagnosed with various methods
Abnormal newborn screening for reduced T-cell receptor excision circle levels
increased alpha-fetoprotein (AFP) levels;
reduced IgA, IgE, and IgG2 levels;
poor antibody response to pneumococcal polysaccharide vaccines;
abnormal peripheral blood karyotype analysis including presence of a 7;14 translocation (in 5%–15% of patients);
cerebellar hypoplasia on MRI
Increased lymphocyte sensitivity to ionizing radiation
No evidence-based standards for cancer screening -- recommended to annual physical exam
For heterozygous -- single pathogenic ATM variant
Increases risk of adult onset breast, prostate, and pancreatic cancer
Thus, parents who have child with AT -- higher chance for above mentioned CA
The A-T Children's Project ~ https://www.atcp.org/
Autosomal recessive
Biallelic pathogenic variants in nibrin (part of MRN complex)
~40% affected individuals -- malignancies before age20
T-cell and B-cell lymphomas (common NBS-associated malignancy)
Medulloblastoma, glioma, and rhabdomyosarcoma being reported
Heterozygous carriers of pathogenic variants -- at risk for adult onset
Breast CA
Prostate CA
Cancer screening/surveillance/management protocols for NBS
Require multidisciplinary team
Management of immunodeficiency
Management of recurrent infection
Endocrine and nutrition
Growth deficiency
Oncology risk for
Leukemia
Lymphoma
Solid tumor
This group of patients sensitive to ionizing radiation -- thus treating patients with cancers must be aware of the side effect from radiation
Bloom syndrome
Autosomal recessive
Biallelic pathogenic variants in BLM gene (BLM DNA helicase)
Unwinding DNA double helix
Maintain genomic instability during DNA replication -- by limiting sister chromatid exchange
Defective in this gene -- 10 timeless higher rate of sister chromatid exchange
BLM characteristics
pre- and postnatal growth deficiency,
short stature,
sun sensitivity,
gastroesophageal reflux,
recurrent infections,
decreased fertility in males,
insulin resistance,
cancer predisposition
Cancer during pediatric
gastrointestinal,
genital and urinary tract carcinoma,
lymphoma,
acute lymphoblastic leukemia,
acute myeloid leukemia (AML),
sarcoma,
Wilms tumor,
medulloblastoma,
retinoblastoma
Cancer screening/surveillance/management protocols for BLM
No established cancer screening protocol
Cancer risk
Leukemia
Lymphoma
Colon cancer
Breast cancer -- regular MRI beginning at 18 years
Many resources try to help this group of patients
Rothmund–Thomson Syndrome
Type 2 RTS
Increase cancer risk
Biallelic pathogenic variants in RECQL4 DNA helicase
RECQL4 function
DNA replication
DNA damage repair
Maintenance of telomeres
Mitochondrial DNA integrity
RTS developed osteosarcoma at earlier age
Small number
Basal cell carcinoma
Skin squamous cell carcinoma
Blood cancers have been reported!
Cancer screening/surveillance/management protocols for RTS
Require multidisciplinary team
Genetic counseling for cancer risk - osteosarcoma
Annual skin exam
Ophthalmology for cataract screening+management
Routine check with dentist
Avoid excessive UV/IR
Dyskeratosis Congenita
Telomere biology disorder
Pathogenic variants in genes important for
Stability+maintenance of telomeres
Nucleoprotein complex essential for chromosomal stability
X-linked
DKC1
Autosomal dominant (AD)
TERC/TINF2
Autosomal recessive (AR)
CTC1, NHP2, NOP10, PARN, or WRAP53
Either AD or AR
ACD, RTEL1, or TERT
Risk for
MDS
BMF
Leukemia
Head and neck cancer
Cancer screening/surveillance/management protocols for DC
Cancer risk
Leukemia
Hepatic tumour
Head and neck squamous cell carcinoma
Oral cancer
Fanconi Anemia
Autosomal recessive at least 20 associated DNA repair genes
Pathogenic variants
X-linked recessive
FANB
Autosomal recessive
FANCR (RAD51)
Maintain genomic stability through repairing DNA interstrand cross-links and interacting with other DNA damage response pws
Diagnostic screening
Observe chromosomal breakage after exposure of T cells to diepoxybutane or mitomycin C
Risk of solid tumour by age 50 years
Head and neck cancer ~ 30% chance
Acute myeloid leukemia ~ 10% chance
Cancer screening/surveillance/management protocols for FA
Parents with some FA subtypes -- might have higher risk for cancer development
Xeroderma Pigmentosum (XP)
Pathogenic variants in NER genes
DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA, or XPC
Severe sun sensitivity
Risk for
Skin cancer
Leukemia
Squamous cell carcinoma (head+neck,
Brain
Spinal cord
Other solids tumours
Super rare disorder 1/1 million ppl
Cancer screening/surveillance/management protocols for XP
Minimize UV exposure, esp, UVA+UVB
Heterozygous Carriers of Pathogenic Variants in DNA repair gene
Heterozygous may elevated cancer risk
Varied by gene and cancer
No clear evidence whether heterozygous connected to cancer development in children
Conclusion
It is recommended to have center of excellence to take care of these specific groups of patients
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