Lecture 20 - Cancer genetics Flashcards
What is taxonomy?
The branch of science concerned with classification especially of organisms: systematics
How are tumours classified?
o Genomic level – DNA sequences – mutations, losses and gains
o Epigenetic level – the overlay of modifications to the genome that influence gene expression
o Gene expression level
o Tumour microenvironmental level – the influences of the surrounding host stroma
o Microbiota level – the impact of micro-organisms that impact tumour cells and the host
What genetic information drives cancer?
- Tumour drivers
- Tumour stroma
- Tumour microflora
Some genes are mutated, inappropriately expressed or lost during the course of cancer initiation and progression
What is the process of RNA sequencing?
- RNA isolation: RNA is extracted from the sample of interest using methods that preserve the integrity and quantity of RNA molecules.
- Library preparation: RNA is converted into cDNA (complementary DNA) using reverse transcription. The cDNA is then fragmented, adapters are added, and the fragments are amplified by PCR to create a library of RNA fragments suitable for sequencing.
- Sequencing: The library is sequenced using high-throughput sequencing technology, such as Illumina or PacBio.
- Data analysis: The sequenced reads are aligned to a reference genome or transcriptome to determine the identity and abundance of RNA molecules. The expression levels of individual genes and transcripts can be calculated using bioinformatics tools such as RSEM or Kallisto
How is molecular profiling used to classify tumours?
Molecular profiling is the analysis of the genetic, epigenetic, transcriptomic, and proteomic alterations in cancer cells. This information can be used to classify tumors into distinct subtypes
RNA sequencing is a type of molecular profiling tool
What are some examples of inherited forms of cancer?
o Familial adenomatous polyposis (FAP)
o BRCA1 and 2
What are the functions of the BRCA1 and BRCA2 genes?
Tumour suppressor genes
DNA repair: BRCA1 and BRCA2 are involved in the repair of double-stranded DNA breaks through the homologous recombination (HR) pathway. This process is critical for maintaining genomic stability and preventing the accumulation of mutations that can lead to cancer.
Cell cycle regulation: BRCA1 and BRCA2 are involved in cell cycle checkpoint control, which ensures that cells do not progress through the cell cycle when DNA damage is present. This process helps to prevent the accumulation of mutations that can lead to cancer.
Transcriptional regulation: BRCA1 and BRCA2 are involved in the regulation of gene expression, including the expression of other genes involved in DNA repair and cell cycle control.
Describe the different ways that functional TSGs can be lost
- Cancer results from the loss of the normal copy
o Loss of heterozygosity (LOH)
o Tends to be inherited in a dominant manner
o Can result from a point mutation in the second normal allele
o Can also occur if the chromosome carrying the good copy is lost
o Increasingly recognised that promoter methylation can silence a TSG allele – EPIGENETIC event
What molecular tests are used to detect TSG loss events?
o Direct genome
o RNA sequencing
o Protein truncation assays or micro assays
o Functional evaluations
**Family history or early onset cancers can trigger molecular investigations
What are Krukenberg tumours?
- An example of anatomical misdirection
- A rare tumour that grown on the ovaries but is not a tumour of the ovaries – comes from the bowel (which has metastasized to the ovary)
- Needs to be treated as a bowel cancer
What is immune checkpoint inhibitor blockade?
Immune checkpoint inhibitor blockade is a type of cancer immunotherapy that involves blocking immune checkpoints to stimulate the immune system to attack cancer cells.
What is an example of an immune checkpoint?
One of the most well-known immune checkpoints is the programmed cell death protein 1 (PD-1) and its ligand PD-L1. Some cancer cells express PD-L1 on their surface, which binds to PD-1 on immune cells and suppresses their activity. By blocking PD-1 or PD-L1 with antibodies, immune cells can be released from this suppression and attack cancer cells.
What are some therapeutic approaches to intervene in the tumour-stroma dialogue?
Targeting signalling pathways
Immune modulation
Targeting tumour-associated fibroblasts
Modulation of ECM
Targeting angiogenesis
Modulation of metabolism
Low dose -cyclophosphamide
Anti-PD-1 antibody blockage
What is Low dose -cyclophosphamide?
It is given at lower doses than standard chemotherapy regimens and is believed to work by suppressing the immune system’s regulatory T cells, which can inhibit the body’s natural immune response against cancer cells
What is Anti-PD-1 antibody blockage?
Anti-PD-1 antibody blockade is a type of cancer immunotherapy that involves blocking the interaction between programmed cell death protein 1 (PD-1), a checkpoint protein on T cells, and its ligands, PD-L1 and PD-L2, which are expressed on tumor cells and other immune cells. This interaction normally helps to regulate the immune response and prevent the immune system from attacking healthy cells, but it can also allow cancer cells to evade the immune system
