Chromosomal aberrations in cancer

Question 1

Philadelphia chromosome is the result of the :…

Answer 1

Translocation between chromosome 9 and 22

Question 2

Which of the following statements on sarcomas are true: a) Translocation-associated sarcomas have the highest mutation burden compared to other sarcomas
b) can be classified in fusion driven sarcomas, sarcomas of intermediate complexity
and sarcomas with high-unbalanced karyotypes.
c) often in sarcomas, the DNA binding domain of one transcription factor is duplicated
and the transactivation domain of another transcription factor is deleted leading to
a chimeric protein.
d) Osteosarcoma accounts for 75% of all bone tumors

Answer 2

b) can be classified in fusion driven sarcomas, sarcomas of intermediate complexity

Question 3

Mitotic spindle assembly checkpoint (SAC) is triggered by :
a) unattached kinetochores
b)DNA damage
c)Formation of the mitotic checkpoint complex
d)Ionizing radiation

Answer 3

A) unattached kinetochores

Question 4

Why is DNA compacted into a 3D structure

Answer 4

DNA is compacted to fit into the nucleus and create regions accessible to enzymes incolved in processing, repair, and splicing of DNA, thus regulating gene expression and function

Question 5

What is chromatin composed of

Answer 5

DNA and histone proteins, where the DNA wraps around nucleosomes formed by 8 histone molecules

Question 6

Define chromatosome

Answer 6

composed of a nucleosome (8 histones) along with chromatin

Question 7

What happens to chromsomes in mitosis vs interphase

Answer 7

Chromsomes are visible in mitosis as they align on the mitotic spindle, whereas in interphase, they are less distinguishable due to being clustered together

Question 8

Describe the compartments theory of chromosomal organization
This theory suggests that chromosomes have their own distinct compartments within … A laser targeted on the nucleus would only affect certain chromosomes if this theory were true

Answer 8

This theory suggests that chromosomes have their own distinct compartments within the nucleus. A laser targeted on the nucleus would only affect certain chromosomes if this theory were true

Question 9

Explain the tangled theory of chromsomal organization

Answer 9

According to thus theory, chromosomes are tangled together within the nucleus. If accurate, a. laser on the nucleus would affect all chromosomes

Question 10

What defines a chromosomal territory (CT)
CTs are areas within … that individual chromsomes occupy, having distinct … for short and long arms along with the centromere

Answer 10

CTs are areas within the nucleus that individual chromsomes occupy, habing distinct domains for short and long arms along with the centromere

Question 11

How are genes organized within the CT and inter-chromatin (IC) regions?

Answer 11

In the IC region, chromatin loops exists, hosting actively transcribed genes. Active genes are positioned on the surgace of these loops

Question 12

Why is chromatin packaging crucial for transferring genetic material to daughter cells
Chromatin must be properly packaged for…during cell division to ensure the accurate … to daughter cells

Answer 12

Chromatin must be properly packaged for transport during cell division to ensure the accurate transfer of genetic msterial to daughter cells

Question 13

What are the mahor cell cycle checkpoints and their regulatory proteins

Answer 13

Regulatory Proteins: Cyclin D, Cyclin E, Cyclin-dependent kinases (CDKs), Retinoblastoma protein (Rb).
Function: Assesses cell size, nutrient availability, DNA damage, and extracellular signals before committing to DNA replication in the S phase.
G2 Checkpoint:

Regulatory Proteins: Cyclin A, Cyclin B, CDK1 (also known as Cdc2), Wee1, Cdc25.
Function: Ensures DNA replication is complete and undamaged before entering mitosis (M phase). Checks for DNA damage and replication errors.
Spindle Assembly Checkpoint (SAC):

Regulatory Proteins: MAD1, MAD2, MAD3 (also known as BUB1, BUBR1, BUB3), APC/C (Anaphase-Promoting Complex/Cyclosome).
Function: Monitors proper attachment of spindle fibers to kinetochores, ensuring chromosomes are aligned and ready for separation during anaphase.
DNA Damage Checkpoint:

Regulatory Proteins: ATM (Ataxia Telangiectasia Mutated), ATR (ATM and Rad3-related), CHK1, CHK2, p53.
Function: Detects DNA damage and halts the cell cycle to allow for repair. If the damage is irreparable, it can induce apoptosis (cell death) or senescence.

Question 14

What contributes to the condensation of chromosomes during cell division

Answer 14

PRoteases such as Condensin I, and II, Cohesin, Ki-67, and BAF are involved in condensing and attaching chromsomes to the mitotix spindle

Question 15

What triggers the spindle assembly checkpoint during cell division

Answer 15

This checkpoint is activated when a chromosome is not properly attached to its corresponding kinetochore on the microtubule

Question 16

How does aberrant mitosis contribute to tumor formation?

Answer 16

Aberrant mitosis, causing unequal chromosome distribution, enables malignant cells to exhibit unlimited growth potential and pass these defects to progeny, leading to the development of tumors.

Question 17

What significant predictions did Boveri make in the 1900s regarding cancer?

Answer 17

Boveri made predictions about cell cycle checkpoints, oncogenes, and tumor suppressor genes, all of which were later found to be true.

Question 18

Describe the Philadelphia chromosome and its association with CML.

Answer 18

reciprocal translocation between chromosomes 9 and 22. This genetic alteration, longer chromosome 9 and shorter chromosome 22, is linked to CML.

Question 19

How are different fusion genes formed due to translocation breakpoints?
Depending on the breakpoints, fusion genes may arise. The majority occur in exons … of the ABL gene or exon … on the BCR gene (M-BCR). These breakpoints determine the size of the resulting fusion protein.

Answer 19

Depending on the breakpoints, fusion genes may arise. The majority occur in exon 1 and 2 of the ABL gene or exon 13 and 14 on the BCR gene (M-BCR). These breakpoints determine the size of the resulting fusion protein.

Question 20

What is the significance of the SH1 domain in the ABL gene?

Answer 20

The SH1 domain, also known as the kinase domain, is the most crucial domain within the ABL gene

Question 21

How does the fusion protein formed from chromosomes 9 and 22 influence Abl kinase activity?

Answer 21

The fusion protein retains the structure of BCR at the N-terminus and Abl kinase at the C-terminus. Consequently, the kinase becomes constitutively active, leading to de-regulation and spontaneous activation of oncogenic pathways, causing leukemia (CML).

Question 22

Describe the different phases of CML presentation.

Answer 22

CML progresses through three stages:
Chronic Phase: Usually asymptomatic, lasting around 5-6 years with a small number of blasts and differentiated cells.
Accelerated Phase: Characterized by the accumulation of more genetic abnormalities, around 15-30% of white blood cells have a blast phenotype, leading to symptoms such as fatigue, weight loss, and an enlarged spleen.
Blast Crisis: Marked by a significant increase in blast cells in the bone marrow and blood, often with extremely elevated white blood cell counts compared to a healthy individua

Question 23

What were the initial therapies used for CML and their approximate survival rates?

Answer 23

Initially, therapies like INF-alpha and low-dose AraC (cytosine arabinoside) led to a 60-70% survival rate. Bone marrow transplants, though an alternative, were risky and required an exact HLA match.

Question 24

How does Imatinib function in CML treatment?

Answer 24

Imatinib is a targeted drug that inhibits the oncogene present in tumor cells (BCR-ABL) while being absent in healthy cells. This drug has shown a 95% survival rate and reduces BCR-ABL transcripts.

Question 25

What contributes to resistance against Imatinib in some CML patients?

Answer 25

Approximately 30-70% of CML patients develop mutations in the BCR-ABL1 kinase domain, which reduces the effectiveness of Imatinib and leads to resistance.

Question 26

How have subsequent generations of drugs addressed the issue of resistance in CML treatment?

Answer 26

Second-generation drugs like nilotinib, dasatinib, and bosutinib have shown fewer instances of mutations and resistance. Third-generation drugs like ponatinib have no known mutations related to resistance.

Question 27

What could be reasons for relapse in CML patients even after successful therapy?

Answer 27

Relapse might occur due to the presence of a mutant clone before the initiation of therapy. The relapse rate tends to depend on the size of the mutant clone present at the beginning of Imatinib treatment.

Question 28

What are the two primary classes of chromosomal abnormalities found in human cancers?

Answer 28

Human cancers exhibit two main classes of chromosomal abnormalities:
1-Balanced chromosomal rearrangements forming chimeric fusion genes like BCR-ABL1.
2-Chromosomal imbalances causing genomic gain (trisomy/partial trisomy) or loss (monosomy, large-scale deletion).

Question 29

What are chimeric fusion genes, and what functions can they acquire?

Answer 29

Chimeric fusion genes result from the fusion of two separate genes, leading to new functionalities such as:
Genes acquiring a new kinase function, as seen in BCR-ABL1.
Generation of aberrant transcription factors, like PML-RARA in acute promyelocytic leukemia treated with retinoic acid.

Question 30

Can you give examples of diseases caused by specific chimeric fusion genes?

Answer 30

1-FLI1-EWSR1 fusion gene in Ewing’s Sarcoma, resulting from a translocation between chromosomes 11 and 22.
2-PML-RARA in acute promyelocytic leukemia due to a reciprocal translocation between chromosomes 15 and 17.

Question 31

What does deregulated expression of structurally normal genes involve?

Answer 31

It entails moving a gene under the control of a different promoter/enhancer, leading to aberrant expression. Examples include MYC expression in Burkitt’s Lymphoma and ERG expression in prostate cancer.

Question 32

How does the MYC gene contribute to Burkitt’s Lymphoma?

Answer 32

In Burkitt’s Lymphoma, translocation between chromosomes 8 and 14 moves MYC, a master regulator of cell growth, under the control of an active promoter, causing excessive expression and transformation.

Question 32

What distinguishes fusion-driven sarcomas in terms of their genetic alterations?

Answer 32

Fusion-driven sarcomas exhibit near-diploid karyotypes with translocations leading to gene fusions, often initiating de novo rather than as a secondary cancer.

Question 33

What is a key characteristic of gene fusions in sarcomas?

Answer 33

The majority of gene fusions encode chimeric transcription factors that dysregulate target genes, influencing the tumor’s development.

Question 34

What are the prominent themes observed in fusion-driven sarcomas?

Answer 34

Fusion-driven sarcomas display several key themes:
Fusion of DNA binding domains and transactivation domains between transcription factors, altering gene expression and RNA metabolism.
Creation of constitutively active receptor tyrosine kinases (RTKs) that trigger cell proliferation and survival pathways.
Formation of chimeric chromatin regulators.
Development of autocrine mechanisms, such as specific growth factors, feeding tumor growth.

Question 35

What characterizes the PAX3-FOXO1 fusion in alveolar rhabdomyosarcoma (ARMS)?

Answer 35

The fusion of PAX3 and FOXO1A results in the loss of DNA-binding domain of FOXO1A, incorporating it as a transactivating domain of PAX3. This chimeric protein induces over-proliferation of myoblasts within differentiating muscle cells, leading to tumor formation.

Question 36

How does the EWS-Fli1 fusion function in Ewing’s sarcoma?

Answer 36

The chimeric protein acts as a de novo pioneer factor, binding to chromatin regions that were typically inactive and transforming them into active ones. Moreover, it binds to GGAA microsatellites, and it retains the ability to regulate the promoters and enhancers that are the targets of the Fli1 TF, affecting transcription.

Question 37

What characterizes Group 2 and Group 3 sarcomas based on genomic complexity?

Group 2
Types: Includes … and dedifferentiated liposarcomas.
Genetic Cause: Driven by chromosome … amplifications, particularly affecting genes … and …
Impact: These changes mess with normal cell instructions, promoting cancer growth.

Group 3 Sarcomas
Types: Encompasses sarcomas like leiomyosarcoma and osteosarcoma.
Genetic Characteristics: They have messy genetic patterns involving genes like …and …
Effect: These messy changes affect how cells grow and divide, making treatment more complex.

Answer 37

Types: Includes well-differentiated and dedifferentiated liposarcomas.
Genetic Cause: Driven by chromosome 12 amplifications, particularly affecting genes CDK4 and MDM2.
Impact: These changes mess with normal cell instructions, promoting cancer growth.
Group 3 Sarcomas
Types: Encompasses sarcomas like leiomyosarcoma and osteosarcoma.
Genetic Characteristics: They have messy genetic patterns involving genes like TP53 and RB1.
Effect: These messy changes affect how cells grow and divide, making treatment more complex.

Question 38

Why does the EWS-Fli1 fusion protein show varying effects in different cell types?

Answer 38

While the fusion protein is present in all tumor cells, its expression alone is insufficient to fully transform cells. Transformation in other cell types suggests that additional cellular factors in EWS contribute to complete cellular transformation.

Question 39

What are the distinctive chromosomal abnormalities observed in osteosarcoma (OS)?

Answer 39

OS, the most frequent primary bone sarcoma, displays a pattern of chromosomal abnormalities known as kataegis, involving an extremely high number of structural variants in specific genome points. These variants don’t converge on a single gene, occur in non-recurrent patterns, and often happen due to active transcriptional genes colliding with replication forks, leading to clusters of structural variants.
To initiate this process, inactivation of TP53, RB1, and ATRX is necessary.

Question 40

What are the predominant growth-factor pathways affected in osteosarcoma (OS) and related sarcomas?

Answer 40

The most common growth-factor pathways affected in OS are:
Insulin-like growth factor 1 (IGF1)-receptor pathway in rhabdomyosarcomas and leiomyosarcomas.
PDGFR pathway in desmoplastic round-cell tumors and OS.
c-KIT receptor pathway in Ewing’s sarcomas and GIST.
c-MET receptor pathway in synovial sarcomas and rhabdomyosarcomas.

Question 41

What factors contribute to spatial proximity as a trigger for genomic rearrangements?

Answer 41

Spatial proximity is influenced by the close positioning of certain chromosomes or gene loci within the nucleus, increasing the likelihood of translocations, as seen in CML (Chronic Myeloid Leukemia) arising from the close proximity of BCR and ABL genes.

Question 42

How do cellular stressors such as radiation or replication stress contribute to DNA damage and rearrangements?

Answer 42

Ionizing radiation or replication stress can induce DNA damage, leading to stalled or collapsed replication forks, which promotes rearrangements. Transcribed regions are more prone to damage.

Question 43

What role do inappropriate DNA repair mechanisms play in genomic rearrangements?

Answer 43

Certain DNA sequences adopt structural configurations prone to breaks, and inadequate repair mechanisms can exacerbate rearrangements.

Question 44

How do DNA sequences and chromatin features impact the probability of genomic rearrangements?

Answer 44

Epigenetic modifications increase the likelihood of rearrangements by influencing the binding of complexes like RAG to specific chromatin regions, as observed in the interaction between RAG complex and H3K4me3.

Question 45

What consequences arise due to chromosomal instability (CIN) within cancer cell populations?

Answer 45

CIN generates karyotypic diversity, contributing to intratumor heterogeneity, allowing tumors to adapt to various conditions such as therapy or radiation.

Question 46

How do tumors adapt to high levels of CIN for propagation?

Answer 46

Tumors develop CIN-tolerance mechanisms and often have defects in proteins regulating cell cycle checkpoints, such as p53.

Question 47

Describe the composition of tumor mass in Type A

Answer 47

Tumor mass in Type A is mainly constituted by cells possessing a normal karyotype. Genetic diversity arises primarily through single nucleotide variants.

Question 47

Explain the impact of intermediate levels of CIN on tumor cells.

Answer 47

Intermediate levels prompt tumor cells to downregulate APC/C function, induce autophagy, and transition to near-triploid karyotypes, enhancing cancer cell fitness while balancing tumor suppressor genes and oncogenes.

Question 48

What characterizes Type B tumors concerning rare karyotypes?
In Type B tumors, some cells express rare karyotypes but are typically constrained by … constituting a smaller part of the tumor due to checkpoint restrictions.

Answer 48

In Type B tumors, some cells express rare karyotypes but are typically constrained by checkpoints, constituting a smaller part of the tumor due to checkpoint restrictions.

Question 49

How does Type D differ from Type C regarding their tumor growth and chromosomal abnormalities?

Answer 49

Type D tumors exhibit extreme aneuploidy and massive somatic copy number aberrations, growing slowly due to partial control of chromosomal instability. Type C tumors, like Type A, contain cells with minimal karyotypic changes and are rare within the tumor mass.

Question 50

What distinguishes Type E tumors from others in terms of chromosomal abnormalities and instability?

Answer 50

Type E tumors exhibit high chromosomal abnormalities due to instability and lack of proper controls, resulting in a tumor mass with extensive chromosomal changes, such as observed in osteosarcoma.

Question 51

Why is diagnosing sarcomas based solely on morphological categories challenging?

Answer 51

can look alike under a microscope, but their genetic differences might cause confusion in diagnosis.

Question 52

What role does molecular profiling play in detecting chromosomal translocations in sarcomas?

Answer 52

Helps identify new entities within tumors with identical morphological features

Question 53

What distinguishes the four molecular subtypes of medulloblastoma?

Answer 53

Medulloblastoma has four molecular subtypes (SHH, WNT, Group 3, Group 4) with different cell origins, genetic compositions, and prognoses.

Question 54

How does the copy number status of Chr14q and Gli2 amplification level predict outcomes in medulloblastoma?

Answer 54

Patients with amplification of Gli2 are resistant to targeted therapies, such as SMO antagonists, affecting treatment response in medulloblastoma.

Question 55

Whats kataegis and which cancer is it involved with

Answer 55

localized hypermutation phenomenon characterized by clustered mutations in specific regions of the genome…. breast cancer