Cytogenetics Part 2 - Structural Chromosomal Abnormalities

Chromosome Structure and Nomenclature

• Chromosome abnormalities are classified as numerical or structural.
• Numerical abnormalities involve an abnormal number of normal chromosomes.
• Structural abnormalities involve one or more abnormal chromosomes with structural rearrangements.
• Each band in a karyotype is named according to:
  • Chromosome
  • Position of the band within the region
• International System for Cytogenetic Nomenclature (ISCN) is a consistent numbering system.
• Numbering starts at the centromere with:
  • p arms (petit, small, at the top)
  • q arms ("a line of people")
• Each arm is divided into regions, and the assigned number increases with distance from the centromere.

Structural Chromosomal Abnormalities

• Involve one or more abnormal chromosomes with a structural rearrangement.
• Occur frequently (1/500 births).
• Result from chromosome breakage and re-joining of fragmented ends.
• May not cause a disease phenotype if the rearrangement doesn't alter genetic material content/expression.

Main Classes of Structural Rearrangements

• Translocations
• Deletions and duplications
• Inversions

Translocations

• Part of one chromosome moves to another.
• Require breakage of both chromosomes with repair in an abnormal arrangement.
• Balanced translocation: no loss/gain of DNA; individual is clinically normal but at risk of producing chromosomally unbalanced gametes.
• Types:
  • Reciprocal (balanced)
  • Robertsonian

Reciprocal Translocation

• Breakage of two non-homologous chromosomes with exchange of fragments.
• Chromosome number remains 46.
• Incidence: ~1 in 500.

Robertsonian Translocation

• Involves acrocentric chromosomes (13, 14, 15, 21, 22).
• Forms a new chromosome consisting of the long arms of two fused acrocentrics.
• Short (p) arms are lost.
• Incidence: ~1 in 1000.
• Carrier has 45 chromosomes, including a derivative chromosome replacing the two missing acrocentric ones; e.g., $45, XX, der(14;21)$. No net gain or loss of genetic material.
• Cause of 5% of Down’s syndrome.

Deletions

Terminal Deletions

• Cri du chat syndrome: deletion on chromosome 5 (del(5)(p15)).

Interstitial Deletions

• Chromosome breaks at two sites, and the material between the breaks is deleted.
• Microdeletion syndromes affecting chromosome 15:
  • Prader-Willi syndrome (paternal deletion)
  • Angelman’s syndrome (maternal deletion)

Ring Formation

• Breakage at the ends of short and long arms.
• Loss of telomeres.
• Centromere allows progression through cell division; seen in Turner syndrome ($46,X,rX$).

Duplications

• Duplicated genetic material.
• Charcot-Marie-Tooth neuropathy type 1 (CMT1): 70-80% involves duplication of PMP22.

Inversions

• Chromosome breaks at two positions.
• May have no effect on phenotype if no genetic material is lost/gained.
• Types:
  • Paracentric: not involving the centromere
  • Pericentric: involving the centromere

Chromosomal Abnormalities in Cancer

• Translocations are associated with several cancers.
• Accumulation of inherited (germline) and somatic mutations can lead to uncontrolled growth/cell cycle deregulation.
• Proto-oncogenes can be activated into oncogenes.

Specific Translocations in Leukemia

• Chronic myelogenous leukemia (CML): Philadelphia chromosome; $t(9;22)(q34;q11)$

Genes Involved in Leukemia and Lymphoma

• CML: ABL, BCR
• Burkitt’s lymphoma: MYC, IGH
  • ABL = Abelson Tyrosine-Protein Kinase 1
  • BCR = Breakpoint Cluster Region Protein (CML gene)
  • MYC = Myelocytomatosis Viral Oncogene
  • IGH = Immunoglobulin Heavy Locus

Chromosomal Changes in Solid Tumors

• Examples:
  • Synovial sarcoma: $t(X;18)(p11.2; q11.2)$; genes: SSX1, SSX2, SYT
  • Myxoid liposarcoma: $t(12;16)(q13;p11)$; genes: CHOP, FUS
  • Ewing’s sarcoma: $t(11;22)(q24;p12)$; genes: FLI1, EWS
  • Wilm’s tumour: $del(11)(p13p13)$; gene: WT
  • Retinoblastoma: $del(13)(q14q14)$; gene: RB1; inactivation of RB1 (tumor suppressor gene). Cytogenetically visible deletion in the region of RB1 gene in 3% of retinoblastoma patients.