9. Cancer Cytogenomics Flashcards
Mosaicism vs chimerism
Mosaicism: presence of 2 or more unique cell populations in an individual, developed from single fertilised egg
Chimerism: 2 or more cell populations derived from distinct fertilised eggs
Errors occurring in stem cells results in mosaicism of…
Whole body
Errors occurring in differentiating cells causes mosaicism in…
Specific tissues
Errors occurring in differentiated cells causes mosaicism in…
Specific organs
Classes of disease associated with mosaicism
-mendelian (SNPs/indels)
-chromosomal/CNVs
-epigenetic (imprinting)
-mitochondrial (heteroplasmy)
Non-pathogenic examples of mosaicism
X-chromosome inactivation
-X-inactivation is random between different cells, some inactive one while others inactivate the other
Immunogenetic mosaicism
Neuronal cell types
Pathogenic examples of mosaicism
Cytogenetic aberrations
-Pallister Killian syndrome, 4 copies of p arm chr13
-fetuses would die if not for mosaicism
Cancer
Cytogenomic mechanisms of cancer
Gene fusion with oncogenic properties
-balanced structural chromosomal rearrangements
De-regulated oncogene expression
-structural rearrangements (eg moving enhancer sequences)
-numerical or unbalanced structural changes (eg amplification of gene)
Tumour-suppressor inactivation
-numerical or balanced/unbalanced structural changes)
Philadelphia chromosome
-balanced rearrangement
-reciprocal translocation between chromosomes 9 and 22
-creates dysregulated tyrosine kinase activity
Why does Philadelphia chromosome cause cancer
-ABL1 (from chr 9) has tyrosine kinase function
-tyrosine kinase helps regulate cell cycle, it’s tightly regulated and not highly expressed
-BCR (from chr 22) is a ‘housekeeping’ gene and is highly expressed
-fusion: 5’ end of BCR (promoter region) is joined to ABL1
-causes constitutively active tyrosine kinase activity
-out of control cell cycling -> cancer
Chronic myelogenous leukaemia (CML) BCR-ABL1 fusion
Breakpoint in BCR
-major breakpoint after exon 13 or 14
-fusion product contains promoter and exons 1-13/14
Transcripts
-e13a2 (b2a2)
-e14a2 (b3a2)
Acute lymphoblastic leukaemia (ALL) BCR-ABL1 fusion
Breakpoint in BCR
-minor breakpoint after the promoter, doesn’t include exons
e1a2 transcript
Detecting Ph’ with FISH: major BCR breakpoint (CML)
-1 probe for 9q34 region (eg red probe)
-another probe for 22q11.2 region (eg green probe)
-no abnormality would show 2 red signals and 2 green signals
philadelphia chromosome would show:
-1 green signal for chr 22 (no change in intensity)
-1 red signal for chr 9 (no change in intensity)
-1 weak red signal (indicates less material due to disruption)
-1 hybrid signal (yellow)
Detecting Ph’ with FISH: minor BCR breakpoint (ALL)
-1 probe for 9q34 region (eg red probe)
-another probe for 22q11.2 region (eg green probe)
-no abnormality shows 2 red, 2 green signals
Philadelphia chromosome presence would show:
-1 green signal
-1 red signal
-2 yellow signals
Cause of Burkitt lymphoma
Oncogene juxta-positioned to an enhancer gene
-MYC (8q24) is moved close to an immunoglobulin gene:
-IGH (14q32)
-IGK (2p12)
-IGL (22q11)
-upregulated transcription of TFs -> enhanced cell division
MYCN (2p24.3) causes cancer by which mechanism
Oncogene amplification
Retinoblastoma caused by which mechanism
Tumour-suppressor inactivation
