Preneoplasia and the early detection of lung cancer

As discussed above, lung cancer results from the
accumulated effects of genetic and epigenetic al-
terations over time. Strong evidence for this posi-
tion derives from molecular genetic studies whichshow that some genetic alterations found in frank
tumors can also be identified in preneoplastic lung
cells. Using a series of microsatellite markers and
precise microdissection of cancer and lung preneo-
plastic lesions in smoking-damaged lung epithelium
as well as primary lung cancers, several groups have
shown that as cells progress histologically from hy-
perplastic epithelium through dysplasia, carcinoma
in situ, to invasive carcinomas, they acquire more
frequent and extensive genetic alterations [27,28].
The earliest genetic change that has been identified
in preneoplastic bronchial epithelial cells often in-
volves the short arm of chromosome 3. The specific
region is a 630-kb minimal homozygously deleted
portion of cytoband 3p21.3 [24]. This locus encom-
passes approximately 20 genes, including RASSF1A,
FUS1, and SEMA3B, which are discussed in the next
section.
Themost common genetic alterations and the rel-
ative timing of their appearance during lung tumori-
genesis are of particular interest because knowledge
of their occurrence can be potentially used for risk
assessment of who is themost likely to develop lung
cancer. However, these changes primarily represent
a “full defect” induced by cigarette smoking and
only rarely do sites of these changes progress to full-
fledged cancer.
In exposure-related cancers such as lung cancer,
progenitor epithelial cell clones frequently undergo
epigenetic and genetic alterations that expand into
“fields” of cells, exacerbating the problem of clonal
instances of genetic damage. The presence of spe-
cific genetic changes such as a definedmutation can
be used to track clonally-related cells. In one such
study, a group of pathologists examined 10 widely
dispersed sites in the tracheobronchial tree of a pa-
tient who died of severe atherosclerosis and found
patches of cells with the identical p53 point muta-
tion in seven of these sites [29]. While there was
no evidence of cancer in any organ at autopsy, the
presence of this mutation indicated that a lung cell
with the stem-like properties existed and migrated
throughout the lung.
The combination of chronic exposure to cigarette
smoke and chromosomal instability lead to LOH
in 3p21.3 (several genes), 9p21 (p16), and 17p.13
(p53) and frequent amplifications in eight (c-Myc),which contained defined tumor suppressor genes
or oncogenes. Loss of tumor suppressor gene func-
tion and activation of oncogenes contribute to the
initiation, development, and maintenance of lung
cancer by conferring six distinct properties, called
the “hallmarks of cancer” [9]. The hallmarks in-
clude self-sufficiency in growth signals (activation
of oncogenes), insensitivity to growth-inhibitory
signals (inactivation of TSGs), evading apoptosis,
immortalization, sustained angiogenesis, and tissue
invasion and metastases. In the following section,
we will discuss the genes involved in conferring
these “hallmarks” on lung cancer cells.