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/

Nijmegen Breakage Syndrome (NBS)

• 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

• http://weill.cornell.edu/bsr/

• http://www.bloomssyndromeassociation.org

• RECQ2016

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

• http://www.rtsplace.org/

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

• https://www.dcoutreach.org/guidelines

• 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

• http://fanconi.org/index.php/publications/guidelines

• 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

• http://www.xps.org/

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