What diseases are caused by genome instability?

Diseases Caused by Genome Instability

Genome instability disorders lead to multiple serious diseases including various cancers, developmental anomalies, and immunodeficiency syndromes, with specific conditions determined by which DNA repair pathway is affected. 1

Major Genomic Instability Disorders

DNA Repair Disorders

• Biallelic Mismatch Repair Deficiency (BMMRD/CMMRD)

  • Caused by biallelic mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2)
  • Characterized by high cancer risk beginning in childhood
  • Leads to colorectal cancer (70% penetrance, median age 16), brain tumors (70% penetrance, median age 9), lymphoma (20-40% penetrance), leukemia (10-40% penetrance) 1
  • Distinguished from Lynch Syndrome by absence of DNA-MMR activity from birth 1

• Ataxia Telangiectasia

  • Caused by biallelic pathogenic variants in ATM gene
  • Affects DNA double-strand break repair and cell cycle checkpoints
  • Diagnostic features include elevated alpha-fetoprotein and abnormal karyotype involving chromosomes 7 and 14 1

• Bloom Syndrome

  • Caused by biallelic mutations in BLM gene (homologous recombination pathway)
  • Characterized by sister chromosome exchange abnormalities
  • Associated with immunodeficiency (low immunoglobulin levels) 1

• Fanconi Anemia

  • Involves DNA interstrand crosslink repair defects
  • Multiple genes involved (FANCA, FANCC, FANCD1/BRCA2, etc.)
  • Leads to bone marrow failure and increased cancer risk 1

• Xeroderma Pigmentosum

  • Defects in nucleotide excision repair
  • Extreme sensitivity to UV radiation
  • High risk of skin cancers 1

• Nijmegen Breakage Syndrome

  • Defects in DNA double-strand break repair
  • Characterized by microcephaly and immunodeficiency 1

• Rothmund-Thomson Syndrome

  • Caused by mutations in RECQL4 gene
  • Features include poikiloderma, skeletal abnormalities, and cancer predisposition 1

Telomere Biology Disorders

• Dyskeratosis Congenita
  • Multiple inheritance patterns (X-linked, autosomal dominant, autosomal recessive)
  • Involves genes in telomere maintenance (DKC1, TERC, TERT, etc.)
  • Characterized by bone marrow failure and abnormal telomere length 1

Chromosomal Instability Syndromes

• Mosaic Variegated Aneuploidy
  • Characterized by constitutional mosaicism for chromosomal gains and losses
  • Associated with growth retardation and cancer predisposition 1

Cancer Risk in Genomic Instability Disorders

Genomic instability disorders significantly increase cancer risk through several mechanisms:

1. Early-onset cancers: Patients develop malignancies at much younger ages than the general population 1

2. Multiple cancer types: Affected individuals are at risk for various cancers depending on the specific disorder:

   • BMMRD: Colorectal cancer (70%), brain tumors (70%), lymphoma (20-40%), leukemia (10-40%), small bowel cancer (10%) 1
   • Other disorders: Specific cancer spectrums based on the affected DNA repair pathway 1

3. Treatment sensitivity: Many patients show exquisite sensitivity to chemotherapy and radiation, which may further increase the risk of second cancers 1

Clinical Manifestations Beyond Cancer

Genomic instability disorders typically present with multiple systemic manifestations:

• Developmental anomalies: Congenital malformations and growth abnormalities 1
• Neurological manifestations: Ataxia, microcephaly, developmental delay 1
• Immunodeficiency: Lymphopenia, low immunoglobulin levels 1
• Endocrine problems: Various hormonal disturbances 1
• Bone marrow failure: Particularly in Fanconi anemia and telomere biology disorders 1

Diagnostic Approach

Diagnosis of genomic instability disorders relies on:

1. Clinical manifestations: Recognition of characteristic phenotypic features 1, 2
2. Laboratory testing:
   • Chromosome breakage analysis
   • Telomere length measurement
   • Biochemical screening (e.g., alpha-fetoprotein levels)
   • Sister chromatid exchange analysis 1, 2
3. Genetic testing: Next-generation sequencing to identify pathogenic variants 2

Clinical Implications

The recognition of genomic instability disorders is crucial for:

1. Early cancer detection: Implementing appropriate surveillance protocols 1
2. Treatment planning: Avoiding excessive toxicity from standard cancer therapies 1
3. Genetic counseling: Informing families about inheritance patterns and recurrence risks 2
4. Cancer risk reduction strategies: Implementing preventive measures when possible 2

Pitfalls and Caveats

• Heterogeneity: The penetrance and expressivity of genomic instability disorders vary widely, requiring individualized approaches 1
• Treatment sensitivity: Standard cancer therapies may cause excessive toxicity in these patients, requiring dose modifications 1
• Diagnosis challenges: Some disorders may only be recognized after cancer has developed and treatment complications occur 1
• Second cancers: Patients are at high risk for subsequent malignancies, necessitating lifelong surveillance 1

Understanding the specific genetic basis of genome instability is essential for proper diagnosis, genetic counseling, cancer screening, and treatment selection in affected individuals.