Am J Clin Pathol 2012;138:31-41 31
31 DOI: 10.1309/AJCPXBA69LNSCVMH 31
© American Society for Clinical Pathology
Anatomic Pathology / Genomic Studies and Biorepositories
Comprehensive Genomic Studies
Emerging Regulatory, Strategic, and Quality Assurance
Challenges for Biorepositories
Sandra A. McDonald, MD,1 Elaine R. Mardis, PhD,2 David Ota, MD,3 Mark A. Watson, MD, PhD,1
John D. Pfeifer, MD, PhD,1 and Jonathan M. Green, MD1,4
Key Words: Genomic studies; Biorepositories; Biobanks; Quality assurance; Regulatory standards
A b s t r a c t
As part of the molecular revolution sweeping
medicine, comprehensive genomic studies are adding
powerful dimensions to medical research. However,
their power exposes new regulatory, strategic, and
quality assurance challenges for biorepositories. A key
issue is that unlike other research techniques commonly
applied to banked specimens, nucleic acid sequencing,
if sufficiently extensive, yields data that could identify
a patient. This evolving paradigm renders the concepts
of anonymized and anonymous specimens increasingly
outdated. The challenges for biorepositories in
this new era include refined consent processes and
wording, selection and use of legacy specimens, quality
assurance procedures, institutional documentation,
data sharing, and interaction with institutional review
boards. Given current trends, biorepositories should
consider these issues now, even if they are not currently
experiencing sample requests for genomic analysis.
We summarize our current experiences and best
practices at Washington University Medical School, St
Louis, MO, our perceptions of emerging trends, and
Comprehensive Genomic Analyses as Part
of the Ongoing Genetic Revolution
Given the molecular basis for many diseases, investiga-
tors have long used nucleic acid sequencing approaches to
find the aberrations that occur in genes and, by inference, their
downstream transcription and protein products. A profound
revolution in medicine is underway, as advanced sequencing
technology (also known as next-generation or massively par-
allel sequencing1) has yielded ever larger amounts of data at
progressively lower costs. Thus, genetic changes underlying
malignancy and other diseases can be found across the major-
ity of the genome rather than within one or a few individual
genes. Within the last few years, it has become feasible (from
cost and resource standpoints) to sequence all 3 billion base
pairs in a human genome (whole genome sequencing [WGS]),
or the protein-coding portion (whole exome sequencing
[WES]), consisting of most of the predicted 180,000 exons,
or about 1% of the overall genome.2,3 Other approaches
include genome-wide association studies (GWAS), which
have identified multiple common alleles that are associated
with breast cancer risk in the general population.4-6 Also there
is transcriptome sequencing,7 in which complementary DNA
is analyzed to study the RNA transcriptome (ie, complete
RNA transcribed material) associated with a genome.
Compared with earlier approaches that could analyze
only one or a few genes at a time—requiring a focused
hypothesis as to which genes or regions should be targeted—
comprehensive genomic studies such as the aforementioned
can expose a more complete spectrum of common and rare
mutations underlying human malignancies on personalized
Upon completion of this activity you will be able to:
• identify the regulatory issues that govern, or are currently evolving
in, biospecimen science relating to the use of banked samples for
• identify the key quality assurance principles and operational practices
that govern the selection, evaluation, use, and data generation for
biospecimens for genomic studies.
The ASCP is accredited by the Accreditation Council for Continuing
Medical Education to provide continuing medical education for physicians.
The ASCP designates this journal-based CME activity for a maximum of 1
AMA PRA Category 1 Credit ™ per article. Physicians should claim only the
credit commensurate with the extent of their participation in the activity.
This activity qualifies as an American Board of Pathology Maintenance of
Certification Part II Self-Assessment Module.
The authors of this article and the planning committee members and staff
have no relevant financial relationships with commercial interests to disclose.
Questions appear on p 157. Exam is located at www.ascp.org/ajcpcme.
by guest on December 28, 2015
32 Am J Clin Pathol 2012;138:31-41
32 DOI: 10.1309/AJCPXBA69LNSCVMH
© American Society for Clinical Pathology
McDonald et al / Genomic Studies and Biorepositories
and epidemiologic levels. This yields previously unknown
causal or association data and helps facilitate new therapies.
For example, in an attempt to find causative mutations in
acute myeloid leukemia, the Washington University Medi-
cal School (WUMS) Genome Institute (St Louis, MO) used
massively parallel sequencing initially to sequence the com-
plete tumor and normal genomes from a patient with acute
myeloid leukemia, with the identification of tumor-unique
alterations through comparative analyses of the 2 genomes.8
Subsequently, the Institute has performed this type of data
collection and analysis on hundreds of tumor and matched
normal samples. Such technology has growing relevance,
given not only the continuing lack of effective therapies for
many malignancies but also the increasing recognition of
how genetically complex human neoplasia is. Mutations in
genes associated with carcinogenesis may clearly be associ-
ated with clinical and demographic factors and impact the
optimal choice of therapy.9
Rarer or unsuspected mutations found by genome-wide
approaches are important because they potentially reveal new
clues to tumorigenesis and many nonneoplastic diseases (eg,
inflammatory bowel disease, diabetes, cardiovascular disease,
and schizophrenia) and may be a basis for novel therapies,
especially for select groups of patients. Significantly, rarer
mutations (which can occur as somatic mutations in disease
lesions or constitutional, disease-causing mutations) could be
missed without the patient and specimen numbers and con-
sequent statistical power enabled by biorepositories and their
partnerships with clinical studies. Also, rarer but significant
mutations could be missed by earlier technologies not using
a comprehensive genome-wide approach with the exquisite
precision of DNA sequencing.
The enormous growth in genetic information created by
novel approaches poses marked challenges for informatics
resources and storage, but also opens up exciting new pos-
sible avenues of growth for medicine. We can envision a day
in which the physical storage of tissues and biofluids will
assume secondary importance to the banking of data itself—
disease and matched nondiseased specimens will undergo
comprehensive genomic analysis, and the data will be stored
and evaluated quickly after procurement and routinely used
as a basis for personalized medical therapies. Newly gener-
ated genomic data (such as a recurrent tumor) will be rapidly
compared with archived data (such as a previously resected
primary tumor and reference germline) and all common and
rare mutational differences identified and used in real-time
decisions for therapy—the genomic analogy to the traditional
pathologist role of evaluating new material under the micro-
scope and comparing it with previous slides.
The power of genome-wide approaches carries novel
ethical challenges. These challenges affect personnel who
direct and manage biorepositories, along with the physicians
obtaining and using the specimens, the health care facilities
where the biorepository operates, and institutional review
boards (IRBs) charged with reviewing the research. A unique
central issue is that the research activity itself—genomic
sequencing of a biosample, beyond a certain threshold and
potentially including any of the aforementioned types of
genetic studies—may yield enough data to identify a patient.10
This situation stems from the enormous breadth of infor-
mation that can be ascertained genome-wide, rather than from
just a select number of genes using older approaches using
directed polymerase chain reaction and capillary sequenc-
ing, for example. This situation is also quite distinct from
pathology techniques commonly applied to banked specimens
(eg, Western blotting and immunohistochemical analysis) in
which the data are not sufficiently comprehensive to identify
a patient. The profound implication: The traditional hierarchy
of identified, coded, deidentified, and anonymized/anony-
mous specimens11 on which biorepositories have based so
much of their past operating practices now is largely outdated
and needs to be rethought. In particular, once a banked sample
is used in a genomics-based study, the notion of absolute ano-
nymity is altered, even though, technically speaking, samples
destined for this purpose can still be “deidentified” by being
physically stripped of personal identifiers (and assigned a
specific, highly secure coding system as a privacy safeguard)
before analysis. It should be noted that although a person’s
genotype may be decoded by advanced molecular techniques,
the person technically still cannot be identified without a sec-
ond event that yields similar information and the 2 data sets
then compared with each other.
Along with the patient identity concern, genomic research
carries with it other risks, some previously established but
now enhanced by the increasing “reach” of technology: Com-
prehensive genomic analysis will often reveal information
about the subject that was not the intended aim of the research
protocol, so-called incidental findings.12 Also, information
may be revealed that impacts third parties, ie, relatives of the
participant, who might not have been part of the informed
consent process.12 Such information has a direct bearing on
the future health and welfare of the subject and/or relatives.
The research may also reveal unexpected information with
potentially harmful consequences, such as data regarding
relatedness to other family members, criminal liability, and
aspects of future insurability not specifically protected by
the Genetic Information Nondiscrimination Act.13 There
are mechanisms, of course, for protecting genomic data and
certifying persons who have access to it, some of which are
addressed further on. However, inherent in any statement or
acknowledgment of risks is that no method of protection or
informatics firewall can be considered absolutely secure.
Given the broad data sharing often required as part of
these studies, when coupled with the identifiable nature of the
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41 DOI: 10.1309/AJCPXBA69LNSCVMH 41
© American Society for Clinical Pathology
Anatomic Pathology / Review Article
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