Genomic Alterations in Lung Cancer

Lung cancer has been the leading cause of cancer-related morbidity
and mortality worldwide. 1 These tumors are classified into
two major clinicopathological categories, small cell lung carcinoma
(SCLC) and non–small cell lung carcinoma (NSCLC).
SCLC, accounting for 15% to 20% of lung cancers, displays
neuroendocrine features and a propensity for rapid growth
and early metastasis. NSCLC, accounting for the balance of
approximately 80% of lung tumors, includes adenocarcinoma
and squamous cell carcinoma, the two most common histological
subtypes. Lung cancers, as other carcinomas, display numerous
alterations in gene expression patterns resulting from
acquired genetic and epigenetic mechanisms, including DNA
methylation or histone modification across large chromosomal
regions. Conventional and high-throughput technologies have
detected scores of genomic changes occurring in individual
specimens. However, few of those are recurrent changes among
a large number of tumors, a characteristic that poses a challenge
for the precise definition of molecular subtypes.
It is well-known that lung cancers show genetic instability,
a persistent state that causes several mutational events
leading to gross genetic alterations. This genomic instability
is reflected in the heterogeneity of karyotypes and molecular
profiles within a given tumor type and among different foci
of the same tumor. Genomic changes in cancer may occur at
different levels, ranging from the single nucleotide to an entire
chromosome. Changes at one or few nucleotides, the mutations,
may be completely innocuous or may be responsible
for dramatic functional changes depending on the specific
mutated site. Changes at the chromosomal level are usually
detrimental since most likely affect large number of genes.
Characterization of the genomic changes and identification of
which molecular events contribute to the mechanisms that are
central to tumorigenesis and to the multistep tumor progression
are critical needs. Ultimately, the genomic discoveries will
be translated into clinical tools that may impact the practice of
cancer medicine.
In this chapter, we will review the most important genomic
alterations detected in lung cancers. We will also discuss recent
findings that have contributed to the better understanding of
the molecular features of these tumors and to the development
of strategies for earlier diagnosis and more efficient therapies.