HUMAN PAPILLOMAVIRUS–MEDIATED LUNG CANCER

Human papillomavirus (HPV) has been identified in tumors
from many organs, not just gynecological tumors. Nearly
30 years ago, it was suggested to be a risk factor for lung cancer,
particularly squamous cell carcinoma, 163 and since then,
many studies have investigated the role of HPV in lung cancer
and have reported considerable geographical variation. A recent
metaanalysis of 53 publications, comprising 4508 cases, found
that the mean incidence of HPV in lung cancer was 25% and
was detected in all subtypes of lung cancer, not just squamous
cell. 164 Studies from Europe and America had a lower incidence
of 15% to 17%, whereas Asian lung cancer cases reported a
mean incidence of 38%. This observed high penetrance of
HPV in lung cancer suggests more research is required to elucidate
its role in lung cancer pathogenesis; however, considering
the significant variation observed between studies of cases from
the same geographical location, subsequent studies will need to
have large sample and a detailed study design.
Genetic and epigenetic mechanisms underlying lung cancer
development and progression continue to emerge. Over the
past decade, research into the biology of many diseases has
been spearheaded by the development of whole-genome microarray
technology, allowing the simultaneous analysis of expression,
copy number, and SNPs across thousands of genes.
In lung cancer, gene expression studies have uncovered novel
genes and pathways, as well as identified gene signatures that
can better predict patient prognosis, response to treatment,
and histology 165–168 reviewed. 169,170 High-resolution mapping
of alterations in the lung cancer genome has been able
to identify single genes as targets of genomic gain or loss
through improved definition of known aberrant regions or
by identification of focal alterations undetectable with earlier
technology. 15,171–173 Large-scale sequencing and SNP analyses
have also led to the identification of novel somatic mutations
or SNPs in the lung cancer genome. 7–9,174 Although such genome-
wide screens have the capacity of identifying novel genes
or interactions in relation to lung cancer, the functional relevance
of these findings still need to be elucidated using in vitro
model systems such as tumor cell lines or immortalized human
bronchial epithelial cells. These systems allow the characterization
of single or sequential genetic alterations in relation to
the development, maintenance, and progression of lung cancer
and represent a crucial contribution in the understanding of
the molecular biology of lung cancer. Functional characterization
of genetic alterations and the signaling pathways with
which they interact has enabled the development of targeted
therapies for the treatment of lung cancer (Table 5.2). Ranging
from drugs in clinical use to those in clinical trial, they are
directed against all known pathways of lung cancer initiation
and progression such as proliferation, inhibition of apoptosis,
angiogenesis, and invasion. This chapter has outlined some of
the significant molecular alterations known to be involved in
the initiation and/or progression of lung cancer. By characterizing
these aberrations, researchers endeavor to improve the
detection, diagnosis, treatment, and prognosis of lung cancer
through the integration of clinical and biological factors—to
achieve personalized medicine.