Clinical Chemistry 59:1
158–167 (2013)
Genomic Medicine:
New Frontiers and New Challenges
Maria D. Pasic,1,2 Sara Samaan,3,4 and George M. Yousef1,3,4*
BACKGROUND: The practice of personalized medicine
has made large strides since the introduction of high-
throughput technologies and the vast improvements
in computational biotechnology. The personalized-
medicine approach to cancer management holds
promise for earlier disease detection, accurate predic-
tion of prognosis, and better treatment options; how-
ever, the early experience with personalized medicine
has revealed important concerns that need to be ad-
dressed before research findings can be translated to
the bedside.
CONTENT: We discuss several emerging “practical” or
“focused” applications of personalized medicine. Mo-
lecular testing can have an important positive impact
on health and disease management in a number of
ways, and the list of specific applications is evolving.
This list includes improvements in risk assessment,
disease prevention, identification of new disease-
related mutations, accurate disease classification
based on molecular signatures, selection of patients
for enrollment in clinical trials, and development
of new targeted therapies, especially for metastatic
tumors that are refractory to treatment. Several
challenges remain to be addressed before genomics
information can be applied successfully in the rou-
tine clinical management of cancers. Further im-
provements and investigations are needed in data
interpretation, extraction of actionable items, cost-
effectiveness, how to account for patient heterogeneity
and ethnic variation, and how to handle the risk of
“incidental findings” in genetic testing.
SUMMARY: It is now clear that personalized medicine
will not immediately provide a permanent solution for
patient management and that further refinement in the
1
Department of Laboratory Medicine and Pathobiology, University of Toronto,
Toronto, Ontario, Canada; 2 current affiliation: Department of Laboratory Med-
icine, St. Joseph’s Health Centre, Toronto, Ontario, Canada; 3 Department of
Laboratory Medicine, St. Michael’s Hospital, Toronto, Ontario, Canada;
4
Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s
Hospital, Toronto, Ontario, Canada.
* Address correspondence to this author at: Department of Laboratory Medicine,
St. Michael’s Hospital, 30 Bond St., Toronto, Ontario, M5B 1W8 Canada. Fax
416-864-5648; e-mail yousefg@smh.ca.
Received September 11, 2012; accepted October 24, 2012.
Previously published online at DOI: 10.1373/clinchem.2012.184622
158
Reviews
applications of personalized medicine will be needed to
address and focus on specific issues.
© 2012 American Association for Clinical Chemistry
The concept of personalized medicine, which is to use
the individual’s genetic makeup to predict disease risk,
accurately plot the course of the disease, and tailor the
management plan according to the patient’s unique
needs, was proposed several years ago (1, 2 ). Revolu-
tionary improvements in the analytical tools required
for personalized medicine have accompanied the in-
troduction of high-throughput technologies. These ad-
vances, which enable simultaneous analyses of thou-
sands of molecules, have increased the momentum of
this field. These technologies have developed in parallel
with unprecedented improvements in computational
biotechnology that allow the analysis and interpreta-
tion of the huge data sets obtained in such experiments.
Finally, the introduction of targeted therapy has in-
creased the demand for molecular characterization of
diseases to identify new candidate markers for progno-
sis and prediction (3–5 ) and to facilitate the develop-
ment of new targeted therapies (6 – 8 ).
Such molecular analyses are predicted to be im-
portant for managing cancer patients by offering im-
provements in early cancer detection, accurate predic-
tion of prognosis, and better treatment options with
minimal side effects (1, 9, 10 ). Information gained by
these methods will also help in evolving our under-
standing of disease pathogenesis by switching the focus
to a search for altered “biological processes” from a
focus on the discovery of individual disease biomarkers
(4 ). The change to processes rather than markers will
be useful for investigating complex diseases, such as
cancer, diabetes, and hypertension, which often in-
volve large numbers of genes, pathways, and environ-
mental factors (4, 5 ). Thus, we are stepping into a new
era of “genomic” medicine. It is not surprising that
10% of the labels for drugs cleared by the U.S. Food and
Drug Administration already contain pharmacog-
enomic information (11 ), and this number will only
increase as genomic testing becomes increasingly used
in routine care (12 ).
After a period of initial enthusiasm for personal-
ized medicine, it became apparent that several impor-
Genomic Medicine in Cancer
Table 1. The potential applications of genomic
medicine.
1. Examination of variation among healthy individuals
2. Understanding disease risk, susceptibility, and etiology
3. Disease prevention
4. Early diagnosis at the preclinical stage (to help modify
disease course, e.g., diet and exercise in diabetes)
5. Identification of new disease-related mutations
6. Accurate diagnosis of challenging cases with inconclusive
results for clinical parameters
7. Accurate disease classification based on molecular signature
8. Health management (prognosis and predictive markers)
9. Identification of personal drug-related profile
10. Selection of patients for clinical trials
11. Monitoring disease status (e.g., recurrence)
12. Monitoring tumor evolution in response to treatment
13. Developing new targeted therapies, especially for metastatic
tumors refractory to treatment
tant concerns needed to be addressed before these dis-
coveries can be translated to the bedside (13 ). It is now
clear that personalized medicine is not going to imme-
diately provide a permanent solution for all patient-
management issues and that we need to refine its ap-
plications for specific and focused issues. In this review,
we discuss some of the emerging “practical” or “fo-
cused” applications of personalized medicine. In addi-
tion, we use cancer as an example for highlighting the
challenges to be faced as we step into the era of person-
alized medicine.
Evolution of New Applications in Patient
Management
Table 1 presents an evolving list of specific applications
in which molecular testing can play an important role
in improving health and disease-management plans.
THE USE OF GENOME SEQUENCING AND INTEGRATED
MOLECULAR ANALYSIS FOR ASSESSING DISEASE RISK
Next-generation sequencing has several promising
applications in personalized medicine. Predicting
risk through molecular analysis, usually via next-
generation sequencing, can have an important impact
on disease outcomes. Genome sequencing also can
make important contributions to reproductive health.
Such improvements include prescreening of mothers
for mutations related to metabolic and other mende-
lian disorders (14 ). A recent study showed the ability of
an integrated analysis to identify genetic variants asso-
ciated with the risks of mendelian diseases, develop-
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Table 2. Strategies to increase the cost-
effectiveness of genomic screening strategies.
1. Target screening to a high-risk population
2. Focus on chronic diseases
3. Focus screening on diseases with known interventions
4. Identify molecular changes directly related to short-term
benefits
5. Limit screening to diseases with a higher prevalence
6. Interpret data in a clinical context (e.g., environmental
factors)
ment of a recognized drug response, and pathogenicity
(14 ). This study also highlights the importance of using
the expanding number of disease-specific mutation
and pharmacogenomics databases as valuable sources
for identifying disease risk.
Moreover, an interesting study has demonstrated
the potential power of exome sequencing to render a
“molecular-based diagnosis.” A novel mutation was
identified in a patient with Crohn disease after all stan-
dard diagnostic modalities had failed to reach the cor-
rect etiologic diagnosis (15 ). This and similar reports
have shown the feasibility of using comprehensive
genomic analyses for identifying causes of known dis-
eases. These studies have underscored the need to ad-
dress many of the issues related to implementing
genomic testing directly into the clinic, as we detail
below.
A pressing question to be addressed is how to esti-
mate the accuracy of sequencing technologies for pre-
dicting disease risk. Kohane et al. recently provided an
excellent review on this topic (16 ). Roberts et al. ana-
lyzed the capability of personal genome sequencing for
predicting the risk of 24 different diseases (17 ). On the
negative side, these investigators found that most mo-
nozygotic twins had negative results in sequencing tests
for 23 of the 24 diseases. On the positive side, however,
about 95% of the tested individuals were alerted to
clinically important predispositions for at least 1 dis-
ease. A related major challenge is the ability to reliably
distinguish pathogenic mutations, benign variants,
and variants of uncertain importance. Moreover, anal-
yses of diseases with a complex, multifactorial etiology,
such as hypertrophic cardiomyopathy, which has a vast
genetic variability and a high frequency of novel muta-
tions, have revealed unforeseen difficulties in translat-
ing complex science into the clinical arena.
Other major concerns in this regard are the ability
to translate this information into meaningful health
improvements and the costs of these expensive screen-
ing tools. Table 2 lists several strategies for improving
the cost-effectiveness of genomic screening. One strat-
Clinical Chemistry 59:1 (2013) 159
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egy is to restrict the use of molecular screening tests for
identifying disease susceptibility to individuals in
“clinically appropriate” categories, e.g., populations at
risk (18 ). Furthermore, assessing risks for such chronic
diseases as diabetes, hypertension, and cancer is eco-
nomically efficient, because it will substantially reduce
the burdens of treatment and follow-up for extended
periods of time. It is also advantageous to focus on
identifying the diseases with known interventions that
can modify or alleviate disease progression (18 ). An-
other practical approach is to look for molecular
changes that are directly related to short-term benefits
for managing patient outcomes. Several genomic stud-
ies have tried to identify patients with the greatest like-
lihood of receiving short-term benefits from whole-
genome sequencing tests, specifically in the areas of
diagnosis and management (19 –21 ).
INTEGRATED GENOMICS DATABASES
Several genomewide association studies have applied
analyses of single-nucleotide polymorphisms (SNPs)5
to assess for the presence of genetic variants in different
individuals and their potential associations with dis-
ease risk. The first successful study, published in 2005,
investigated age-related macular degeneration (22 ).
Since then, thousands of genomewide association stud-
ies of humans have investigated ⬎200 diseases and
traits, and almost 4000 SNP associations have been
identified (23 ). On the oncology frontier, several inter-
national projects have been developed to catalog mul-
tilevel somatic alterations in cancer through analyses of
exome sequences, DNA copy numbers, promoter
methylation, and mRNA and microRNA (miRNA)
production. These projects include the Cancer Ge-
nome Atlas (http://cancergenome.nih.gov/) (24 ), the
Cancer Genome Project (25, 26 ), and the International
Cancer Genome Consortium (25 ). Furthermore, to al-
low broad analyses of genomic variation in several dis-
ease conditions, the NIH has launched various initia-
tives, including providing support for genome analyses
of participants in the Framingham Heart Study, col-
lecting samples from infants in the National Chil-
dren’s Study, and conducting genetic analyses of 20
different types of tumors (2 ). Other informative ini-
tiatives include cataloging the variation among
healthy individuals, such as the 1000 Genomes proj-
ect (http://www.1000genomes.org/).
Also evolving are new databases that incorporate
multilevel molecular information for assessing disease
risk and responses to different drugs. The accumulat-
5
Nonstandard abbreviations: SNP, single-nucleotide polymorphism; miRNA,
microRNA; iPOP, integrative personal omics profiling.
160 Clinical Chemistry 59:1 (2013)
ing evidence suggests that integrating multiple levels of
molecular data holds great promise for refining our
understanding of disease pathogenesis and patient
management (14, 27, 28 ). Appropriate data collection
and database integration will be necessary to efficiently
assess the potential clinical and biological importance
of rare genetic variants (1, 29 ).
Moreover, now becoming available are several na-
tional and international public databases that integrate
different levels of molecular high-throughput analyses
to draw meaningful “actionable” conclusions that can
help in managing patients. Examples of such databases
are i2b2 (Informatics for Integrating Biology & the
Bedside; https://www.i2b2.org) (30 ) and locus-specific
mutation databases, such as the Human Gene Muta-
tion Database, or HGMD (http://www.hgmd.cf.ac.uk/
ac/index.php) (31 ). Several databases also catalog so-
matic mutations occurring in different cancers (32 ).
The promising preliminary analyses of such data have
shown that many of these mutations are present in
many types of cancer and that they are targetable via
drug therapy (29 ).
Integrated analyses are best interpreted in the clin-
ical contexts of a specific patient, such as medical his-
tory, family history, physical/clinical assessments, im-
munological factors for risk prediction, and so forth
(33 ). Also important is to recognize that molecular
changes are the product of both genomic alterations
and the environment (food, exercise, and so forth) and
that some mutations and SNPs are reflections of envi-
ronmental changes. Therefore, molecular data ob-
tained via high-throughput technologies must be
interpreted in the context of clinical variables and en-
vironmental conditions to provide a better assessment
of a patient’s risk of disease.
MONITORING THE PERSONAL GENOME
A new, promising approach is “integrative personal omics
profiling” (iPOP) (34 ). iPOP combines genomic, tran-
scriptomic, proteomic, metabolomic, and autoantibody
profiles from the same individual to follow their genomic/
transcriptomic composition over long periods— during
times of health and disease. A recent study demon-
strated that longitudinal iPOP can evaluate healthy
and disease states by connecting the genomic infor-
mation with additional dynamic “omics” activities
(34 ). Chen et al. repeatedly collected data from a
single individual over time. The data analysis re-
vealed heteroallelic changes in both the healthy and
disease states, as well as changes in RNA-editing
mechanisms, that would have been masked other-
wise. The results indicated that differential allele-
specific expression is extensive in humans, with es-
pecially distinct differences between healthy and
disease states (34 ). This approach allowed the inte-
Genomic Medicine in Cancer
gration of multiple profiles associated with different
physiological states across multiple time points,
thereby providing detailed information that, owing
to interindividual variability, would not have been
apparent in group studies (34 ). Furthermore, a large
database can be created with complete profiles from
more individuals with different types of diseases.
Such a database may be valuable in the diagnosis,
monitoring, and treatment of diseases (34 ).
DISEASE DIAGNOSIS AND BIOLOGICAL CLASSIFICATIONS
Molecular signatures can be the basis for discovering
new diagnostic markers for many diseases. There is a
wealth of literature on the use of differential gene ex-
pression and protein production for identifying new
biomarkers for early disease detection and assessment
of prognosis (35, 36 ).
As mentioned above, exome sequencing has iden-
tified a novel mutation that permitted a molecular-
based diagnosis for a patient with Crohn disease. On
another interesting frontier, genomic analyses hold
promise for establishing new biological subclassifica-
tions of many diseases, including cancer, which could
change how cancer is managed. Molecular signatures are
now used to classify tumors according to their “biological
behavior,” rather than by their tissue, organ of origin, or
morphology (37 ). Examples of molecular signatures are
documented in the literature. DNA microarray data have
permitted the subcategorization of lymphomas and glio-
blastomas (38 ), and alternative-splicing data obtained
with microarrays have aided in defining breast cancer
subtypes and improving treatment options (39 ). A recent
study has documented that data on the differential pro-
duction of miRNAs are capable of accurately classifying
the different subtypes of kidney cancer (40 ). Another
study has highlighted the ability of unique molecular pro-
files to accurately predict prostate cancer prognosis, espe-
cially in patients with low or average Gleason scores (41 ),
and miRNA production signatures have accurately pre-
dicted the risk of biochemical failure in prostate cancer at
the time of surgery (42 ). In addition, a growing body of
evidence supports the potential utility of genotype
changes for predicting clinical outcome and response to
treatment (43 ).
An important step toward the translation of these
applications to the clinic is the advent of commercially
available systems for screening large numbers of muta-
tions simultaneously. These systems include Mass-
ARRAY (Sequenom; http://www.sequenom.com),
which can be used with predesigned, optimized panels
(such as the OncoCarta™ panel) or custom-designed
arrays. Another system, the IonAmpliSeq™ Cancer
Panel (Invitrogen/Life Technologies), can simultane-
ously analyze 739 COSMIC (Catalogue of Somatic Mu-
tations in Cancer) mutations at 604 loci. Similar plat-
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forms include the MiSeq Personal Sequencer and
HiSeq platforms (Illumina) and semiconductor se-
quencing (Ion Torrent Systems/Life Technologies).
TARGETED THERAPY AND DRUG TRIALS
Molecular information can also be used for improving
treatment, either through development of targeted
therapy or rediscovery of previously failed drugs for use
in subgroups of patients likely to benefit from them
(2 ). The numbers remain small, however, both for
known “actionable” genetic abnormalities and for the
targeted agents that are to be tested within the next few
years (1 ).
Molecular markers can also be used to predict
treatment efficacy so that patients not expected to re-
spond to therapy will avoid unnecessary treatments.
Furthermore, molecular markers can serve as prognos-
tic markers of disease aggressiveness, information that
could be reflected in treatment plans. An interesting
example is the concern regarding “overtreatment” of
prostate cancer patients who have less aggressive forms
of the cancer and would better be candidates for “active
surveillance.” Such patients are awaiting the develop-
ment of accurate molecular markers that can better
guide their treatment choices (44 ). Well-designed pro-
spective clinical trials are needed to measure patient
outcomes for various genomic applications, the advan-
tages of which are not yet evident compared with cur-
rent standards of care (1, 12 ).
Molecular signatures are also expected to revolu-
tionize the eligibility criteria for clinical trials. Cur-
rently, inclusion criteria for clinical trials are organ
based. The availability of molecular data allows the
possibility of switching to pathway-based selection cri-
teria for clinical trial enrollment, rather than organ-
based criteria (37 ). Inclusion criteria for such trials
should allow patients with different tumor types to en-
roll in a study as long as they have the biological targets
and mutations relevant to the therapy being evaluated.
A recent study has shown that integrative high-
throughput sequencing of patients with cancers in
advanced stages can generate a comprehensive muta-
tional landscape that would facilitate biomarker-
driven clinical trials in oncology (28 ).
Several web-based applications have recently been
established to identify and catalog mutations that have
therapeutic implications and can affect patient enroll-
ment in clinical trials. One such endeavor is My Cancer
Genome (http://www.mycancergenome.com) (45 ).
Another interesting area to explore is to apply
genomic approaches to pharmacogenomics. Genomic
analysis can play an important role in predicting treat-
ment efficacy for individual patients (46 ). To appreci-
ate the importance of pharmacogenomics, consider
that ⬎2 ⫻ 106 adverse drug reactions occur annually in
Clinical Chemistry 59:1 (2013) 161
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the US alone. The approximately 1000 deaths that re-
sult make adverse drug reactions the fourth leading
cause of death (47 ). Moreover, the estimated annual
cost of drug-related morbidity and mortality in the US
is ⬎$76 billion. Added to this is the waste of medica-
tions administered to the patients who do not respond.
On average, a given medication will have a therapeutic
effect in only 25% to 60% of patients (48 –50 ).
Treatments guided by pharmacogenomic evalua-
tions will also overcome an important limitation of
current treatment strategies, which base drug efficacy
on the average response in clinical trials, not the re-
sponses of the individual patients. The reality is that
responses to treatment vary greatly among individuals;
thus, the optimal approach is to determine targeted
therapies individually, in accordance with the unique
genetic composition of each patient (46 ).
THE ROLE OF PROTEOMICS IN GENOMIC MEDICINE
Currently, most techniques for personalized medicine are
based on genomics; however, proteomic techniques—
including measurement of individual circulating or
tissue-based proteins, identification of disease-specific
posttranslational modifications, and generation of
prognostic/predictive protein signatures for fluids or
tissues—are increasingly being used to assist in diagno-
sis, prognosis, therapy selection, and predicting thera-
peutic responses to drugs (25, 51–53 ). Historical pro-
teomic tests, such as measuring estrogen and
progesterone receptor proteins in breast tumor tissues
to predict a patient’s response to tamoxifen, are still
widely used. Recently, mass spectrometry has been
used to identify pancreatic cancer proteomes. These
efforts have led to the identification of new candidate
biomarkers, including at least 1 marker, CUZD1 (CUB
and zona pellucida–like domain-containing 1), that
has a sensitivity and a specificity superior to the cur-
rently used cancer antigen marker CA19-9 (54 ). Others
have used these techniques to identify markers of tax-
ane sensitivity in breast cancer patients receiving adju-
vant paclitaxel and radiation therapy (55 ) and to iden-
tify new prognostic biomarkers (56 ).
We anticipate that we will soon be able to quantify
thousands of proteins and assess the function or disease
of many organs simply by using a drop of blood (57 ).
New Challenges for Genomic Medicine
We are witnessing a revolutionary era with a large
number of omics, including genomics (chromosomes,
SNPs), epigenetics (methylation, miRNA), transcrip-
tomics (mRNA, splice variants), proteomics, cyto-
kines, metabolomics, antibody-omics, and micro-
biomics. Another interesting emerging field is
“metagenomics,” the study of host–microbe genomic
162 Clinical Chemistry 59:1 (2013)
Table 3. Potential challenges of the era of genomic
medicine.
1. Data interpretation and extraction of actionable items
2. Guidelines for implementing new molecular testing
3. Cost-effectiveness of molecular testing
4. Patient heterogeneity and ethnic variation
5. Test optimization and standardization
6. The risk of incidental findings and false-positive results
7. Need for training and teamwork efforts
8. Between-platform variation in results
interactions, the goal of which is to gain a better under-
standing of diseases with complex etiology, such as in-
flammatory diseases, in which microbial elements play
a role in pathogenesis (58 ). On the one hand, metag-
enomics analyses may facilitate a much better under-
standing of pathogenesis at the pathway level of analy-
sis (59 ). On the other hand, however, extracting
meaningful information from these multilevel analyses
is becoming more difficult. There is a need to focus on
developing interpretation pipelines for omics investi-
gations that identify “actionable” or “druggable” items
that can directly improve patient outcomes and that
can connect all the steps between the identification of a
potential therapeutic target in the laboratory setting
and the approval of a therapy for clinical use (i.e., mov-
ing candidate compounds into commercial develop-
ment) (60 ). An interesting strategy that also shows
promise is the classification of molecular changes into
those that represent the “primary etiology” and those
that are “contributing modifiers,” because, ultimately,
not all that glitters is gold.
By the time a cancer is diagnosed, billions of cells
containing gene abnormalities have already been pro-
duced, and many secondary genetic mutations are be-
ing acquired. Some of these secondary mutations may
be drivers (mutations selected for during tumorigene-
sis), and some may be passengers (incidental or effector
mutations). Mutations in both classes arise via such
processes as mutational exposures, genome instability,
and large numbers of cell divisions (61 ). Driver genes
are ideal candidates for actionable targets.
The goal of delivering genetic testing to patients
faces several challenges, including determining which
genetic markers have the most clinical importance,
limiting the off-target effects of gene-based therapies,
conducting clinical trials to identify genetic variants
that correlate with drug response, and regulating ge-
netic testing to protect patients while still encouraging
innovation (2 ). Table 3 is a partial list of some of the
potential challenges to be addressed. Some of these
challenges have recently been addressed in detail (25 ).
Genomic Medicine in Cancer
DEVELOPING AND IMPLEMENTING NEW MOLECULAR TESTS
A challenge that should be considered is the setting of
rules for implementing new molecular testing in the
clinical laboratory. Currently, the trigger for molecular
testing can come from the treating physician in re-
sponse to information obtained from a recent journal
article or at a meeting. The trigger can also be a new
program initiative at the institution. A substantial pro-
portion of new molecular testing is driven by the pa-
tient in response to the electronic media. A well-
structured committee should be in place to evaluate
new testing on the basis of cost-effectiveness and the
higher levels of confidence that evidence-based medi-
cine requires (62, 63 ).
Among the technical challenges that should be
considered when developing a new test is the variation
between different platforms that measure the same
molecular changes. A recent study of 7 diseases dem-
onstrated an agreement of ⱕ50% between the 2 plat-
forms evaluated (64 ).
Cost-effectiveness remains an important concern
in implementing new molecular tests. In this regard,
molecular testing of markers predictive for targeted
therapy in metastatic cancer represents an ideal model
for application, because patients with metastatic cancer
undergo costly drug therapies that have serious adverse
reactions (65 ). Although a genomics-based predictive
test can be expensive, it may eventually lead to substan-
tial financial savings by excluding a large proportion of
patients predicted to be nonresponders. In addition, it
would substantially reduce the costs of treating side
effects and treatment complications.
It must also be recognized that developing a new
test is a complicated multistep process that continues
after the discovery phase. Validation, especially inde-
pendent validation, is one of the necessary steps to be
completed; others steps include standardization, test
interpretation, the technical range, quality control, and
so on (66, 67 ).
Another important consideration is that “test ac-
curacy” improves with time; consequently, reevaluat-
ing test performance might be necessary. An example
of this consideration is hormone receptor testing in
breast cancer, in which improvements in sensitivity
and specificity for the antibody used and additional
evidence on hormone treatment efficacy prompted a
change in the cutoff for positivity.
THE NEED FOR TRAINING AND TEAMWORK EFFORTS
In the era of personalized genomics, it is important to
emphasize the concept of collaboration rather than
competition. Making the huge costs of such projects
economically feasible requires different centers world-
wide to work together. International legislation will be
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necessary to make the results of all studies publicly
available and easily accessible.
Another important step to be addressed before
personalized genomics can move into clinical applica-
tions is the consolidation of multidisciplinary teams of
clinicians, laboratory scientists, and bioinformaticians
who can extract meaningful information from the mil-
lions of data points regarding molecular changes.
Accompanying the evolution of applications in
genomic medicine is the need to provide caregivers in-
formation about these new applications. Understand-
ing the benefits and challenges of molecular testing is a
key issue that will have to be addressed. Genetic tests
are not perfect because most gene mutations do not
predict outcomes perfectly. Thus, clinicians will need
to understand the specificity and sensitivity of new di-
agnostic measures (2, 12 ). It will also be necessary to
educate clinicians about whether or when to order cer-
tain diagnostic tests. For instance, it would be inappro-
priate to order a test when the clinician is unsure about
how to use the results [e.g., for rare sequence variants in
BRCA16 (breast cancer 1, early onset) and BRCA2
(breast cancer 2, early onset) genes in a breast cancer
patient] (12 ). In addition, the feedback between clini-
cal practice and data interpretation is also an important
factor to consider. The information that clinicians can
give to biochemists and bioinformaticians is poten-
tially crucial.
Equally important is the need to train the new gen-
eration of clinicians and laboratory scientists to under-
stand the different dimensions of these evolving
applications. Training programs, such as the TRIG
(Training Residents in Genomics) curriculum (http://
www.pathologytraining.org), have already been estab-
lished. Studies have suggested that the “genetic liter-
acy” of the general public is inadequate to prepare
citizens for this unprecedented access to genomic in-
formation. Given that the current generation of high
school students will come of age in an era when per-
sonal genetic information is becoming increasingly
used in healthcare, ensuring that students understand
the genetic concepts necessary to make informed med-
ical decisions is of vital importance (68 ).
THE RISK OF THE INCIDENTALOME IN GENETIC TESTING
As the number of combined tests increases, the false-
discovery rate will become very high, perhaps reaching
60% if 10 000 SNPs are analyzed simultaneously. This
increased false-positive rate represents a phenomenon
known as the “incidentalome,” a concatenation of a
6
Human genes: BRCA1, breast cancer 1, early onset; BRCA2, breast cancer 2,
early onset.
Clinical Chemistry 59:1 (2013) 163
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Fig. 1. Schematic showing the multistep process of translating genomics into the clinical setting.
Multilevel molecular analysis should be integrated and interpreted by a multidisciplinary team that will decide on the proper
clinical implementation. Genomic markers can be used to assess disease risk or serve as diagnostic or prognostic markers; they
can also have therapeutic applications. aCGH, array-comparative genomic hybridization.

huge number of complex positive findings that are
poorly understood (16 ).
Kohane et al. highlighted the fact that substantially
increasing the number of tested molecules will produce
substantial increases in the numbera of false-positive
results, especially in a population with a low disease
prevalence (16 ). That will create several problems, in-
cluding unnecessary and costly follow-up studies for
falsely identified diseases. Such studies will add to the
already burdened healthcare system.
The lack of accuracy and precision for screening
tests will put physicians into the challenging situation
of either ignoring the results of incidental findings
(with the subsequent risk of liability) or expending
more resources to perform confirmatory “gold stan-
dard” testing. Several steps have been suggested to re-
duce the impact of the incidentalome. They include
assessing the overall disease prevalence and using in-
formation system technologies to understand the
“real” risks associated with positive results in screening
tests and to help physicians make cost-effective deci-
sions. We obviously have a long way to go before we
truly understand the relationship between the millions
of SNPs and disease risk. Interestingly, even SNPs that
have a documented effect on the population with dis-
ease might not confer a risk for the same effect in an
asymptomatic general population (69 ).
PATIENT HETEROGENEITY AND ETHNIC VARIATION
Ethnic variation should be considered when interpret-
ing genomic data and should be carefully addressed
when translating results of high-throughput genetic
analyses to the clinic. Another important challenge is
the heterogeneity that exists among patients with the
same cancer type. Recent studies have shown that only
a small number of gene mutations (also called “moun-
tains”) are present in the majority of a large population
of patients with a particular cancer, whereas most other

164 Clinical Chemistry 59:1 (2013)

Genomic Medicine in Cancer
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genes (known as “hills”) are mutated less frequently.
Studies of cancer genome landscapes have found gene
“mountains” in a large proportion of tumors and gene
“hills” in ⬍5% of tumors (70 ); however, most muta-
tions in cancers that are likely to be driver mutations do
not occur in mountains. Ultimately, the hills drive tu-
mor progression (70 ). The landscape of individual pa-
tients has also been shown to overlap very little with the
overall landscape of consensus mutations. This fact ac-
counts for the great heterogeneity in biomarker expres-
sion observed among cancer patients (70 ). Adding to
the complexity of the problem is the fact that not all
driver mutations that occur with tumor progression
are essential for tumor maintenance; consequently,
they may not be good therapeutic targets (61 ). The
ability to identify driver mutations and to distinguish
them from the many incidental mutations will help in
capturing the full genetic heterogeneity in cancer, a feat
that will require a very large sample size (61 ).
Another interesting obstacle is the presence of in-
tratumoral heterogeneity. A recent elegant study has
shown that analyzing a single sample obtained from a
single region of a tumor can underestimate intratu-
moral heterogeneity (i.e., the tumor’s genomic land-
scape). Such heterogeneity may present a big challenge
for biomarker-identification approaches. It can also af-
fect therapeutic choices (71 ).
ETHICAL AND LEGAL CONSIDERATIONS
Several ethical considerations should be carefully ad-
dressed. They include the accessibility of test results, espe-
cially for other family members who might be at risk for
the same disease, prospective employers, and legal au-
thorities (72 ). Another interesting point is the reporting
of incidental findings. Should the patients be informed of
only results that are directly related to the disease of con-
cern, or should all results, including incidental findings,
be reported? There are also concerns about reporting the
potential risk of developing a disease for which no pro-
phylactic measures exist and whether such reporting
would lead to anxiety in the patient. The issue of securing
these large amounts of data is also a concern (73 ). Patent-
ing issues (Who owns the genes?) is another ongoing de-
bate in the scientific community. Finally, direct-to-
consumer genetic testing should be evaluated cautiously
in terms of its reliability and the impact of these tests on
the public. In addition, providing these tests to the public
must be regulated (72 ).
Concluding Remarks
Despite the many existing challenges, there is light at
the end of the tunnel. The cost of high-throughput
analyses has dramatically declined. For instance, $1000
full-genome sequencing will become a reality in the
very near future. Additionally, targeted approaches
that focus on specific “actionable” molecules will bring
down the costs of molecular testing to a very reasonable
level (28 ). Furthermore, the costs of whole-genome se-
quencing will be small when they are amortized over an
individual’s expected lifetime, because the baseline
genomic information can be consulted at any stage of
life. Finally, as the cost of biomarker discovery de-
creases, the rate of discovery will accelerate (12 ).
We are indeed moving into a new revolutionary
era of personalized medicine. The recognition of the
merits and limitations of genomic medicine can guide
us to more-realistic expectations and foster new direc-
tions for research (74 ). At present, we can generate
data much faster than we can interpret them. Fig. 1 is a
proposed outline of the multistep process required to
achieve “real-life” applications of high-throughput
genomic data. The contribution of genomic analysis is
no longer controversial (69 ), and genomic data, com-
bined with transcriptomic, proteomic, and metabolo-
mic data, are expected to provide a much deeper un-
derstanding of the healthy and disease states (10 ).
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 3 re-
quirements: (a) significant contributions to the conception and design,
acquisition of data, or analysis and interpretation of data; (b) drafting
or revising the article for intellectual content; and (c) final approval of
the published article.
Authors’ Disclosures or Potential Conflicts of Interest: No authors
declared any potential conflicts of interest.

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