CHAPTER 4 The Molecular Genetics of Lung Cancer

A brief history of cancer genetics
That cancer is a genetic disease was first understood
near the turn of the last century [1]. After the dis-
covery that DNA was the genetic material, cytoge-
netic studies showed that neoplasms were nearly
always clonal with respect to karyotype and chro-
mosomal pattern. These early genetic studies led to
the concept of the clonal inheritance of somatically
acquired genetic abnormalities in cancer pathogen-
esis [2].
By the late 1960s, there were two competing hy-
potheses both of which derived from the observa-
tion that retroviral-like sequences of DNA and RNA
were frequently found in tumor cells: the idea popu-
larized by Temin involved retrotranscription of viral
genes into host cell DNA (this hypothesis eventu-
ally led to a Nobel Prize for Temin and his postdoc-
toral researcherDavid Baltimore); the other idea de-
veloped by Huebner and Todaro led to the concept
of the oncogene—genes that promote the develop-
ment of cancer [3,4]. The distinction between these
two ideas was the source of the oncogenic element:
in Temin’s view, the carcinogen derived from an in-
fectious agent,whereas for Todaro and Huebner, the
source was an endogenous, vertically transmitted,
retroviral-like gene. Both proposals turned out to
partially correct. By directly testing these compet-
ing hypotheses,Nobel laureates, Varmus and Bishop
were able to show that normal cells contain gene
sequences that are homologous to viral oncogenes;
these sequences are “proto-oncogenes” ready to be
activated during cancer pathogenesis.
Around the same time Alfred Knudson used
statistical inference to devise the complementary
concept of recessive anti-oncogenes. In a classic pa-
per, Knudson postulated that if the overall muta-
tion rate between patients with the inherited form
of retinoblastoma versus the sporadic version were
similar, then the frequent incidence of multifocal
or bilateral retinoblastomas in familial cases must
occur on the background of a germline mutation
in a critical gene [5]. The implication of this study
was that, at least in retinoblastoma, two mutations
were sufficient for the onset of disease: the so-called
“two-hit hypothesis.” Several years later, the gene
that is responsible for familial retinoblastoma was
cloned [6]. In the two decades since retinoblastoma
was first cloned and characterized, several hundred
genes—either oncogenes or tumor suppressors or
their accomplices—have been implicated in cancer
pathogenesis [7,8].
The brief overview presented above suggests that
there are at least two distinct genetic components
to cellular transformation: there are large, clonal
chromosome aberrations (aneuploidy) including
translocations, amplifications, and deletions, and
there are alterations that occur at the level of
the gene, which often include point mutations,
small amplifications, and deletions. By studying the
genetic lesions that frequently occur in primary
tumor material, cancer geneticists have made sig-
nificant inroads into a general understanding of the
mechanisms of cancer pathogenesis [9]. Modern
molecular biology techniques including cloning, the
polymerase chain reaction, and genome-wide DNA
Lung Cancer, 3rd edition. Edited by Jack A. Roth, James D. Cox,
and Waun Ki Hong. c  2008 Blackwell Publishing,
ISBN: 978-1-4051-5112-2.microarrays have increased the rate with which
new genes are discovered and disease associations
determined. The next step in the biotechnology
revolution will be to translate our growing under-
standing of cancer genetics into rational diagnos-
tic and drug development platforms, and ultimately
into better treatment strategies. This chapter dis-
cusses the genetic basis of lung cancer in light of the
ongoing translational and clinical challenges these
diseases present to physicians, and describes new
approaches to developingmolecularly targeted ther-
apies to treating lung cancer.