4- Cancer In Families And Individuals Flashcards
What are TSG normal functions
Regulating cell division
Cell damage checkpoints
Dna repair
Apoptosis
What is the normal function of oncogenes
Cell growth and proliferation e.g. growth factors, transcription factors, tyrosine kinases
What is haploinsufficiency
When only one TSG allele is hit but this is sufficient to cause phenotypic effect
What happens to expression of oncogenes and TRGs in cancer
Oncogenes: overexpressed
TSGs: These are deleted or inactivated
What genetic changes can lead to cancer
Mutationsinthepromoter
For tumour suppressor genes, they reduce transcription and for oncogenes, they increase transcription
o Mutationsinthecodingregion
They truncate or inactivate tumour suppressor genes (this is the main inherited type). They increase activity of oncogenes
o Genomicamplificationorwholechromosomegain
In oncogenes, they increase gene copy number (aneuploidy or translocations) and therefore transcription
o Genomicdeletionorwholechromosomeloss
In tumour suppressor genes, they are removed (aneuploidy or translocations), either fully or partly, and therefore transcription is reduced
o Genefusionviachromosomerearrangement
In oncogenes, this can cause the formation of a novel protein
Describe the 1st and second hit in TSGs
The first mutation is often caused by a mutation and the second is usually caused by a large deletion
The first mutation usually reduces the transcription level, but is insufficient to produce a phenotypic effect. The second allele needs to be inactivated also, which causes a total loss of transcription for the malignant phenotype to be conferred
How do chromosome rearrangements lead to oncogenesis
Chromosome rearrangements can lead to gene copy number changes via deletion or duplication
They can also cause gene fusion, via translocation or inversion
What is loss of heterozygosity
LOH describes a region of apparent homozygosity, probably via a deletion in cancer tissue, that may mark the location of a tumour suppressor gene
How are somatic and germline mutations different
99% of cancers are sporadic or non inherited. The remaining 1% are inherited i.e., they have a germline component
how do inherited mutations in BRCA1 and BRCA2 genes influence risk of breast and ovarian cancer
2 4% of breast cancer cases are caused by a germline mutation of BRCA1 and BRCA2 genes i.e. the first hit is a germline mutation in these genes
60% of these are at risk of developing cancer by age 90, and they have an earlier average age of onset than those without this germline mutation
BRCA1 and BRCA2 normal function is DNA repair, via a process called homologous
recombination. A truncated or non functional protein causes impaired DNA repair, so mistakes or damage go uncorrected
What is Familial adenomatous polyposis(FAP)
Characterised by the growth of many intestinal polyps, one or more of which is likely to become cancerous. It accounts for >1% of all colorectal cancers. Caused by a mutation in the APC gene, which controls cell division. This mutation almost always confers cancer in later life
What is Hereditary non polyposis colorectalcancer(HNPCC or Lynchsyndrome)
3% of all cases, this is the most common inherited form (90% of familial cases). The mutation is in MLH1 and MSH2 genes, which are DNA repair genes, and comes with an 80% risk of developing cancer in later life
How is pharmogenetic testing used in cancer and give examples
pharmacogenomics tests are used to identify which patients are most likely to respond to certain drugs based on the presence or absence of particular somatic mutations
For example:
o KRAStestwith cetuximab forcolorectalcancere
KRAS mutation = less likelihood of a response
o EGFRtestwithgefitinibfornonsmall celllungcancer
EGFR mutation = greater likelihood of response
o BCR ABL1“T315I”testwithdasatinibforchronicmyeloidleukaemia
BCR ABL1 T315I mutation = unlikely to respond
What are the hallmarks of cancer
Dysregulated growth •Autologous pro-growth signalling •Insensitive to anti-growth signalling •Evasion of apoptosis •Limitless replication •Sustained angiogenesis •Invasion/metastasis
What is CML
Chronic myeloid leukaemia – this is a clonal myeloproliferative disorder of the pluripotent
haematopoietic stem cell leading to an overproduction of mature granulocytes i.e. neutrophils
and monocytes
It is triphasic, with a chronic stage, an accelerated stage and a terminal acute stage
The consistent pathogenic marker is a translocation between chromosomes 9 and 22 – t(9;22) –
resulting in a fusion gene called BCR ABL1, which produces tyrosine kinase. The c22 formed is called the Philadelphia chromosome
