ONCOGENES AND TUMOR SUPPRESSOR GENES

In addition to epidemiological evidence, experimental evidence
of the role of genes in lung cancer causation has been
accumulating. First, it seems probable that genetic changes are
responsible for the pathogenesis of most, if not all, human malignancies.
107 In particular, lung carcinogenesis is the result of a
series of genetic mutations that accumulate progressively in the
bronchial epithelium, first generating histologically identifiable
premalignant lesions and finally resulting in an invasive carcinoma
(see Chapter 5). The premalignant genetic changes may
occur many years before the appearance of invasive carcinoma.
Cytogenetic and molecular studies have shown that mutations
in proto-oncogenes and TSGs are critical in the multistep
development and progression of lung tumors. Allele loss analyses
have implicated the presence of other TSGs involved in lung
tumorigenesis. These studies revealed frequent occurrences of
chromosomal deletions including regions of 3p, 5q, 8p, 9p, 9q,
11p, 11q, and 17q. These studies are outside the scope of this
chapter (see Chapter 6). 108–110 A recent genome-wide analysis
found common amplifications of the human telomerase gene
on chromosome 5p and in NK2 homeobox 1 (also known
as thyroid transcription factor-1 [TITF-1]) on chromosome
14q13.3. 111
These data have been further explored by genomic profiling
of 128 lung cancer cell lines and tumors that revealed
frequent focal DNA amplification at cytoband 14q13.3. The
smallest region of recurrent amplification spanned TITF-1.
When amplified, TITF-1 exhibited increased expression at both
the RNA and protein levels. Small interfering RNA (siRNA)-
mediated knockdown of TITF-1 in lung cancer cell lines with
amplification led to reduced cell proliferation, manifested by
both decreased cell cycle progression and increased apoptosis.
These findings indicate that TITF-1 amplification and overexpression
contribute to lung cancer cell proliferation rates and
survival and implicate TITF-1 as a lineage-specific oncogene in
lung cancer