Devita, Hellman, and Rosenberg's Cancer

LWBK1006-03 LWW-Govindan-Review November 24, 2011 11:19

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

Answer 3.4. The answer is D.

Formation of bonds between smoke carcinogens and DNA resulting in

DNA adducts is an important aspect of the carcinogenicity of cigarette

smoke. DNA adducts that are not removed result in miscoding dur-

ing replication leading to mutations. Mutations have been frequently

observed in the KRAS oncogene in lung cancer and in the TP53 tumor

suppressor gene in various cigarette smoke-induced cancers. Processes,

other than formation of DNA adducts, that contribute to cancer for-

mation are activation of cellular receptors byN-nitrosamines and nico-

tine and the silencing of certain genes through methylation of the gene

promoters. Nucleotide excision repair enzymes are part of the cellular

repair systems that remove DNA adducts and repair the DNA. There

are no data to suggest that carcinogens in cigarette smoke inhibit these

enzymes.

Answer 3.5. The answer is D.

Various carcinogens have been detected in smokeless tobacco prod-

ucts. The most abundant areN-nitrosamines 4-(methylnitrosamino)-

1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN).

Smokeless tobacco use is known to cause three cancers: pancreatic cancer,

esophageal cancer, and cancer of the oral cavity. Based on animal studies,

the most probable carcinogens causing these cancers in smokeless tobacco

users are NNN for esophageal cancer, NNK for pancreatic cancer, and

both NNN and NNK for cancers of the oral cavity.

Answer 3.6. The answer is A.

More than 30 years ago, Alfred Knudson postulated that predisposition

to cancer arises as the result of a heterozygous germ line mutation, which

then requires a second acquired mutation in the unaffected allele for tumor

to develop, also called the “two-hit hypothesis.” The hypothesis was vali-

dated in patients with retinoblastoma. These individuals inherit a mutated

Rbgene and then acquire mutation in the normal allele of the gene lead-

ing to cancer. Further studies also revealed that the genes involved in

carcinogenesis of the familial form of the cancer can also be involved in

the sporadic forms of that cancer.

Answer 3.7. The answer is C.

For cancer to initiate, the cancerous cell has to eventually acquire the abil-

ity to proliferate or abrogate apoptosis. It is recognized that two classes

of tumor suppressors may cooperate in tumor formation: (a) those that

control proliferation and survival through control of the cell cycle and (b)

those that are involved in the control of genomic integrity. Loss of genes

involved in maintaining genomic integrity may lead to mutations in genes

that control proliferation or apoptosis. Apart from alterations in genes

involved with cellular functions of proliferation and survival, changes in

genes involved in other cellular functions such as angiogenesis may be the

driving force for carcinogenesis. In addition, even though genetic changes