Devita, Hellman, and Rosenberg's Cancer

LWBK1006-01 LWW-Govindan-Review November 24, 2011 11:17

14 DeVita, Hellman, and Rosenberg’s CANCER: Principles and Practice of Oncology Review

Answer 1.27. The answer is B.

Cell-cycle inhibitors that lead to senescence include p16INK4a and p53,

among others. It follows that mice and humans with impaired p16INK4a

and p53 function develop normally other than an age-dependent increase

in cancer and increased susceptibility to cancer in response to carcino-

gen exposure. Aside from the other correct answers listed, other evi-

dence is supportive. Minimal residual disease data demonstrate frequent

oncogenic events as evidence for a need for tumor suppression. Mice are

highly susceptible to inactivation of p16INK4a and/or p53 as evidenced

by experiments demonstrating development of primary tumors at 8 weeks

of age (normal life span is approximately 100 weeks).

Answer 1.28. The answer is D.

Knockout of INK4a and ARF loci separately and in combination leads to

an increase in spontaneous tumors. Silencing of p16INK4a via hyperme-

thylation has been well described and is associated with numerous types

of cancers. Inhibition of methylation is thought to increase expression

of p16INK4a. Gene therapy as a method to replace p16INK4a activity

has been achieved in the laboratory. ARF leads to MDM2 activation and

subsequent p53 degradation. Inhibition of MDM2 activity is thought

to increase p53 levels and lead to apoptosis and senescence. p53 and

p16INK4a do not interact directly.

Answer 1.29. The answer is A.

Chromosomal rearrangements are thought to contribute to the malig-

nant phenotype of many different cancers. Such rearrangements are the

result of breakage-fusion-bridge cycles. Unprotected chromatids can fuse

to form a dicentric chromosome. The fused chromosomes break during

anaphase and create atelomeric chromosomes. Atelomeric chromosomes

can fuse with other chromosomes and perpetuate the cycle. Amplification,

deletions, and aneuploidy can arise this way. Methylation is an epigenetic

phenomenon that is not thought to be directly related to chromosome

fusion.

Answer 1.30. The answer is C.

It is thought that one of the mechanisms of cancer pathogenesis is

related to short telomeres that contribute to genomic instability followed

by increased telomerase activity. Paradoxically, genomic instability can

increase with decreased telomerase activity in the presence of concomitant

p53 deficiency, suggesting that telomerase inhibition by itself is likely not

sufficient as a cancer therapeutic. However, increased sensitivity to radi-

ation and DSB-inducing chemotherapeutics is associated with decreased

telomerase activity and suggests possible additive or synergistic effects.

Answer 1.31. The answer is D.

Phosphorylation of tyrosine residues by tyrosine kinases is an impor-

tant signal for cell stimulation and cancer growth. Each transmembrane