Describe how the following factors can lead to dysregulation of gene function, leading to cancer:
- chromosomal changes
- gene amplification
- epigenetic changes
Provide examples to illustrate your answers.
Curriculum Reference: Dysregulation of Cancer Associated Genes
This question is similar to Question E4 in the 2009 version of CA05, with the last line "Provide examples to illustrate your answers" tacked on at the end. It would also be useful to know about the role of micro-RNA, see the curriculum reference above.
Chromosomal Abnormalities
There are numerous categories of chromosomal abnormalities important for cancer promotion.
- Translocations occur when the distal arm of one chromosome is swapped with the distal arm of another. If an oncogene is located near a translocation, it may be attached to an incorrect promoter region, leading to increased expression of that oncogene. Similarly, a tumour suppressor gene may be deactivated if it loses its promoter region with a translocation. Finally, translocations may lead to production of chimeric proteins that may disrupt normal cell regulation.
- Aneuploidy is thought to occur later in the development of cancer. If extra copies of a chromosome containing an oncogene are present, more of the protein may be expressed. Alternatively, loss of chromosomes that code for tumour suppressing genes will lead to less expression of those proteins.
- Deletion refers to the loss of part of a chromosome, usually containing numerous genes. Tumour suppressor genes may be lost in this segment.
Examples
- Translocations seem to be common in haematological malignancy: A translocation of chromosomes 14 and 18 places the BCL2 gene, a potent anti-apoptosis protein, next to the promoter region for an immunoglobulin gene. This leads to follicular lymphoma. Burkitt's lymphoma is associated with a similar translocation of C-MYC to the same immunoglobulin gene.
- Deletion of chromosome 13q14 results in loss of the RB1 gene, and is seen in retinoblastoma.
- Aneuploidy is seen in many tumours
Gene Amplification
Gene amplification occurs when multiple copies of the same gene are present within the genome. These may be double minutes (copies of the gene distributed throughout many chromosomes) or homogenous staining regions (numerous adjacent copies of the gene). The presence of extra copies lead to increased production of the associated protein – if this is an oncogene then self sufficiency in growth signals may be achieved.
Examples
- The most commonly seen amplification in radiation oncology practice is of ERBB2 (or HER2). Upwards of 20 copies may be present in some malignancies, which helps to drive tumour progression and is a poor prognostic factor.
Epigenetic Changes
Instead of mutation (alteration of genetic code), the expression of genes in a cell may be altered by the degree of methylation. Methylated DNA is not expressed, and this method is used by normal cells to prevent unwanted protein production. Malignant cells have global DNA hypomethylation, with the exception of certain segments that are hypermethylated. These segments may include tumour suppressor genes, which are silenced without the need for mutation to occur.
Promotor or suppressor regions of DNA may be altered by histones, molecules involved in maintaining the structure of DNA. Histone modifying enzymes are known to be overexpressed in some tumours, which may lead to silencing of tumour suppressing genes.
Examples
- Hypermethylation of BRCA1 is seen in many breast cancers
Links
Back to CA05
Over to Question E4 from the 2009 CA05 assignment
