Path Book: Chapter 5 Neoplasia pg. 173-177

Question 1

What is the genetic hypothesis of cancer?

Answer 1

implies that a tumor mass results from the clonal expansion of a single progenitor cell that has incurred genetic damage (i.e., tumors are monoclonal).

Question 2

What are the main normal regulatory genes that are targets of DNA damage for cancer formation?

Answer 2

1) growth-promoting proto-oncogenes,
2) growth-inhibiting tumor suppressor genes,
3) genes that regulate programmed cell death (i.e., apoptosis), and
4) genes involved in DNA repair

Question 3

What are oncogenes?

Answer 3

Genes that induce a transformed phenotype when expressed in cells. A major discovery in cancer was the realization that most oncogenes are mutated or over expressed versions of normal cellular genes, which are called proto-oncogenes. Most known oncogenes encode transcription factors, growth regulating proteins, or proteins involved in cell survival and cell–cell and cell–matrix interactions.

They are considered dominant because mutation of a single allele can lead to cellular transformation.

Question 4

T or F. Usually both normal alleles of tumor suppressor genes must be damaged for transformation to occur.

Answer 4

T. However, recent work has clearly shown that, in some cases, loss of a single allele of a tumor suppressor gene can promote transformation.

Question 5

Tumor suppressor genes are usefully placed into two general groups:

Answer 5

“governors” and “guardians.”

Question 6

What are governors?

Answer 6

“Governors” are classic tumor suppressor genes, such as RB, where mutation of the gene leads to transformation by removing an important brake on cellular proliferation.

Question 7

What are guardians?

Answer 7

“Guardian” genes are responsible for sensing genomic damage. Some of these genes initiate and choreograph a complex “damage control response.” This response leads to the cessation of proliferation or, if the damage is too great to be repaired, the induction of apoptosis.

Question 8

What is TP53?

Answer 8

“guardian of the genome,” is a prototypic tumor suppressor gene of this type. Other guard- ian genes are directly involved in recognizing and repairing specific kinds of DNA damage; these are the genes that are mutated in the autosomal recessive syndromes of DNA repair.

Question 9

What is a mutator phenotype?

Answer 9

Mutation of TP53 or other sensors of genomic damage does not directly transform cells, as loss of guardian function has no direct effect on cellular proliferation or apoptosis. Instead, loss of the guardian genes permits and accelerates the acquisition of mutations in oncogenes and tumor suppressor genes that can lead to the development of cancer. This increase in mutation rate is often referred to as a mutator phenotype.

Question 10

The genetic changes that characterize cancer-associated mutations may be subtle (e.g., point mutations or inser- tions and deletions) or large enough to produce karyotypic changes.

Answer 10

The genetic changes that characterize cancer-associated mutations may be subtle (e.g., point mutations or inser- tions and deletions) or large enough to produce karyotypic changes.

Question 11

What do point mutations typically manifest as?

Answer 11

Point mutations can either activate or inactivate the resulting protein products. For example, point mutations in proto-oncogenes, such as RAS or EGFR, frequently result in overactivity of the protein, usually by altering an internal regulatory amino acid and producing a constitu- tively active protein. However, point mutations in tumor suppressors, such as those affecting RB or TP53 genes, reduce or disable the function of the encoded protein.

Question 12

The common types of nonrandom structural abnormalities in tumor cells are:

Answer 12

(1) balanced translocations,
(2) deletions, and
(3) cytogenetic manifestations of gene amplification.

Question 13

Balanced translocations are highly associated with certain malignancies, particularly specific kinds of ___ and ___ neoplasms.

Answer 13

hematopoietic and mesenchymal neoplasms.

Question 14

Translocations can activate proto-oncogenes in two ways:

Answer 14

1) Some translocations result in overexpression of proto- oncogenes by removing them from their normal regulatory elements and placing them under control of an inappropriate, highly active promoter.
2) Other oncogenic translocations create fusion genes encoding novel chimeric proteins.

Question 15

What are two examples of how translocations result in overexertion of porto-oncogenes by removing them from their normal regulatory elements and placing them under control of an inappropriate promoter?

Answer 15

two kinds of B cell lymphoma

1) In more than 90% of cases of Burkitt lymphoma the cells have a translocation, usually between chromosomes 8 and 14, which leads to overexpression of the MYC gene on chromosome 8 by juxtaposition with immunoglobulin heavy chain gene regulatory elements on chromosome 14.
2) In follicular B cell lymphomas, a reciprocal translocation between chromosomes 14 and 18 leads to overexpression of the antiapoptotic gene, BCL2, on chromosome 18, also driven by immunoglobulin gene elements.

Question 16

What is an example of translocation creating fusion genes encoding novel chimeric proteins?

Answer 16

Philadelphia (Ph) chromosome in chronic myelogenous leukemia, consisting of a reciprocal and balanced translocation between chromosomes 22 and 9.

The fusion protein is constitutively expressed with BCR-ABL with potent tyrosine kinase activity.

As a consequence, the derivative chromosome 22 (the Philadelphia chromosome) appears abbreviated. This cytogenetic change, seen in more than 90% of cases of chronic myelogenous leukemia, is a reliable marker of this disease, and the few Ph chromosome–negative cases show molecular evidence of the BCR-ABL rearrangement, the crucial consequence of Ph translocation.

Question 17

_____ are most commonly the targets of gene rearrangements, which may take the form of translocations, inversions, or interstitial deletions. Why?

Answer 17

Lymphoid cells, because these cells purposefully make DNA breaks during the processes of antibody or T cell receptor gene recombination.

Question 18

What is the second most prevalent karyotypic abnormality in tumor cells?

Answer 18

Chromosomal deletions

Question 19

Compared with translocations, deletions large enough to be observed karyotypically are more common in nonhematopoietic solid tumors. At a molecular level, however, deletions are commonly found in hematopoietic tumors as well.

Answer 19

Compared with translocations, deletions large enough to be observed karyotypically are more common in nonhematopoietic solid tumors. At a molecular level, however, deletions are commonly found in hematopoietic tumors as well.

Question 20

T or F. Tumor suppressors generally require inactivation of both alleles in order for them to contribute to carcinogenesis.

Answer 20

T. Deletion commonly targets tumor suppressors

NOTE: A common mechanism for this is an inactivating point mutation in one allele, followed by deletion of the other, nonmutated allele.

Question 21

Proto-oncogenes may be converted to oncogenes by amplification, with consequent overexpression, of otherwise normal proteins. Such amplification may produce several hundred copies of the proto-oncogene in the tumor cell. In some cases the amplified genes produce chromosomal changes that can be identified microscopically. Two mutually exclusive patterns are seen:

Answer 21

multiple small, extrachromosomal structures called “double minutes” and homogeneously staining regions.

Question 22

What do the homogeneously stained regions associated with gene amplification result from?

Answer 22

from the insertion of the amplified genes into new chromosomal locations, which may be distant from the normal location of the involved genes; because regions containing amplified genes lack a normal banding pattern, they appear homogeneous in a G-banded karyotype.

Question 23

What is Aneuploidy?

Answer 23

A number of chromosomes that is not a multiple of the haploid state; for humans that is a chromosome number that is not a multiple of 23.

Question 24

Aneuploidy is especially common in what kinds of cancer?

Answer 24

Aneuploidy is remarkably

common in cancers, particularly CARCINOMAS.

Question 25

What does aneuploidy commonly arise from?

Answer 25

errors of the mitotic checkpoint, the major cell cycle control mechanism that acts to prevent chromosome mis-segregation.

The mitotic checkpoint prevents aneuploidy by inhibiting the irreversible transition to anaphase until all of the replicated chromosomes have made productive attachments to spindle microtubules.

Complete absence of the mitotic checkpoint leads to rapid cell-autonomous lethality as a consequence of massive chromosome mis-segregation.

Question 26

What are microRNAs?

Answer 26

non- coding, single-stranded RNAs, approximately 22 nucleotides in length, that function as negative regulators of genes.

Question 27

How do microRNAs work?

Answer 27

They inhibit gene expression posttranscriptionally by repressing translation or, in some cases, by messenger RNA (mRNA) cleavage.

Question 28

How can miRNAs lead to cancer?

Answer 28

MiRNAs can participate in neoplastic transformation either by increasing the expression of oncogenes or reducing the expression of tumor suppressor genes. If an miRNA inhibits the translation of an oncogene, a reduction in the quantity or function of that miRNA will lead to overproduction of the oncogene product. Conversely, if the target of a miRNA is a tumor suppressor gene, then overactivity of the miRNA can reduce the tumor suppressor protein.

Question 29

What is Epigenetics?

Answer 29

reversible, heritable changes in gene expression that occur WITHOUT mutation. Such changes involve posttranslational modifications of histones and DNA methylation, both of which affect gene expression.

In normal, differentiated cells, the major portion of the genome is not expressed. These regions of the genome are silenced by DNA methylation and histone modifications.

Question 30

How are ‘epigenetics’ different in cancer cells?

Answer 30

Cancer cells are characterized by a global DNA hypomethylation and selective promoter-localized hypermethylation. Tumor suppressor genes are sometimes silenced by hypermethylation of promoter sequences, rather than by mutation.

Genome-wide hypomethylation has been shown to cause chromosomal instability