Basic Concepts of Molecular Pathology
Timothy Craig Allen, MD, JD; Philip T. Cagle, MD; Helmut H. Popper, MD
T his month’s issue of the Archives of Pathology & Labora-
tory Medicine includes a unique special section on
‘‘Molecular Signatures of Lung and Pleural Tumors’’ that
represents the proceedings of a special Joint Symposium
of the European Working Groups for Molecular Pathology
and Pulmonary Pathology at the 21st European Congress
of Pathology in Istanbul, Turkey, in September 2007. This
symposium and the subsequent special section were or-
ganized by Dr Helmut Popper of the Institute of Pathology
at the Medical University of Graz, Graz, Austria, president
elect of the Austrian Society of Pathologists and immediate
past president of the European Working Group for Pul-
monary Pathology. In this brief review, we have provided
some definitions of terms and concepts used in the pro-
ceedings of the ‘‘Molecular Signatures of Lung and Pleu-
ral Tumors’’ special section for those readers who are not
already familiar with molecular pathology.
Molecular pathology may have once been a specialized
component of the research laboratory or the clinical lab-
oratory, but today molecular diagnostic and prognostic
techniques are in common use within the anatomic pa-
thology laboratory, especially in the realm of infectious
organism diagnosis and cancer diagnosis. Molecular test-
ing continues to expand as more easily obtainable archival
paraffin-embedded tissue replaces fresh and frozen tis-
sues as the source of DNA and RNA needed for molecular
analysis, and as newer technologies allow for more
streamlined methods of testing. This review addresses the
increased application of molecular testing in lung pathol-
ogy, specifically how the current state of molecular pa-
thology may be applied to practical, everyday lung pa-
thology diagnosis.
GENES
Genes, made up of nucleic acids, contain the informa-
tion necessary for the construction of proteins from amino
acids within a cell. Genes code for proteins required for
metabolic reactions and cellular structure. DNA makes up
genes, and RNA transcribes the genetic code held within
the DNA into proteins. The genetic code within the genes
is composed of nucleic acids, for which nucleotides are the
Accepted for publication June 17, 2008.
From the Department of Pathology, The University of Texas Health
Science Center at Tyler (Dr Allen); the Department of Pulmonary Pa-
thology, The Methodist Hospital, Houston, Tex (Dr Cagle); and the Insti-
tute of Pathology, Medical University of Graz, Graz, Austria (Dr Popper).
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Timothy Craig Allen, MD, JD, Department of Pathology,
University of Texas Health Science Center at Tyler, 11937 US Hwy 271,
Tyler, TX 75708-3154 (e-mail: timothy.allen@uthct.edu).
Arch Pathol Lab Med—Vol 132, October 2008
building blocks. Nucleotides, made up of a sugar-phos-
phate backbone with a nitrogenous base, are either pu-
rines—adenine (A) and guanine (G) in DNA and RNA—
or pyrimidines—thymine (T) and cytosine (C) in DNA
(uracil [U] replaces T in RNA). The nucleotides that make
up the genes are arranged in a double-stranded right-
handed helix. Nucleotides in DNA are arranged sequen-
tially so that a gene will code for a matching protein.
Within a double helix pattern, A, a purine, always binds
with T, a pyrimidine, and G always binds with C, giving
a nucleotide sequence for which 1 strand is a ‘‘mirror im-
age’’ of the other strand.1–6
There are 46 chromosomes (23 pairs) in a human dip-
loid cell, on which all genes are located. Chromosomes are
paired, and as such a gene is found on a locus on each of
the 2 paired chromosomes, giving 2 copies, or alleles, of
genes. Gametes are haploid rather than diploid and there-
fore contain only 1 allele for each gene. Diploid status is
reestablished when the nuclear material from an egg and
sperm combine during fertilization.1–6
Transcription, the synthesis of messenger RNA (mRNA)
from a DNA strand, is a key step in the formation of pro-
tein coded by DNA. During transcription, enzymes called
topoisomerases break a DNA strand and allow the DNA
double-helix to uncoil, giving 2 DNA strands, 1 of which
is the template for mRNA, called the DNA template. Base
pairs are matched with the DNA template to produce a
mirror image of the DNA template, except with the sub-
stitution of U for T, forming a strand of mRNA. A series
of 3 base pairs in a gene, called a codon, code for a specific
amino acid, so that a series of codons code for a particular
sequence of amino acids resulting in the synthesis of a
specific protein. Translation, the assembly of the protein
molecule from the mRNA template, occurs with the ad-
dition of amino acids in a particular sequence based on
the specificity of the mRNA. Transfer RNA assists in
translation.1–6
After translation, modifications to the newly formed
protein occur in order for it to function, to move within
the cell, or to fold properly. Methylation, acetylation, phos-
phorylation, glycosylation, posttranslational cleavage, and
the addition of lipid groups are examples of posttransla-
tional modifications. End regions of chromosomes are
made up of telomeres, hundreds of repeats of the nucle-
otide sequence TTAGGG. Some of these telomere sequenc-
es are lost each time a cell divides, until they are lost and
the cell can no longer divide. This process is called senes-
cence. A polymerase called telomerase is able to replace
the DNA sequences at the end regions, allowing for con-
tinuing cell division—a significant feature in some can-
cers.1–6
Basic Concepts of Molecular Pathology—Allen et al 1551
 The polypeptide chain formed by the specific amino
acid sequence causes the newly formed protein to fold into
a tertiary arrangement giving it a 3-dimensional structure.
Often, the newly formed protein is inert until made func-
tional by a posttranslational modification such as phos-
phorylation or proteolytic cleavage. Phosphorylation, the
addition to the protein of a phosphate group catalyzed by
enzymes called kinases, may cause, for example, translo-
cation of the protein from the cytosol into the nucleus.
Dephosphorylation is the removal of a phosphate group
catalyzed by enzymes called phosphatases. Phosphoryla-
tion and dephosphorylation of proteins are often impor-
tant in the activation and deactivation of cell cycle pro-
teins, signaling pathway proteins, and transcription factor
proteins.1–6
Protein degradation is necessary to remove damaged
proteins and limit signaling proteins such as those in-
volved in cell survival and cell death. This degradation
often needs to proceed quickly. Reversible cross-linkage
to a polypeptide, termed ubiquitin, leads to the rapid deg-
radation of proteins and is called ubiquinylation or poly-
ubiquinylation.7
The control of gene expression is for the most part con-
trolled by regulation of transcription initiation. Proteins
called transcription factors, also termed transactivators or
trans-acting factors, bind to DNA and regulate RNA poly-
merase activity, affecting gene expression either by induc-
ing or activating the gene or by inhibiting the gene by
reducing transcription levels.8–13 Transcription factors are
necessary for RNA polymerase to initiate transcription,
and transcription factors called transcriptional activators
stimulate transcription of an RNA molecule from its DNA
template.14,15
THE TOOLS OF MOLECULAR PATHOLOGY
A variety of techniques exist for molecular pathology
diagnosis, including nucleic acid extraction, Southern blot-
ting, restriction fragment length polymorphism, sequenc-
ing, liquid bead microarrays, mass spectrometry, and
comparative genomic hybridization, among others. Nu-
cleic acid extraction historically has used organic tech-
niques using chloroform and phenol; however, automated
nucleic acid extraction exists today and is frequently used
to purify nucleic acids for their use with other molecular
methods. For practical laboratory-based molecular diag-
nosis of lung disease, polymerase chain reaction (PCR)
and fluorescence in situ hybridization (FISH) are 2 of the
most important techniques commonly used.
Fluorescence In Situ Hybridization
In situ hybridization uses DNA or RNA probes to eval-
uate intact cells for genetic changes. Probes visualized
with a chromogen that produces a colored chemical at the
reaction site is called chromogenic in situ hybridization
and probes using fluorescent labels are called FISH. Eval-
uation of genetic alterations within intact cells allows for
the detection of genetic alterations occurring in a specific
group of cells or within a small number of examined cells
and is a major benefit of the use of in situ hybridization
in anatomic pathology. It is commonly used with cytologic
and surgical specimens to detect tumor cells and certain
microorganisms, and with surgical specimens of tumors
for its prognostic utility and to determine treatment re-
sponse.16–22 Chromogenic in situ hybridization uses a
1552 Arch Pathol Lab Med—Vol 132, October 2008
probe that can be seen as a chromogenic reaction under
light microscopy, whereas FISH is available as probe sets
and multiprobe FISH cocktails. Peripheral blood, urine,
sputum, endoscopic brushings and washings, and paraf-
fin-embedded, formalin-fixed tissue are all suitable for
FISH. However, fixation of tissue with formalin for longer
than 48 hours may yield poorer FISH results.23
DNA and RNA probes hybridize to a specific target se-
quence that is of interest, for example, genes implicated in
a specific type of cancer or an inherited disease, or to a
certain microorganism.16–22 Probes are made using DNA
fragments cloned from yeast or bacterial artificial chro-
mosomes and, with FISH, are directly or indirectly fluo-
rophore labeled, most often using Texas Red, fluorescing
red, and fluorescein isothiocyanate, fluorescing green.24
Directly labeled probes have a fluorophore-labeled nucle-
otide inserted into the probe, so binding of the probe to
its target in 1 hybridization step is all that is required to
visualize the probe. Indirectly labeled probes have a re-
porter molecule such as biotin or digoxigenin attached co-
valently, requiring the additional step of the application of
a fluorophore-labeled avidin or fluorophore-labeled anti-
digoxigenin. The additional step required with indirectly
labeled probes is a disadvantage; however, indirectly la-
beled probes generally allow for stronger signals because
of greater signal amplification.24 There are 4 general types
of probes: chromosome enumeration probes, locus-specific
indicator probes, telomeric probes, and chromosome
paints. Chromosome enumeration probes hybridize to re-
petitive DNA sequences located near chromosome centro-
meres, and because the loss of a centromere is generally
indicative of the loss of an entire chromosome, they are
used to enumerate the number of copies of a certain chro-
mosome within a cell.25,26 Locus-specific probes are probes
to unique sequences and are most frequently used to de-
termine whether specific genes are amplified, translocat-
ed, or deleted. Telomeric probes hybridize to unique DNA
sequences located very close to telomeres. The probes do
not hybridize to telomeric sequences. Chromosomal paints
are a mix of probes that probe to the entire length of 1 or
more chromosomes.
A FISH specimen must undergo prehybridization to al-
low a probe to efficiently hybridize to cellular DNA tar-
geted by the probe while protecting the cell from mor-
phologic disruption. Following prehybridization, the
probe and cellular DNA are denatured so that the probe
can hybridize to the cellular DNA it is targeting. Hybrid-
ization usually takes between 4 and 12 hours. A type of
DNA called Cot DNA is added during hybridization to
hybridize highly repetitive DNA sequences that are locat-
ed within the genome so that the probe DNA does not
nonspecifically bind these repetitive sequences and yield
a multitude of nonspecific signals rather than the appro-
priately specific signal.24,25,27,28 The nonbound probe is then
removed by washing, a nuclear counterstain that weakly
fluoresces is added so that the nucleus can be identified,
and an antifade is added to retard fluorophore photo-
bleaching. The signal produced by the FISH fluorophore
is then examined with fluorescence microscopy.
Polymerase Chain Reaction
Since its introduction in 1985,29 PCR has been refined
to be an efficient and sensitive method of studying the
molecular pathology of primary and metastatic neo-
plasms, inflammatory mechanisms, and infectious diseas-
Basic Concepts of Molecular Pathology—Allen et al
es.30–37 Today, automated instruments designed for the lab-
oratory tabletop are available. Polymerase chain reaction
amplifies DNA via a repeated 3-step process of denatur-
ation, annealing, and extension. Double-stranded DNA
that is the target is denatured at high temperature to yield
2 intact single strands of complementary DNA. Then at a
lower temperature, specially designed single-stranded
DNA primers anneal or bind to a specific targeted area of
the single-stranded DNA. Because there are very large
numbers of DNA primers relative to the full-length com-
plementary DNA strand, the target DNA anneals with the
primer DNA much more frequently than with the com-
plementary DNA when cooling occurs. In the third step,
extension, Taq polymerase identifies the now partially
double-stranded DNA and extends the primers by poly-
merization, to yield, at the end of the first cycle, 2 double-
stranded copies of a portion of the target DNA generated
from 1 copy. Because the DNA primers only recognize the
DNA for which they have been specifically designed, only
that specific segment of DNA, making up a small part of
the entire DNA present in the original DNA, is preferen-
tially amplified. Subsequent cycles produce numerous
shorter double-stranded DNA PCR products, so that more
than a billion copies of the original double-stranded DNA
are produced after 30 cycles, and more than a trillion are
produced after 40 cycles. Following amplification, post-
PCR analysis of the markedly increased amount of tar-
geted DNA sequence product can be performed. The tar-
get sequence can be shown to be present in a specimen
by the use of amplicons run on polyacrylamide or agarose
electrophoresis, or via Southern blotting with probe hy-
bridization, comparing the lengths of the targeted DNA
sequence with DNA ‘‘ladder’’ markers. DNA sequencing
can be performed on the amplicons, or studies to identify
mutations may also be performed.38,39 Because PCR enor-
mously amplifies DNA, great caution must be used in per-
forming PCR to avoid cross-contamination of a specimen
with even very small amounts of DNA.
Real-time PCR is becoming a more and more popular
method of molecular pathology research and diagnosis
that eliminates the need for post-PCR analysis and allows
for relatively quick detection of DNA targets, including
specific mutations.40–44
The best way to examine specific genes present in a
certain cell type, such as in tumor cells, is to examine those
cells’ mRNA. As RNA is not stable enough to work with
easily in a laboratory, reverse transcription can be used to
convert mRNA into its complementary DNA. With reverse
transcription, mRNA is the template used for the produc-
tion of a strand of DNA, opposite or reverse of typical
cellular transcription. The complementary DNA can be
used as the template for PCR in a process called reverse
transcriptase–PCR (RT-PCR). Reverse transcriptase–PCR
can be used to examine genes that are expressed, over-
expressed, underexpressed, or not expressed in a specific
cell type by the isolation of specific mRNA.44–47 Altered
gene expression is a characteristic of malignant transfor-
mation, and those alterations allow for the identification
of the presence of cancer cells via the detection of mRNA
transcripts specific to those tumor cells. Tumor markers
have been identified that are specific to solid organ can-
cers, and RT-PCR is highly sensitive in detecting differ-
entially expressed tumor-related mRNAs. Some studies
have indicated that RT-PCR can detect as few as 1 cancer
cell in a million normal cells.44,48 Real-time quantitative RT-
Arch Pathol Lab Med—Vol 132, October 2008
PCR has become popular for detecting and quantifying
RNA targets in a variety of cancers. It requires no post-
PCR analysis and is efficient and automated. Several stud-
ies have used real-time quantitative RT-PCR to evaluate
lymph nodes for micrometastases, including for non–small
cell lung carcinoma (NSCLC), and to examine peripheral
blood for potential dissemination of lung cancer cells dur-
ing lobectomy.49–52
LOSS OF HETEROZYGOSITY
Normal human DNA contains 2 alleles for every genetic
locus, the majority of which are identical, or homozygous,
and the loss of 1 allele results in no pathologic change.
Some genetic loci have 2 differing copies of alleles and are
heterozygous. The majority of these heterozygous alleles
allow for normal variance and do not result in pathologic
changes; however, some of these heterozygous loci have
the potential to cause pathologic genetic variations, with
resultant disease. If there is a loss of the normal, or ‘‘wild-
type,’’ allele at a locus, with resultant ‘‘loss of heterozy-
gosity,’’ the remaining aberrant allele can cause cellular
damage. At homozygous loci, the loss of an allele can oc-
cur and be followed by gene silencing or point mutation,
causing loss of tumor suppressor genes.53,54 Detection of
loss of heterozygosity using older methods such as South-
ern blot analysis and restriction fragment length poly-
morphism analysis are low-throughput, tedious, and in-
efficient; however, newer, high-throughput single nucleo-
tide polymorphism arrays have allowed for more efficient
examination of loss of heterozygosity.55–57
Cancers, including lung cancers, commonly exhibit loss
of heterozygosity, causing the inactivation or silencing of
genes critical for growth regulation and homeostasis. Cig-
arette smoking has been associated with loss of hetero-
geneity of sites on chromosome 3, and the association
is greater in patients who began smoking at a young
age.58–61 More than 90% of small cell carcinomas and more
than 70% of NSCLCs contain loss of heterozygosity.57,62,63
Among NSCLCs, squamous cell carcinomas exhibit loss of
heterozygosity in more than 90% of cases, compared with
adenocarcinomas, showing loss of heterozygosity in ap-
proximately 70% of cases. In NSCLC, loss of heterozygos-
ity generally involves genetic foci on chromosomes 1p, 3p,
8p, 9p, 13q, 17p, 19p, Xp, and Xq. In small cell carcinomas,
loss of heterozygosity generally involves chromosomes 3p,
4q, 5q, 4q, 10q, 13q, 15q, and 17p.57,62–66 Losses found in
both small cell carcinomas and NSCLCs, involving chro-
mosomes 3p, 13q, and 17p, are probably related to inac-
tivation of critical tumor suppressor genes including reti-
noblastoma, p53, and fragile histidine triad (FHIT).57,62,63
Loss of heterozygosity in premalignant conditions and
malignant diseases of the lung represents both early- and
late-stage changes in the progression of disease; however,
the continuum of losses makes it hard to evaluate the spe-
cific contribution of each loss. Loss of heterozygosity has
also been identified in some benign lung diseases, includ-
ing asthma and chronic obstructive pulmonary disease,
probably reflecting the genetic predisposition identified in
these diseases.67–70 Loss of heterozygosity has also been
identified in cases of usual interstitial pneumonia (idio-
pathic pulmonary fibrosis) and suggests premalignant po-
tential in those cases.71
Basic Concepts of Molecular Pathology—Allen et al 1553
SIGNAL TRANSDUCTION AND SIGNALING PATHWAYS pathway repairs small isolated foci of DNA damage in-
cluding reduced or oxidized single bases or fragments
Extracellular messenger molecules such as hormones,
and small, nonbulky adducts. The nucleotide excision re-
inflammatory cytokines, and growth factors, called li-
pair pathway repairs DNA damage involving both
gands, bind to specific cell surface receptors and activate
strands. The defects cannot be simply replaced because no
messengers within the cytosol leading eventually to acti-
matrix for the DNA segment is available. These defects can
vation of nuclear transcription factors that, due to the ex-
cause DNA helical structure deformity, such as cross-links,
tracellular message, direct the transcription of a specific
bulky chemical adducts, and pyrimidine dimers. The
gene product, such as the transcription of a protein in-
DNA damage response pathway, also termed the double-
volved in cell growth. This cascade of events is termed
strand break repair pathway, involves a cascade of events and
signal transduction, and the series of steps within the cas-
repairs damage to double-stranded breaks. The direct
cade is termed signal transduction pathway or signaling path-
damage reversal pathway repairs DNA damage caused by
way. Growth factor receptors are a common cell surface
alkylating compounds in cigarette smoke.94–102
receptor, on which polypeptide growth factors such as epi-
dermal growth factor are ligands attaching to those recep- CELL CYCLE
tor protein-tyrosine kinases, activating the receptor and
The cell cycle is a sequential series of very tightly reg-
causing it to bind with intracellular proteins, which in
ulated events governing cell proliferation, including entry
turn continue the signaling pathway. Epidermal growth
into DNA replication, replication, entry into cell division,
factor receptor is a member of the type I growth factor
cell division, and cell rest. The cell cycle is divided into 5
receptor tyrosine kinase family. Epidermal growth factor
phases: G0 (cell at rest), G1 (preparation for DNA synthe-
receptor has other ligands that bind to it other than epi-
sis), S (DNA synthesis or replication), G2 (integrity check
dermal growth factor, including transforming growth fac-
of replicated DNA), and M (mitosis with nuclear and cel-
tor ␣, and these ligands, receptors, and signaling path-
lular division), which provide orderly control of DNA rep-
ways play a central role in many lung cancers as well as
lication and cell division in response to external and in-
some nonneoplastic pulmonary diseases.72–77
ternal stimuli. Cyclin-dependent kinases form complexes
The extracellular ligands’ ‘‘messages’’ are transmitted
with proteins called cyclins that tightly regulate the pro-
via a signaling pathway. Cell differentiation and prolifer-
gression of the series of steps in the cell cycle by activating
ation, cell survival, and cell death and apoptosis are reg-
and inactivating proteins by phosphorylation, including
ulated by signaling pathways, the majority of which
proteins that act as ‘‘brakes’’ on cell cycle progression and
‘‘cross-talk’’ with other signaling pathways in a complex
cell proliferation. The cell cycle is controlled by many in-
manner. Several important signaling pathways have been
teracting pathways and positive and negative feedback
well studied. For example, the Wnt/B/catenin pathway,
loops, and it may be stimulated appropriately or inappro-
termed the canonical Wnt signaling pathway, involves Wnt
priately in various inflammatory diseases. Cell cycle reg-
binding to Frizzled cell surface receptors, which in turn
ulation loss is a very important step in uncontrolled cell
activate Disheveled, causing the inhibition of protein ki-
proliferation during carcinogenesis.
nase glycogen synthase kinase 3, which in turn releases
Cell cycle checkpoints prevent damaged DNA to be
dephosphorylated ␤-catenin from the adenomatous pol-
passed on to daughter cells by temporarily arresting the
yposis coli–axin complex. ␤-Catenin associates with T-cell
cell cycle at specific steps. It allows damaged DNA to be
factor/lymphoid enhancer–binding factor transcription
repaired, or, if the damage is too severe, to send cells into
factors causing the induction of Myc.78–84 Other important
apoptosis (programmed cell death). The primary check-
signaling pathways include the JAK/STAT pathway, in-
point in the cell cycle is the restriction point in G1 where
volving signal transducers and activators of transcription
‘‘commitment’’ to the cell cycle occurs. Other checkpoints
(STAT) proteins and Janus kinase (JAK) nonreceptor pro-
include an S-phase checkpoint and a G2-M checkpoint.103–106
tein tyrosine kinases; the Ras/Raf-1/MAPK pathway, a
A complex of damage sensor proteins, the Rad9-Rad1-
significant pathway in carcinogenesis, including epithelial
Hus1 heterotrimer complex and the Rad17-RFC complex,
cell proliferation; the nuclear factor-␬B transcription factor
detect DNA damage at these checkpoints. After DNA
and nuclear factor-␬B signaling pathways that regulate
damage is repaired, the DNA damage checkpoint is si-
immune system proteins, cell survival and proliferation
lenced and the cell cycle restarts.
proteins, and apoptosis proteins; and the PI3K/Akt/
Growth factor signaling initiates the cell cycle and
mTOR pathway important in regulating cell survival;
maintains the transition through the G1 phase; however,
among many others.85–93
once the cell passes through the cell cycle’s restriction
point, it no longer requires growth factor signaling, and
DNA REPAIR PATHWAYS
the cell is ‘‘committed’’ to the cell cycle. The retinoblas-
Errors in replication, extracellular influences such as UV toma (Rb) gene product, pRb, governs progression past
light, radiation, and chemicals, and endogenous influences the restriction point of the cell cycle and governs the ex-
such as oxygen radicals routinely cause DNA damage, pression of genes involved in DNA synthesis. Progression
generally depurination, deamination, nonenzymatic meth- of the cell cycle also depends on activation of cyclin D.107,108
ylation, and hydrolysis, sometimes with the attachment of One of the main functions of p53, the TP53 gene product,
a chemical group to DNA, the combination of which is is to ‘‘protect’’ the DNA through the arrest of the cell cycle
termed an adduct. Several DNA repair pathways exist to at checkpoints in response to DNA damage or to promote
excise the damaged DNA and replace it with newly syn- the induction of apoptosis when damage is too severe.109,110
thesized DNA based on its undamaged complementary As such, p53 has been referred to as the guardian of the
DNA strand. These DNA repair pathways are important genome. Both Rb and p53 have critical roles in the man-
in an individual’s susceptibility to lung cancer and re- agement of the cell cycle, and abnormalities of Rb and p53
sponse to lung cancer therapy. The base excision repair are the most common abnormalities associated with the
1554 Arch Pathol Lab Med—Vol 132, October 2008 Basic Concepts of Molecular Pathology—Allen et al
cell cycle dysregulation of malignancy; however, due to
the large number of redundancies, feedback loops, and
interacting pathways, many abnormalities can produce ef-
fects mimicking direct f Rb or p53 loss. The CDKN2A gene
encodes for 2 unrelated protein products, p16INK4A, a
cyclin-dependent kinase inhibitor, and p14ARF. Abnor-
malities of either of these can produce effects mimicking
abnormalities of the Rb or p53 genes.111,112 Indeed, abnor-
malities of CDKN2A, p16, p14, and MDM2, as well as other
genes and their products upstream or downstream of Rb
and p53, can produce loss of cell cycle control mimicking
the direct loss of Rb and p53.
CONCLUSION
Diagnostic and prognostic techniques using molecular
technology are increasingly being used in anatomic pa-
thology laboratories. Understanding genes responsible for
proliferation, differentiation, and apoptosis, the basic tools
used for evaluation of molecular changes, and factors in-
volved in genetic susceptibility will help the pathologist
better understand current and future molecular testing
methodologies and their relevance to the diagnosis and
therapy of lung diseases.
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