Genetics: Aneuploidy and Structural Variants

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Questions and Answers

Aneuploidy refers to one or more individual chromosomes that are either in extra copy or missing.

True

Trisomy 21 is also known as Patau Syndrome.

False

The incidence of translocations is approximately 1:500 newborns.

True

Copy number variants (CNVs) are usually larger than 1000 base-pairs.

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Microsatellites are made up of repeat units that can range from 5 to 10 base-pairs.

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Most copy number variants carried in our genomes are pathogenic.

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Single nucleotide polymorphisms represent a single base-pair difference in DNA.

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Turner syndrome is associated with viable trisomy of the X chromosome.

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We all carry approximately 3.5 million SNPs in our genomes.

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The majority of mutations occur within genes, suggesting they commonly cause diseases.

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Small-scale genetic variations can potentially lead to changes in the amino acid sequence.

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Clinical relevance of pathogenic mutations is exclusively harmful.

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Large-scale mutations, such as trisomy 21, result in gross changes in gene expression.

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SNPs are always associated with disease-causing effects.

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The CFTR delta-508 mutation involves the deletion of a specific amino acid.

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Pathogenic mutations can lead to a premature stop of translation.

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Humans have approximately 0.1% genetic variability among their genomes.

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The primary purpose of sexual reproduction in humans is to maintain genetic uniformity.

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Different haplotypes do not affect an individual's immune response to diseases.

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Pathogenic mutations can include frameshift mutations.

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Missense mutations result in different amino acids being produced.

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Personalized medicine is unrelated to pharmacogenetics.

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Germ-line genetic variation includes only large scale variations such as CNVs and translocations.

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Nonsense mutations introduce a stop codon into the sequence.

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Genomic instability in cancer cells prevents rapid evolution of the cancer.

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Genetic variability can enhance a population's ability to adapt to environmental stresses.

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Different cancers arise from the same type of tissue.

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Sickle Cell Anemia provides an advantage in malaria resistance.

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Tumor profiling is a growing field that specializes in genetic characterization of cancers.

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Genomic instability in cancer cells leads to large scale deletions and amplifications.

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Cancer arises only from germline mutations.

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'Driver' mutations contribute to the persistence of genomic instability in cancer.

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Different clones of cells within a single type of cancer can respond differently to treatments.

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All cancers arise from the same tissue type.

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The evolutionary purpose of sexual reproduction is to reduce genetic differences within a population.

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Different haplotypes can significantly influence an individual's immune response to diseases.

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Germ-line genetic variation includes only small-scale variations such as SNPs.

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Pathogenic mutations can include both frameshift mutations and stop mutations.

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The majority of genetic differences in human genomes are caused by small-scale variations rather than large-scale variations.

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Personalized medicine is completely independent of pharmacogenetics.

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Aneuploidy refers to instances where chromosomes are either present in an extra copy or completely absent.

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Genetic variability can have detrimental effects on a population's survival against diseases.

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The incidence of copy number variants (CNVs) is notably rare within the human genome.

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The incidence of copy number variants (CNVs) in the human genome is negligible.

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Translocations can occur during the process of meiosis and involve the exchange of DNA between non-homologous chromosomes.

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Microsatellites are short repeated DNA sequences, but they always have the same number of repeats in all individuals.

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Most copy number variants larger than 1 million base-pairs tend to be benign.

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The presence of viable monosomy (such as Turner syndrome) involves the absence of one chromosome from an individual’s genetic complement.

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Single nucleotide polymorphisms (SNPs) can result in changes to the protein sequences encoded by genes.

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Learning disabilities and developmental delays are commonly associated with aneuploidy.

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The majority of small-scale pathogenic mutations can lead to changes in the amino acid sequence.

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Large-scale pathogenic variations, such as translocations, typically have no impact on gene expression.

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Pathogenic mutations can only occur in exons, as these are the only parts of the genome that contribute to disease.

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Nonsense mutations can lead to premature stop codons, halting protein translation.

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The CFTR delta-508 mutation results in the addition of an amino acid, enhancing protein function.

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Single nucleotide polymorphisms (SNPs) are commonly associated with major disease-causing effects.

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All types of mutations, regardless of their location in the genome, can lead to disease.

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Translocations can rearrange multiple genes, which may contribute to pathogenic mutations.

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The majority of single nucleotide polymorphisms (SNPs) have significant disease-causing effects.

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Pathogenic mutations are more likely to occur in exons than in non-coding regions.

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Silent mutations result in the production of different amino acids compared to the original sequence.

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Small-scale pathogenic variations often lead to changes in gene expression.

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The CFTR delta-508 mutation leads to a functional protein capable of exiting the endoplasmic reticulum for further processing.

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Large scale germ-line genetic variation includes only translocations and does not account for chromosome number issues.

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Fragile X syndrome is a direct consequence of large-scale mutations, such as translocations.

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Sexual reproduction is primarily aimed at reducing genetic variation in human populations.

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Pathogenic mutations only result from large-scale genetic variations in the genome.

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Copy number variants (CNVs) are often smaller than 1000 base-pairs.

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Premature stop mutations can lead to proteins that are longer than their non-mutated forms.

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The vast majority of human DNA is identical across different genomes with only about 0.1% variability.

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Different response to environmental stresses can be attributed to variations in immune response genes.

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Haplotypes do not influence the pharmacological response of individuals to drugs.

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Germ-line genetic variation is exclusively limited to variations like SNPs and does not include larger mutations.

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The evolutionary benefits of genetic variability include adaptation to new diseases and environmental conditions.

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Microsatellites are short repeated DNA sequences that can vary in length from individual to individual.

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Most copy number variants larger than 1 million base-pairs are benign.

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Translocation mutations always result in loss of genetic material.

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Aneuploidy can lead to a variety of developmental disorders, including Turner syndrome.

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All individuals carry mutations that cause significant changes in gene expression.

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Single nucleotide polymorphisms (SNPs) only affect the coding regions of genes.

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The incidence of viable trisomy such as Patau syndrome is approximately 1 in 1000 newborns.

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Most microsatellites can cause diseases due to their repetitive nature.

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Frameshift mutations are caused by the introduction of new stop codons in the DNA sequence.

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Genomic instability in cancer cells allows for the retention of safety mechanisms that restrict rapid cell division.

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Different genetic clones within the same cancer type may only respond to the same pharmacological agent.

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Cancer arises solely from somatic mutations without any influence from genetic variations that are inherited.

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The concept of driver mutations is unrelated to the persistence of genomic instability in cancer.

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Study Notes

Aneuploidy

One or more chromosomes are present in an extra copy or are missing.
Trisomy 21 (Down syndrome) is an example.
It is rare, occurring in approximately 1 in 1000 newborns.
Typically, aneuploidy results in significant changes in gene expression, leading to clinical consequences.
Other viable trisomy syndromes include trisomy 13 (Patau Syndrome), trisomy 18 (Edwards Syndrome), and XXY (Kleinefelters).
Viable monosomy (X – Turner) is also known.

### Translocations/transversions

Exchange of DNA between two different chromosomes during meiosis.
Occurs in approximately 1 in 500 newborns.
Clinical consequences depend on the event.
- Is there a net gain or loss of DNA?
- Is there disruption of the gene sequence?
- Do issues arise during gametogenesis (meiosis)?

Copy Number Variants (CNVs)

Deletions or duplications of DNA larger than 1000 base pairs.
Can be several million bases in size.
Present in all individuals.
Most are benign, but larger ones (>1 million base pairs) are often pathogenic, potentially causing learning disability, autism, epilepsy, etc.

Microsatellites

Short (2-5bp) repeat units in DNA sequence.
The number of copies varies between individuals.
Common: all individuals carry approximately 10,000 microsatellites in their genomes.
Rarely disease-causing.

Single Nucleotide Polymorphisms (SNPs)

A single base-pair change in the DNA sequence.
All individuals carry around 3.5 million SNPs.
The majority are benign or have a very small effect on disease, but in rare cases, they can be strongly disease-causing.

Insertions/Deletions

Small sections of DNA (one or a small number of base pairs) that are present in some individuals but not others.
Common: all individuals carry approximately 20,000 in their genomes.
Rarely disease-causing.
Can be damaging if they occur in exons.

Pathogenic Mutations

Alter gene function deleteriously.
Can:
- Knock-out or increase copy number of a gene (CNV)
- Rearrange multiple genes (i.e., transversion/translocation)
- Change the amino acid sequence (non-synonymous mutation)
- Lead to premature stop of translation (non-sense mutation)
- Alter splicing (splice-site mutation)

Large-Scale Pathogenic Mutations

Result in gross changes in gene expression.
Protein levels from multiple different genes are altered.
E.g., trisomy 21 and its impact on gene expression.

Small-Scale Pathogenic Mutations

Result in:
- Changing of amino acid sequence
- Skipping or introduction of an exon (aberrant splicing)
- Premature stop to translation
- E.g., CFTR delta-508 (deletion of an amino acid - phenylalanine), resulting in the protein being unable to leave the ER for further processing.
- The genetic code is critical in the interpretation of small-scale coding variation.
  - Silent/synonymous mutations have the same amino acid.
  - Missense/nonsynonymous mutations have a different amino acid.
  - Nonsense/stop mutations introduce a stop codon.
  - Frameshift mutations are caused by insertions or deletions.

Genetic Variation In Malignant Cells

Cancer is characterized by "genomic instability."
Genomes change and cause cancer, and cancer causes changes in the genome.
Genetic instability leads to rapid “evolution” of cancer cells.
Critical "driver" mutations allow:
- Genomic instability to persist
- Safety mechanisms to be bypassed
- Rapid growth and division of cells
- Metastasis
Genomic instability leads to:
- Large-scale deletions and amplifications
- Chromosomal rearrangements
- Epigenetic changes
Genetic instability allows for rapid “evolution” of cancer.

Cancer is not a single disease

Different cancers arise from different tissues.
Different "clones" of cells exist within one cancer.
Some clones may be sensitive to one pharmacological agent, but not to another.
Genetic characterization of cancers is a growing field.
- Specific genes (BCR-Abl, HER2 etc)
- Tumor profiling

Large-Scale Genetic Variation

Aneuploidy refers to the presence of an extra copy or missing chromosome.
- Trisomy 21 (Down syndrome) is an example, with an incidence of approximately 1 in 1000 newborns.
- Other viable trisomies include Trisomy 13 (Patau Syndrome), Trisomy 18 (Edwards Syndrome), and XXY (Klinefelters).
- Viable monosomy (X - Turner) also exists.
Translocations/Transversions involve the exchange of DNA between two different chromosomes during meiosis.
- Incidence: approximately 1 in 500 newborns.
- Clinical relevance depends on the specific event and whether there is a net gain or loss of DNA, disruption of gene sequence, or issues in gametogenesis.
Copy number variants (CNVs) are deletions or duplications of DNA segments greater than 1000 base pairs in size.
- Incidence: All individuals carry multiple CNVs in their genome.
- Clinical relevance: Most are benign, but larger ones (>1 million base-pairs) are often pathogenic, leading to conditions like learning disability, autism, and epilepsy.

Small-Scale Genetic Variation

Microsatellites are short (2-5bp) repeat units in DNA sequences.
- The number of copies varies between individuals.
- Incidence: Common; all individuals carry approximately 10,000 microsatellites in their genome.
- Clinical relevance: Rarely disease-causing; the vast majority are benign.
Single Nucleotide Polymorphisms (SNPs) are single base-pair changes in DNA.
- Incidence: Each individual carries around 3.5 million SNPs.
- Clinical relevance: Similar to microsatellites, the vast majority are benign or have small effects on disease, but in rare cases, they can be strongly disease-causing.
Insertions/Deletions are small sections of DNA (one or a limited number of base-pairs) present in some individuals but not others.
- Incidence: Common; all individuals carry approximately 20,000 in their genome.
- Clinical relevance: Rarely disease-causing; the vast majority are benign, but can be damaging if they occur within exons.

Pathogenic Mutations

The majority of mutations occur outside of genes (98% of the genome is non-genic) and do not cause disease.
Pathogenic mutations alter gene function in a deleterious way. They can:
- Knock-out or increase gene copy number (CNV).
- Rearrange multiple genes (transversions/translocations).
- Change the amino acid sequence (non-synonymous mutation).
- Lead to premature translation termination (nonsense mutation).
- Alter splicing (splice-site mutation).

Large-Scale Pathogenic Mutations

Large-scale pathogenic variations (ploidy, translocations, CNVs) result in gross changes in gene expression.
- This alters protein levels from multiple different genes.
- For example, trisomy 21 has a significant impact on gene expression.

Small-Scale Pathogenic Mutations

Small-scale pathogenic variations result in:
- Changes in amino acid sequence.
- Skipping or introduction of an exon (aberrant splicing).
- Premature translation termination.
- Example: CFTR delta-508 (deletion of phenylalanine) prevents protein processing.

Genetic Variation in Malignant Cells

Cancer is characterized by "genomic instability." Genetic changes lead to cancer and vice versa.
Genomic instability allows rapid "evolution" of cancer cells.
Critical "driver" mutations enable:
- Persistence of genomic instability.
- Bypassing safety mechanisms.
- Rapid growth and division of cells.
- Metastasis.
Genomic instability in cancer cells leads to:
- Large-scale deletions and amplifications.
- Chromosomal rearrangements.
- Epigenetic changes.
- This accelerated "evolution" contributes to cancer development.

Cancer as a Complex Disease

Different cancers arise from different tissues.
Multiple "clones" of cells can exist within a single cancer.
Different clones may respond differently to pharmacological agents.
Genetic characterization of cancers is an emerging field.
- Specific genes implicated (BCR-Abl, HER2, etc.).
- Tumor profiling.

Large Scale Variation

Aneuploidy is when an individual chromosome is present in an extra copy or missing. This is a relatively rare occurrence, affecting 1 in 1000 newborns.
Examples of Aneuploidy include trisomy 21 (Down Syndrome), trisomy 13 (Patau Syndrome), trisomy 18 (Edwards Syndrome), trisomy XXY (Kleinefelters) and monosomy X (Turner Syndrome).
Clinical Relevance of Aneuploidy: Usually results in large-scale changes in gene expression with associated clinical consequences such as learning disability and developmental delay.
Translocations/Transversions: Exchange of DNA between two different chromosomes during meiosis. They affect approximately 1 in 500 newborns.
Clinical Relevance of Translocations/Transversions: Impacts depend on the specific event. Factors considered are whether there is net gain or loss of DNA, if there is disruption of gene sequence, and if meiosis is affected.
Copy Number Variants (CNVs): Deletions or duplications of sections of DNA larger than 1000 base pairs, and can be several million bases in size.
Clinical Relevance of CNVs: Most CNVs are benign, but larger ones are more likely to be pathogenic and lead to conditions like learning disability, autism, and epilepsy.
Incidence of CNVs: Everyone carries multiple CNVs in their genome.

Small Scale Variation

Microsatellites: Short repeated units of DNA (2-5 base pairs) that vary from individual to individual. They are present in approximately 10,000 copies in the human genome.
Clinical Relevance of Microsatellites: Rarely disease-causing, vast majority are benign.
Single Nucleotide Polymorphisms (SNPs): A single base-pair difference in the DNA sequence.
Clinical Relevance of SNPs: Most SNPs are benign, but some can have a strong or disease-causing effect.
Incidence of SNPs: Everyone carries around 3.5 million SNPs in their genome.
Insertions/Deletions: Small sections of DNA (one or a small number of base pairs) that are present in some individuals but not others.
Clinical Relevance of Insertions/Deletions: Most are benign, and can be damaging if they occur in exons (sections of DNA that code for proteins).

Pathogenic Mutations

Pathogenic mutations alter gene function deleteriously.
Pathogenic mutations can:
Knock-out or increase copy number of a gene (CNV)
Rearrange multiple genes (transversion/translocation)
Change the amino acid sequence (non-synonymous mutation)
Lead to premature stop of translation (nonsense mutation)
Alter splicing (splice-site mutation)

Large-Scale Pathogenic Mutations

Large-scale pathogenic variants (ploidy, translocations, CNVs) result in gross changes in gene expression, altering protein levels from multiple different genes.
Example: Trisomy 21 impacts gene expression

Small-Scale Pathogenic Mutations

Small-scale pathogenic variants result in:
Changing of amino-acid sequence
Skipping or introduction of an exon (aberrant splicing)
Premature stop to translation
Example: CFTR delta-508 (deletion of an amino acid – phenylalanine) results in a protein that can't leave the ER for further processing.

Genetic Code

The genetic code is critical in interpreting small-scale coding variations. It explains different types of mutations:
Silent/synonymous = same amino acid
Missense/nonsynonymous = different amino acid
Nonsense/stop = stop codon introduced
Frameshift (from insertion/deletion)

Genetic Variation in Malignant Cells

Cancer cells are characterized by 'genomic instability' - genetic changes lead to cancer and cancer causes genetic mutations.
Genetic instability allows for rapid 'evolution' of cancer cells, allowing:
Genomic instability to persist
Safety mechanisms to be bypassed
Rapid growth and division of cells
Metastasis

Genomic Instability in Cancer Cells

Genomic instability in cancer cells leads to:
Large-scale deletions and amplifications
Chromosomal rearrangements
Epigenetic changes

Cancer and Genetic Variation

Cancer is not a single disease. Different cancers arise from different tissues and within a cancer, different 'clones' of cells often exist.
Genetic characterisation of cancers is a growing field. This includes:
Specific genes (BCR-Abl, HER2 etc)
Tumour profiling

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Description

This quiz covers key concepts related to aneuploidy, including its types like trisomy and monosomy, and explores the impact of chromosomal translocations and copy number variants (CNVs). Understand the frequency, clinical consequences, and underlying mechanisms of these genetic phenomena. Test your knowledge on how these changes affect gene expression and health outcomes.