Retinoblastoma and RB1 Gene Quiz

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Questions and Answers

What is the primary cause of secondary osteosarcoma after familial retinoblastoma?

Exposure to environmental carcinogens

Mutation of the RB1 gene

Inheritance of a cancer suppressor gene

Loss of the allele from the non-diseased parent (correct)

Which feature is associated with the RB1 gene in tumors?

Activation of oncogenes

Complete functionality in tumors

Deletions leading to loss of function (correct)

Increased expression of truncated transcripts

What observation led to the conclusion that cancer suppressor factors are present in normal cells?

Normal cells transforming into tumor cells

Mutations leading to tumor formation

Fusion of normal cells with tumor cells resulted in loss of transformed properties (correct)

Identification of specific chromosome sequences

What did the correlation between chromosomes and cancer suppression indicate?

Certain chromosomes contain cancer suppressor genes Signup and view all the answers

What are the common types of mutations found in the RB1 gene related to tumorigenesis?

Deletions and point mutations Signup and view all the answers

What property does the mutant FGFR3 confer to NIH 3T3 cells?

Enhanced transformed properties Signup and view all the answers

Which type of alteration is NOT commonly observed in tumor genome analysis?

Polymorphisms Signup and view all the answers

What role does genetic polymorphism play in disease association?

It is a sequence variation that might not relate to any disease Signup and view all the answers

What genetic event is frequently involved in retinoblastoma progression?

Germline and somatic mutations Signup and view all the answers

Which statement accurately describes the retinoblastoma tumor suppressor gene identification?

It was discovered using positional cloning linked to chromosomal deletions. Signup and view all the answers

What technique is employed to analyze the expression and mutation of FGF receptor genes?

Single-strand conformation polymorphism (SSCP) Signup and view all the answers

What is the consequence of FGFR3 mutations in superficial bladder tumors?

FGFR3 exhibits activating mutations and becomes constitutively active. Signup and view all the answers

What is the primary focus of the research on FGFR genes?

Investigating expression, mutation, and functional status of FGF receptor genes. Signup and view all the answers

How does the research challenge previous assumptions about kinases in cancer?

It highlights the complexity of tumor suppressor functions within specific gene families. Signup and view all the answers

What type of alterations are primarily identified in the FGFR3 gene in transitional cell carcinomas (TCC)?

Somatic mutations that contribute to oncogenesis. Signup and view all the answers

What is the main genetic alteration associated with Chronic Myeloid Leukemia (CML)?

t(9;22) translocation Signup and view all the answers

Which method is used to detect BCR-ABL fusion transcripts in CML cells?

RT-PCR Signup and view all the answers

What role does the ABL tyrosine kinase play in CML?

It is an oncogene activated by gene fusion. Signup and view all the answers

How does tumor size relate to malignancy?

Malignancy can be independent of tumor size. Signup and view all the answers

What surprising finding was associated with the FGFR2 gene in bladder cancer?

It acts as a tumor suppressor despite being a kinase. Signup and view all the answers

What does the bicolour FISH assay typically detect?

Translocations involving chromosomes 9 and 22. Signup and view all the answers

Which of the following chromosomal changes is associated with bladder carcinomas?

Loss on chromosome 10. Signup and view all the answers

In the context of bladder cancer, what hypothesis was proposed regarding the FGF receptor gene family?

Multiple FGF receptors may function as tumor suppressors. Signup and view all the answers

What is the primary role of the RB1 gene?

To act as a tumour suppressor Signup and view all the answers

What is the result of hypermethylation of the H19 gene in tumors?

Loss of the functional allele Signup and view all the answers

Which cancers were observed to have a preferential loss of the maternal allele of certain genes?

Paediatric tumours Signup and view all the answers

What occurs to the VHL gene in 20% of clear-cell renal carcinomas?

Hypermethylation leading to transcriptional silencing Signup and view all the answers

Which of the following is a characteristic of tumour suppressor genes categorized as 'caretakers'?

Maintaining genome integrity Signup and view all the answers

What is the impact of DNA methylation on tumour suppressor genes?

It generally leads to gene transcriptional silencing Signup and view all the answers

Which gene's hypermethylation is linked to specific loss in Wilms tumours?

H19 Signup and view all the answers

What mechanism describes the loss of functionality of tumour suppressor genes due to epigenetic alterations?

Transcriptional gene silencing by DNA methylation Signup and view all the answers

What is the consequence of the point mutation in the c-H-ras proto-oncogene?

Always active due to constitutively present GTP-binding activity Signup and view all the answers

What type of genetic alteration is frequently seen in Burkitt's Lymphomas affecting c-MYC?

Balanced translocation Signup and view all the answers

How is the overexpression of N-MYC associated with neuroblastomas confirmed?

Through Southern blot analysis with a specific probe Signup and view all the answers

What is a characteristic of N-MYC amplification in neuroblastoma cells observed through FISH?

Multifocal green signals indicating multiple copies Signup and view all the answers

What effect does N-MYC transfection have on SH-EP neuroblastoma cells?

Morphological transformation and enhanced malignancy Signup and view all the answers

What is the relationship between N-MYC gene activation and tumor prognosis in neuroblastomas?

Amplification is associated with poor prognosis Signup and view all the answers

What type of genetic rearrangement is identified in Chronic Myelogenous Leukaemia (CML)?

Chromosomal translocation Signup and view all the answers

Which chromosome is mainly associated with the Philadelphia chromosome in CML?

Chromosome 22 Signup and view all the answers

What does the c-MYC-IgH translocation lead to in Burkitt's Lymphomas?

Promoter-driven overexpression of c-MYC Signup and view all the answers

What is the function of the RAS protein when it is bound to GTP?

It functions in a constitutively active state Signup and view all the answers

Study Notes

Cancer Biology - Molecular Bases of Oncogenesis

Cancer is a disease arising from malignant, abnormal proliferations, stemming from defective regulation in cell survival, division, and differentiation.
Carcinogenesis, the process of cancer development, involves genetic alterations, which are implicated in all cases.
Somatic alterations are sporadic cancers, present only in the diseased tissue.
Germline alterations are hereditary cancers, affecting 5% of cancers and linked to genetic predisposition, affecting all cells of the organism.
Epigenetic alterations modify gene expression profiles throughout the process and affect all cancers

Genetic Bases of Oncogenesis

Genetic material transfers induce cellular transformation.
Viruses are a cause of cancer; viruses have infectious etiology.
Cancer cells' genomic DNA can be transferred without an infectious agent, affecting the information of the genome of viruses and tumor cells.
Genes implicated in these processes are viral oncogenes (v-onc) in viruses and cellular oncogenes (c-onc) in tumor cells.
Oncogenes come from proto-oncogenes, which are essential genes whose function is altered.
Hereditary cancers are associated with transmissible predispositions.
All cancers involve genetic alterations.

Genes Implicated in Oncogenesis

Oncogenes (or proto-oncogenes) are positive regulators of cell survival and proliferation.
Gain of function mutations in an oncogene are sufficient to trigger a dominant alteration in an allele (often just one).
Oncogenic addiction refers to how tumors often remain dependent on the original initiating oncogene even with further alterations.
Tumor suppressor genes are negative regulators of cell survival and proliferation.
Loss-of-function mutations in tumor suppressor genes commonly need mutations in both alleles for the recessive effect to manifest.
DNA repair systems genes act as "caretakers" to repair DNA lesions.
These repair genes also act in a recessive manner, requiring mutations in both alleles.
Microenvironment genes regulate processes such as angiogenesis and act on the stroma (supporting tissue of a gland or organ).

Cancer as a Multi-Step Process

Cancers are multigenic diseases, not monogenic diseases such as cystic fibrosis or muscular dystrophy.
Most cancers exhibit alterations of multiple genes, typically in long periods spanning 5 to 20 years.
Cancer development follows a non-random sequence of genetic changes to promote cancer formation.
Genetic diversity leads to heterogeneity in cancers; different subtypes and patients react and progress differently to cancers.
This heterogeneity exists within the same tumor due to differences in sub-clones, and these variations impact prognosis and treatment.

Model of Colorectal Cancer Progression

A multi-step model illustrates the progressive development of colorectal cancer from normal tissue to invasive cancer with metastasis.
Key processes involved include DNA hypomethylation, mutations (e.g., K-ras, APC, Tp53), and the overexpression or inactivation of specific genes (e.g., C-myc, CCND1).
These stages indicate a progressive accumulation of genetic alterations leading to the development of cancer.

Discovery of Cellular Oncogenes

Functional cloning can identify specific DNA fragments from cancer cells contributing to cellular transformation.
This involves transferring DNA into non-cancerous cells, observing transformation, and then identifying the responsible DNA fragment.
The c-Ha-ras1 cellular oncogene was discovered using these methods.

Confirmation of the c-Ha-ras1 Properties

Demonstrates that c-Ha-ras1 is a dominant oncogene capable of transforming cells by transfection into mouse embryonic fibroblasts.
The expression of the gene is altered without modifying the coding sequence, but the regulation of the gene is altered.
Mutation-activated Ha-ras induces significant changes in cell morphology (cell shape and appearance).
Cells with mutated Ha-ras exhibit anchorage-independent growth, meaning growth outside of a support matrix, which are critical characteristics of cancer cells.
A further experiment demonstrates the ability to induce tumor formation in immunodeficient mice following transfection.

Mechanism of Activation

The activation of c-Ha-ras1 was due to a single nucleotide substitution.
This specific activation caused a glycine to valine mutation at position 12.
This single mutation leads to the constitutive activation of the tyrosine kinase.

Genomic Rearrangements in Burkitt's Lymphoma

Burkitt's lymphoma is characterized by a specific gene translocation between chromosome 8 and 14.
This translocation places the c-myc oncogene under the control of an active promoter on chromosome 14.
The c-Myc oncogene, due to the chromosomal rearrangement is overexpressed, causing uncontrolled cell proliferation.
Chromosome nomenclature (ex: 8q24) describes positions on chromosomes, with p being the short arm and q being the long arm of the chromosome.

Oncogene Discovery - N-MYC

N-MYC is a cellular oncogene discovered using both homology- and positional-cloning techniques.
N-MYC is found frequently amplified in neuroblastomas, a specific type of paediatric cancer.
N-MYC shows a direct relation to the aggressiveness of the tumor.
Increased copies of the N-MYC gene in cancer cells translate to higher protein levels.

Analysis of N-MYC Cellular Oncogene Amplification

Fluorescence in situ hybridization (FISH) is a method to visualize and analyze the number of copies of the N-MYC gene to identify amplification.
FISH uses two different probes; the centromeric probe (red) and the N-MYC-specific probe that produces a green signal.
Amplification of the N-MYC gene in cancer cells is associated with a poor prognosis.

Association of N-MYC with Tumor Aggressiveness

N-MYC amplification is a significant predictor of treatment response or survival rates for neuroblastoma.
Patients with neuroblastoma and N-MYC gene amplification have poorer survival rates.
The presence of amplified N-MYC directly correlates with worse prognostic factors in neuroblastomas.

Activation of ABL Tyrosine Kinase by Gene Fusion

Philadelphia Chromosome: A chromosomal abnormality which typically fuse the BCR gene with the ABL gene resulting in a fusion protein, BCR-ABL, frequently occurring in CML.
BCR-ABL is a fusion oncogene which constitutively activates the ABL tyrosine kinase, driving cell proliferation and thus the formation of CML.
STI571/Glivec (Imatinib Mesylate), an inhibitor of the BCR-ABL fusion protein, is now a standard and effective treatment for CML.

Histopathological and Molecular Model of Bladder Carcinomas

This study examines bladder cancer's progression, identifying patterns of molecular changes as well as tumor stages (Ta, T1, 2T2 tumors).
Key markers include deletions in chromosome 10, affecting FGFR2, leading to a tumor suppressor alteration.
The study also investigates chromosomal deletions in chromosome 4, affecting FGFR3. Researchers identified activating mutations of FGFR3 in many instances.
The studies challenged previous assumptions about kinase receptors in cancer development.

Alternative Splicing of FGFR Genes

FGFR genes produce multiple protein isoforms through alternative splicing, creating a diversity of protein functions.
The study shows how these proteins can be anchored in plasma membranes or secreted.
Different isoforms of FGFRs, such as FGFR1, 2, 3, and 4, show alterations in cancers.

Search for structural alterations of FGFR3 in TCC

FGFR3 demonstrates somatic alterations in transitional cell carcinomas (TCC) of the urinary bladder.
Researchers identified activating mutations in FGFR3 affecting the kinase domain, specifically within exons 7, 10, and 15 through various screening techniques.
These mutations commonly result in amino acid substitutions at critical functional regions of the FGFR3 protein, contributing to oncogenic activity.

FGFR3 is mutated in superficial bladder tumors

Sanger sequencing confirms that FGFR3 mutations are prevalent in 75% of superficial bladder carcinomas (representing 80% of diagnosed bladder tumors).
This supports FGFR3 as a therapeutic target.

FGFR3 exhibits activating mutations in bladder tumours

Studies using Western blot and immunoprecipitation demonstrate that mutant FGFR3 shows constitutive activation of the tyrosine kinase in comparison with normal or wild-type FGFR3.
This indicates that mutations in FGFR3 promote its constitutive activation.

Mutated FGFR3 is oncogenic...

Studies in NIH 3T3 cells, immortalized mouse fibroblasts, using FGFR3 point mutations (e.g., R249C, S249C), demonstrate the oncogenic potential of mutated FGFR3.
Mutant FGFR3 exhibits characteristics of transformed cells, including elevated proliferation rates, anchorage-independent growth, and cellular morphology changes, which confirm the oncogenic nature of the mutations.

Oncogene activation by gene fusion in CML

The Philadelphia chromosome, a translocation between chromosomes 9 and 22, is a hallmark of chronic myeloid leukemia (CML).
The translocation fuses the BCR gene (breakpoint cluster region) on chromosome 22 with the ABL gene (Abelson murine leukemia viral oncogene homolog 1) on chromosome 9.
This fusion creates a BCR-ABL oncogene that drives CML development.

Identification of losses of heterozygosity (LOH)

LOH, or loss of heterozygosity, occurs when one normal allele of a tumor suppressor gene is lost in a tumor cell.
This is a key event in the development of many cancers, including familial retinoblastoma, and sporadic osteosarcomas.
This loss typically involves the same chromosomal region in both the familial and sporadic cases, which suggests that the same gene may be implicated in both types of tumor.

Mechanisms of inactivation of tumor suppressor genes

Various methods inactivate tumor suppressor genes, including deletion, mutation, mitotic recombination, monosomy, isodisomy, and epigenetic modifications like methylation.
These methods lead to the loss of function in the tumor suppressor gene and the development of cancer
Loss of heterozygosity(LOH) is indicative of the loss of one allele of the tumor suppressor gene.

Tumor suppressor genes from the category of "caretakers"

These genes are responsible for maintaining genome integrity.
Defects in these caretaker genes contribute to alterations in genes which play a pivotal role in cell survival and proliferation, indirectly leading to oncogenesis.
Examples include DNA mismatch repair genes.

Post-transcriptional epigenetic gene silencing

MicroRNAs (miRNAs) are small, non-coding RNAs that participate in post-transcriptional regulations.
They regulate gene expression, either directly by binding to target mRNAs, and influencing proteins.
miRNA expression patterns can be altered in cancer cells, indirectly contributing to oncogenesis.
Specific miRNAs related to either tumor suppressor or oncogen expression can be upregulated or down regulated in cancer.

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Description

Test your knowledge on the relationship between familial retinoblastoma and secondary osteosarcoma. This quiz covers key concepts related to the RB1 gene, tumorigenesis, and cancer suppression mechanisms. Enhance your understanding of genetic factors in cancer development.