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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
CA Cancer J Clin. Author manuscript; available in PMC Feb 19, 2013.
Published before final editing as:
PMCID: PMC3346864
NIHMSID: NIHMS350241

Genetics, Genomics and Cancer Risk Assessment: State of the art and future directions in the era of personalized medicine

Jeffrey N. Weitzel, MD,1 Kathleen R. Blazer, EdD, MS, CGC,1 Deborah J. MacDonald, PhD, RN, APNG,1 Julie O. Culver, MS, CGC,1 and Kenneth Offit, MD, MPH2

Abstract

Scientific and technologic advances are revolutionizing our approach to genetic cancer risk assessment, cancer screening and prevention, and targeted therapy, fulfilling the promise of personalized medicine. In this monograph we review the evolution of scientific discovery in cancer genetics and genomics, and describe current approaches, benefits and barriers to the translation of this information to the practice of preventive medicine. Summaries of known hereditary cancer syndromes and highly penetrant genes are provided and contrasted with recently-discovered genomic variants associated with modest increases in cancer risk. We describe the scope of knowledge, tools, and expertise required for the translation of complex genetic and genomic test information into clinical practice. The challenges of genomic counseling include the need for genetics and genomics professional education and multidisciplinary team training, the need for evidence-based information regarding the clinical utility of testing for genomic variants, the potential dangers posed by premature marketing of first-generation genomic profiles, and the need for new clinical models to improve access to and responsible communication of complex disease-risk information. We conclude that given the experiences and lessons learned in the genetics era, the multidisciplinary model of genetic cancer risk assessment and management will serve as a solid foundation to support the integration of personalized genomic information into the practice of cancer medicine.

Keywords: Genomics, genetic cancer risk assessment, genetic counseling, prevention, genetics, hereditary cancer

Introduction

Scientific and technologic advances in genomics are revolutionizing our approach to genetic counseling and testing, targeted therapy, and cancer screening and prevention, fulfilling the promise of personalized medicine. Features of genetic counseling that pose emerging challenges to oncology and other healthcare providers include: the focus on the family as well as the individual; the emerging role of testing for common as well as rare genomic markers of cancer susceptibility; and the role of the oncologist in the communication of non-oncologic health risks. For physicians, genetic counselors, nurses, and other members of a multidisciplinary cancer care team, the future of personalized medicine is now; however, the current enthusiasm about personalized genomics follows several decades of scientific discovery and clinical translation in human genetics. By analyzing the lessons learned during the development of genetic cancer risk assessment and management, we will define the scope of the challenges currently faced by practitioners seeking to integrate genomic technologies into medical practice.

The Genetics of Hereditary Cancers: The first decades of discovery and translation

Today, personalized medicine, informed by a molecular understanding of disease, has resulted in new classification systems as well as more effective preventive and therapeutic interventions. The National Cancer Institute (NCI) defines personalized medicine as “a form of medicine that uses information about a person’s genes, proteins, and environment to prevent, diagnose, and treat disease.” Simply put, the field of genetics refers to the study of single genes, and the emerging field of genomics refers to the study of all of a person’s genes.1 While the computational challenges of genomics are daunting, the translation of genomics to clinical care derives squarely from genetics practice. Indeed, single or multiplexed genetic profiles (DNA analysis of a single gene or set of genes) have been applied to pre-symptomatic risk assessment, as well as to diagnostic, prognostic, and therapeutic application in several fields, notably cancer care. In oncology, the use of presymptomatic genetic testing and “targeted therapies” tailored to genetic profiles of tumors is part of recommended evaluation for cancers of the colon, lung, breast, and other sites.26

The discussion presented here assumes that personalized genomics must meet the same evidentiary standards as other components of personalized medicine. Thus it is important to state at the outset that the perspective offered here does not recognize a special claim to the “personal utility” of genomic tests for medical conditions outside of a medical context. The requirements for clinical validity and utility of genomic tests are discussed elsewhere2, 7 and the roles for alternate models of provider delivery of genetic and genomic information are presented later in this monograph. The scientific foundation for personalized genomics draws on a range of disciplines including basic genetics, population genetics, genetic and clinical epidemiology, behavioral science, and emerging regulatory science. The clinical foundation of personalized genomics is the practice of medicine; indeed, many clinicians have been integrating personalized genetic services as part of their practice for many decades.89 It is therefore instructive to review some of the insights gleaned from the recent period of scientific discovery and translation to practice of genetic medicine, since the lessons learned are directly relevant to the challenges facing personalized genomics.

The Impact of Genetics and Genomics on the Practice of Cancer Medicine

As depicted in Figure 1,1030 there is now more than a century of experience in the translation of research in genetics and genomics to the practice of cancer medicine. At the turn of the century, the seeming conflict between the “infectious” and “chromosomal” models of cancer causation, represented by the work of Rous and Boveri, respectively, was resolved when the role of proto-oncogenes and retroviruses were unraveled a half a century later. There was a revolutionary aspect in the discovery that human homologues of retroviral oncogenes were present in the normal human chromosomal complement, and that these same genes were dysregulated by chromosomal abnormalities observed in both liquid and solid human tumors.31 More relevant to the model of human cancer susceptibility was the derivation of the “Knudson two hit model” of retinoblastoma, and its empiric validation in the discovery of “tumor suppressor genes” observed as heterozygous mutants in the germline, but with both alleles missing or mutated in the tumor genome.12

FIGURE 1
Timeline of cancer genetics to genomic discovery. Depicted is a snapshot of scientific developments capturing a century of experience in the translation of research in genetics and genomics to the practice of cancer medicine.

The positional cloning of genes associated with susceptibility to common cancer of the breast, ovary and colon in the late 1990s was followed by clinical translational studies.24, 3133 Over the course of the past two decades, more than 50 highly penetrant cancer susceptibility syndromes have been linked to inherited mutations in specific genes (Table 1). The rational integration of “high risk” family testing within preventive oncology practice was a major accomplishment of cancer medicine in that time period.24, 89, 3438 Lessons of that experience included the observation that in some cases, a germline mutation in one of several genes presents a very similar clinical phenotype (e.g., BRCA1 and BRCA2 both are associated with breast and ovarian cancer). This concept of genetic heterogeneity has profound implications on strategies for clinical testing. In other cases, a mutation occurring in a different part of the same gene can correlate with different clinical manifestations (e.g., RET mutations in MEN2A and familial thyroid cancer); this concept of genotype-phenotype correlations is also an important consideration in clinical translation.31 Further, interactions between genes and between genes and environmental exposures may also occur, and this polygenic and multifactorial etiology of cancer is a vital concept that applies to both genetic and genomic tests for disease risk. Recently, the application of high-throughput genomic technologies have ushered in a second wave of discovery of both rare and common genetic variants of intermediate penetrance, and have also made possible the genomic profiling of tumors for diagnostic and prognostic uses, facilitating the emerging molecular targeting of cancer therapies.6

TABLE 1
Genes Associated with Hereditary Cancer Predisposition

As shown in Figure 2, the highly penetrant cancer susceptibility mutations (left side of Figure 2) are relatively rare, with the exception of certain “founder mutations” in genetic isolates (e.g., Ashkenazi Jews). Genetic variants discovered recently by scans of hundreds of thousands of single nucleotide polymorphisms (SNPs) in populations of thousands of individuals, have for the most part represented common but very low risk markers, seen at the far right side of Figure 2.39 As will be discussed in a later section of this monograph, with the completion of the map of the human genome and the cataloguing of its normal variation, and with the impending availability of affordable whole exome or whole genome sequence information, this new wave of genomic application is about to impact the practice of cancer medicine. Sequencing technologies are already being applied to detect mutations in human tumors, with the aim of guiding therapy. In the process, comparisons are commonly made between the tumor genome and the germline genetic sequence. For this reason, it is likely that physicians, genetic counselors/nurses, and other allied cancer care providers will be on the front lines of the translation of germline genomics to clinical practice.

FIGURE 2
Phenotypic effect size and frequency of occurrence. In humans, mutations in highly penetrant cancer susceptibility genes are rare whereas mutations in genes conferring low-to-moderate cancer risks are common. (*) Named genes only reflect the most likely ...

Before embarking on the challenges and approaches characterizing the era of personalized genomics, it is important to recognize certain “hard lessons” learned from the practice of “personalized genetics” in cancer medicine. One of the most obvious lessons learned is that the accuracy of the clinical laboratory is as critical as the accomplishments of the research laboratory. Catastrophic results may follow an analytic failure of a single genotype.40 In the genomics era, disparate results of genomic testing for disease susceptibility have already been noted, suggesting suspected analytic or post analytic error.4143 Encouraged by calls from professional societies,2 and as required by statute in some states such as New York, the same quality assurance standards required for genetic tests are being requested of genomic “profiles.”44 A second lesson of the genetics era is the importance of clinical utility, as this is likely to drive integration into clinical care and third party reimbursement. Just as laboratory practices must be standardized, established models in genetic medicine may serve as a useful framework for the clinical practice of genomic risk assessment for cancer.2, 8, 4547

State of the Art and Evolving Models in the Practice of Genetic Cancer Risk Assessment

The Specialty Practice of Genetic Cancer Risk Assessment

Genetic cancer risk assessment (GCRA) is an interdisciplinary medical practice that employs a growing arsenal of genetic and genomic tools to identify individuals and families with inherited cancer risk. Identifying and deciphering the heritable risk factors for cancer in a given individual or family is complex, and raises considerable psychological, social and ethical considerations. Consequently, GCRA has emerged as a specialized clinical practice that requires knowledge of genetics, oncology, and patient and family counseling skills, and involves more provider time than most other clinical services.8, 4851 The American Society of Clinical Oncology (ASCO), the National Society of Genetic Counselors (NSGC), the Oncology Nursing Society (ONS) and other healthcare professional organizations have set forth guidelines outlining standards for the practice of cancer risk counseling, risk assessment and genetic testing.2, 45, 5254 Table 2 summarizes the key components and activities of comprehensive GCRA, which entails one or more consultative sessions with the patient and may vary based on practice setting and available resources. In the context of this article, GCRA practice includes genetic testing as appropriate and the management of at-risk individuals so that they can make informed choices about cancer screening,5557 surgical,5862 and chemopreventive risk management options,6367 as well as genetically-targeted cancer treatment therapies.6869

Table 2
Key Components of the Genetic Cancer Risk Assessment (GCRA) Process

Tools of GCRA Practice

There are several tools that can enable and enhance state-of-the-art GCRA practice. In contrast to most medical practice, wherein the focus is on the individual, the focus in genetic risk assessment includes the family.9Similar to the photo in dermatology or the video in endoscopy, a pedigree drawing is the most concise and informative means of depicting family relational data. The pedigree is also an essential source of data required for most of the validated cancer gene mutation probability and empiric cancer risk predictive models. However, there are numerous challenges to obtaining, qualifying and recording a multigenerational family history. An overview of family history tools and resources is described below, followed by a summary of the key features of predictive models for both genetic mutation probability and empiric cancer risk.

Family History

The challenge of getting clinicians to obtain, review, and update family history is of global relevance to the goals of personalized medicine. Approaches to obtaining and documenting family history for common diseases such as cancer vary considerably.7072 Other than earlier than expected age of cancer (e.g., colon cancer before age 50), family history is the single most important indicator of strong (single gene) hereditary cancer risk for which early recognition and intervention could be lifesaving. While our focus in this monograph is on cancer, there is a genetic component to most chronic diseases; hence, obtaining a thorough family history may also reveal potential risk for complex diseases such as diabetes or heart disease.73 Moreover, failure to recognize features that signal potential hereditary cancer risk may result in malpractice lawsuits.7475 Healthcare clinicians must therefore be prepared to discuss, document and update family history with their patients on a regular basis.

Obtaining an accurate and detailed family history is the cornerstone of genetic counseling,52 cancer prevention,7677 and health promotion.3738, 7882

Details of the family history are most readily apparent when displayed in the graphical representation of a pedigree,83 using standardized nomenclature depicting family relationships, including adoption, consanguinity, and assisted reproductive technology.84 Use of standardized nomenclature also facilitates communication among clinicians and may reduce medical errors. The pedigree format assists in identification of disease transmission patterns and recognition of hereditary cancer syndromes, and also serves to visually depict gaps in family structure (i.e., few family members who have attained or lived to an age wherein it would be possible to observe a pattern of disease, such as cancer) that may limit evidence of these syndromes.85

Key features associated with hereditary cancer and the essential elements of family cancer history documentation are summarized in the sidebar. While the primary care setting presents a clear opportunity for clinicians to identify patients who could benefit from increased screening, risk-reduction interventions, and/or genetics referral,8687 taking a family history can be time-consuming for the busy clinician, and many are not adequately trained to efficiently obtain and document the family cancer history.8889 The validity of patient-reported family history can also be a challenge. A large study utilizing data from the 2001 Connecticut Family Health Study found that reports of breast, colorectal, prostate, and lung cancer were significantly more accurate for first-degree than for second-degree relatives.90 Additionally, the family history is a dynamic measure, with births, deaths and new diagnoses that should be documented at regular intervals.

Family History Tools and Referral Prompts

There are a growing number of resources available to help document family history and identify candidates for cancer risk assessment. A recent review by Qureshi, et al. (2009) identified eighteen family history tools developed for (or applicable to) collecting family history of breast, colorectal, ovarian, and/or prostate cancers in the primary care setting.91 Each tool assesses at least one type of these cancers via self-administered paper- or Web-based surveys or structured interviews. The review includes useful tables describing the cancer type, clinical implementation and other features of each tool. Full details of the review are presented in the 2007 Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services report.87

One example of a simple, single-disease focused tool that can be completed by patients prior to the clinic visit or in the waiting room is the FHS-7, a 7 question paper-based tool used in a public hospital setting in Brazil to identify women with features suggestive of hereditary breast cancer risk.92 Another is the 3-question Colorectal Cancer Risk Assessment Tool, best used as a first pass at identifying persons who may be at hereditary risk for colorectal cancer.93 A breast cancer focused Web-based tool for use by either patients or providers is the Breast Cancer Genetics Referral Screening Tool (B-RST), which can be completed in less than 5 minutes (available at: http://www.brcagenscreen.org/).94 While relatively easy to implement in most clinical settings, brief screening tools and those with a single disease focus do not elicit a thorough family history. Although in the interim these single disease tools will identify many persons appropriate for a genetics referral, efforts to develop simple tools that recognize multiple common hereditary cancer syndromes are warranted.

More complex tools that collect information on multiple cancers include the Genetic Risk Easy Assessment Tool (GREAT) and Jameslink. The GREAT program systematically collects family cancer history extending to third-degree relatives via a patient-completed computer phone interview.95 The data go directly into the pedigree drawing program, Progeny,96 that automatically provides the patient’s three- to four-generation pedigree to the health care provider. Depending upon the individual family characteristics, GREAT may take the patient from a few minutes to nearly an hour to complete.

Jameslink Cancer Risk Assessment Tool is an in-office touch-screen family history computer kiosk designed to be completed by patients.97 The program generates a tailored letter to the patient, outlining qualitative level of cancer risk and recommendations for screening and genetics consultation if appropriate. Responses serve as a screening tool to trigger clinician in-depth review and confirmation of the family history.

Given increasing time constraints in the clinical setting, tools that allow direct entry of family cancer history by patients can facilitate data collection, allowing the practitioner to be fully engaged in review and analysis of the information, rather than simply transcribing it.98 One patient-friendly Internet-accessible tool is the Surgeon General’s “My Family Health Portrait.”99 A copy of the resulting pedigree can be printed, and the unique identifier associated with the family can be used to import the data into other pedigree drawing programs using an HL7 translator (a national standard for transmission of health care information).100 Other lay-person oriented ‘family tree’ software programs are also available.

GCRA programs often use a formal family history questionnaire to obtain information on first, second and third degree relatives. In some programs, written questionnaires have been adapted to scannable format for ease of entry into a pedigree drawing program.101 In other settings, the cancer risk counselor or other staff call patients prior to the consultation to elicit the family history and prompt patients to seek missing information. These strategies help limit the amount of time spent eliciting the family history during the consultation.

Pedigree Drawing and Database Programs

Many GCRA programs utilize a relational database and pedigree drawing program to store and represent family history data. One example of this type of program is Progeny (Progeny Software, Indianapolis, IN).96 Progeny is not specific to cancer, can be customized to clinical and research needs and is available as a stand alone, multi-client server or Web version with a recently-developed patient entry interface.102 Another example is Cyrillic, which has a standard database version with risk calculation capability and a version for working with genetic marker and haplotype data that can be exported to linkage analysis programs.103 Pedigree data can also be assembled in CancerGene,104 which has a suite of breast/ovarian, colorectal/uterine, pancreatic, and melanoma gene mutation probability and cancer risk estimation models, including, respectively, BRCAPRO,105 MMRpro,106 PancPRO,107 and MelaPRO.108

The Hughes riskApps109 system allows patients or clinical staff to quickly enter family cancer history data by answering a series of questions via a tablet or desktop PC, which can also interact with the My Family Health Portrait pedigree program.98 Breast and ovarian cancer risks are generated and printable along with family history and a graphical pedigree. While both CancerGene and Hughes riskApps are also able to use a Webserver version of BRCAPRO,105 (described below) neither can be modified to create custom data fields that may be important in risk assessment.

Family History and the Electronic Health Record

The adoption of the Electronic Health Record (EHR) to store health data poses challenges to providing quality care. Currently, only a text-based description of family history can be included in most EHR systems. Consequently, there are limitations in the ability to generate automated prompts for genetic risk evaluation based on family history content in the EHR. While guidelines and criteria based solely on individual patient characteristics may be a feasible basis for such prompts even in the absence of family history, an accurate and thorough family history is necessary to take full advantage of mutation probability and empiric risk models. The HITECH Act and the Patient Protection and Affordable Care Act place new emphasis on the widespread and meaningful use of EHRs.110111 Thus, it is critical that the EHR be adapted to accommodate the multigenerational relational data depicted in the family pedigree diagram, ideally conforming to standardized pedigree nomenclature.84 The EHR can only have a major impact on quality of care if it contains structured data and if it interacts with robust clinical decision support tools.98 Further, we need initiatives such as the ASCO Quality Oncology Practice Initiative112113 to ascertain and monitor incorporation and use of family history across the spectrum of medical practice.

Armed with knowledge about key features of hereditary cancer and standard-of-care referral guidelines, clinicians should be able to discern and address the concerns of the “worried well” at average or minimally increased cancer risk from persons at higher risk who warrant genetic risk evaluation.

Developing the Differential Diagnosis

After a pedigree is taken, the cancer risk assessment process includes consideration of differential diagnosis of cancer syndrome(s), which is based on the types of cancer in the family. Excellent reviews of the malignant and benign clinical features of each syndrome are available.114115 Knowledge of each of these syndromes is essential for a thorough consideration of the differential diagnosis for cancer genetics assessment. For example, Hereditary Breast Ovarian Cancer syndrome, caused by a BRCA1 or BRCA2 mutation, typically involves breast and/or ovarian cancer but may also include prostate or pancreatic cancers; Lynch Syndrome, caused by the mismatch repair genes, primarily involves colon and endometrial cancer but may also include ovarian, gastric, and other cancers. Some families with breast cancer combined with unusual features may require consideration of rare syndromes. For example, breast cancer onset under age 30 years may be suspicious for Li-Fraumeni Syndrome, patients with a large head circumference and thyroid nodules would be considered for Cowden Syndrome, and mucocutaneous hyperpigmentation could suggest Peutz-Jeghers Syndrome. Often a physical examination to evaluate the presence or absence of physical features of a suspected cancer syndrome is needed. A review of pathology reports may also be necessary to confirm the cancers in the family and distinguish between histological subtypes associated with specific cancer syndromes. Published referral guidelines often highlight patterns associated with specific genes49, 116118

Models and Criteria Used to Estimate Mutation Probability

Several tools are available to estimate the likelihood of detecting a cancer-predisposing mutation. If a BRCA gene mutation is suspected, there are numerous models available to estimate the probability of an individual carrying a mutation (Table 3a). Such models have been reviewed elsewhere119122 and include Couch,123 Penn 2,124 Myriad,125 BRCAPRO,126128 Tyrer-Cuzick,129 and BOADICEA.130 Each of these models incorporates breast and ovarian cancer in first- and second-degree relatives, age of onset of cancer, and Ashkenazi Jewish ancestry, and some are starting to incorporate other racial/ethnic backgrounds. Beyond that, each of the models incorporates different factors as shown in Table 3a and each are utilized selectively based on the characteristics of the patient’s personal and family history.

TABLE 3
Things All Clinicians Can Do Now to Improve Patient Access to GCRA and Personalized Preventive Care

The use of mutation probability models is important for several reasons. First, calculating a probability of a mutation can help clinicians determine who is an appropriate candidate for testing. Second, due to the high cost of genetic testing, numeric calculations of mutation probability may provide supportive evidence for insurance companies. Some major insurers are willing to consider probability estimates for patients who do not meet their specific testing criteria. Third, for psychosocial reasons, patients who are counseled with numeric estimation of the probability of a mutation may have more realistic expectations about the possibility of a positive result. Finally, for concerned patients with a low probability of a mutation, the numeric presentation may provide substantial reassurance supporting recommendations based on empiric cancer risks in lieu of genetic testing.

Similar models exist for mutation probability in Lynch Syndrome, including MMRPRO,131 Wijnen,132 MMRPredict,133 and PREM1,2,6134 (Table 3b). However, in genetic assessment of colon cancer families, it is more common to use established criteria as an indication for testing, including the Amsterdam I,135 Amsterdam II,136 or revised Bethesda Guidelines;137 the Bethesda Guidelines determine eligibility for tumor analysis to detect abnormalities associated with Lynch Syndrome which would lead to germline genetic testing. The identification of Lynch Syndrome patients using population-based testing of colorectal tumors has been reported.138 A recent study highlighted possible health benefits and cost effectiveness of primary genetic screening for Lynch Syndrome in the general population.139

As shown in Table 3b, there are established diagnostic criteria and mutation probability models for Cowden140141 and Li-Fraumeni Syndromes,142143 as well as mutation probability models for a melanoma-predisposing gene (p16)144 and a hypothetical pancreatic cancer syndrome gene.145

The decision to order genetic testing should be based on clinical judgment and medical necessity, not by probability models alone. Several models may underestimate mutation probability in certain situations such as a limited family structure85 or specific tumor characteristics.137, 146 Therefore, probabilities predicted by a model must be interpreted in the context of a patient’s overall personal and family history. The National Comprehensive Cancer Network (NCCN) publishes guidelines on an annual basis to help clinicians determine which patients are appropriate candidates for genetic referral and genetic testing.116117

Interpretation of Personal and Family History (Absolute Risks) and Use of Risk Prediction Models

In the absence of an identified gene mutation, counseling unaffected individuals about their empiric risk of cancer requires careful consideration of the patient’s personal and family history. Several models exist which allow for empiric breast cancer risk estimation including Gail,147 Claus,148 BRCAPRO,126128 Tyrer-Cuzick,129 and BOADICEA130 (Table 3a). All of these models incorporate first degree relatives with breast cancer, but beyond that they differ vastly in which known breast cancer risk factors are incorporated.119121 Several published tools are also available to assess risks for colon, ovarian, lung, melanoma and other cancers, though few are validated.149

Numeric estimates of cancer risk may guide recommendations for appropriate screening and preventive care. For example, the American Cancer Society recommends breast MRI screening for women whose risk exceeds 20% lifetime breast cancer risk150 as calculated by the Claus, BRCAPRO, Tyrer-Cuzick or BOADICEA model. Similarly, chemoprevention with Tamoxifen has been FDA-approved for women with a 5 year breast cancer risk of >1.66% as calculated by the Gail model, based on 50% risk reduction for breast cancer observed in that population.151 Risk assessment also plays a role in guiding recommendations for colorectal cancer screening. For example, for patients with a first degree relative with colorectal cancer diagnosed between age 50 and 60 years, the NCCN recommends colonoscopy screening every 5 years beginning at age 40.152 In summary, the calculation of cancer risk may trigger thresholds of risk, allowing for tailored recommendations based on the patient’s personal and family history.

Clinical Utility and the Role of Multidisciplinary Team Risk Management

A central concept to GCRA, which is applicable to genomic cancer risk assessment and management, is clinical utility. Risk assessment and management of highly penetrant cancer predisposition syndromes was shown to increase adherence to surveillance, associated with diagnosis of earlier stage tumors.153154 One of the first discernable examples of “proof of principle” of the clinical utility of personalized genetics was the identification of early stage malignancies likely associated with better survival following GCRA for hereditary adult and pediatric tumors.62 The detection of microscopic foci of medullary thyroid cancer following “prophylactic” thyroidectomy for MEN2A presaged the observation of microscopic foci of ovarian cancer in risk reducing oophorectomy specimens in the setting of BRCA-linked hereditary breast and ovarian cancer,23 as well as the detection of microscopic cancer in prophylactic hysterectomy specimens in the setting of Lynch Syndrome.155 Indeed, GCRA and risk reducing surgeries are now well-established aspects of preventive oncology.62 The often difficult decision between prophylactic surgery of the breasts versus intensified radiographic screening was informed by emerging prospective data regarding the efficacy of both surgery as well as MRI screening.5, 154 Strikingly, evidence of a decrease in cause specific mortality, as well as all cause mortality, was recently described in the setting of risk reducing surgery following BRCA testing.61 Insights about the role of the BRCA genes in DNA repair have led to the first targeted therapies for BRCA-associated cancers.69, 156157 Similarly, colonoscopic screening has proven efficacy in early detection and/or prevention of colon cancer in Lynch Syndrome.158 Even before these studies demonstrated decreased mortality, the available body of evidence for relative efficacy of interventions following genetic risk assessment for cancers of the breast, ovary, and colon was subjected to formal evidence-based documentation of clinical utility.159161

Another key aspect of GCRA is the multi-disciplinary involvement of genetic counseling and risk management teams. While some genetic counselors work independently or with generalist physicians, nurses, psycho-oncologists, laboratory scientists, ethicists, and support groups also play important roles in personalizing the process of GCRA. Increasingly, genetic counselors, master’s level specialists in both the biology and psychology of genetic risk assessment and testing, are teamed with oncologists, medical geneticists and other medical specialists to deliver comprehensive hereditary cancer risk management. In the era of genomic counseling, the multi-disciplinary model will become even more important, as medical geneticists, computational biologists, genetic epidemiologists, molecular pathologists, and a new generation of laboratory scientists trained in high throughput sequencing will play a vital role in managing the impending tsunami of personalized genomic data.

Barriers to Access and Effectiveness of GCRA

In addition to the published consensus guidelines noted above, since 1999 the NCCN publishes annually updated guidelines indicating when a person should be referred for genetics assessment.116117 providers by geographical location may be found through resources such as the NSGC (http://www.nsgc.org/FindaGeneticCounselor/tabid/64/Default.aspx), the NCI cancer genetics services directory Website (http://www.cancer.gov/search/geneticsservices/), and the NIH Gene Tests Website (http://www.ncbi.nlm.nih.gov/sites/GeneTests/clinic). However, only a fraction of individuals with a personal or family history warranting risk assessment are provided GCRA services. Limited access to and uptake of GCRA services stems from multiple systemic and personal barriers.

Systemic Barriers

Despite efforts to integrate cancer genetic services into mainstream medicine, one significant barrier is the lack of accessible GCRA programs, particularly for persons residing in rural areas far from a major cancer center.162163 The dearth of available GCRA services is in large part related to the limited number of healthcare providers adequately trained in the relatively new field of clinical cancer genetics (workforce needs are discussed below). Other systemic barriers to receiving GCRA cares include the lack of a regular primary care provider or recommendation for GCRA, and limited linguistically and culturally competent providers.162, 164166 As noted above, limited knowledge among physicians about who should be referred, the value of referral, and how to refer also contributes to low referral levels.162163, 165 Time constraints of busy clinicians, perceived low practice priority,167 physician concerns for the cost of counseling/testing,163 and the oft-held misconception that genetic testing will result in genetic discrimination may also discourage referrals.165, 168 Further, failure to obtain and update the family cancer history during patient encounters hinders recognition of potential hereditary cancer predisposition syndromes.169 Low reimbursement relative to the time required impedes provision of adequate risk counseling, particularly for physicians outside of an academic setting.170

Where GCRA services are available, the primary barrier is lack of or insufficient health insurance coverage for genetic consultations, genetic testing, and recommended follow-up care.171174 While insurance coverage and cost is a patient-related barrier, the root issue is also systemic in health care finance in the U.S. In contrast, many public health care systems outside the U.S. provide more support for genetic services. Most published studies of GCRA uptake and outcomes involve populations dominated by higher socioeconomic and educational status.175176 Although difficult to quantify, many people who are referred never make an appointment or cancel appointments due to lack of coverage, high deductibles or co-pays.177 Furthermore, there are circumstances where genetic testing is clinically indicated and it simply isn’t a covered benefit. This is especially the case for at-risk individuals whose affected family members have died. NCCN and other guidelines do not clearly address the value of genetic counseling, risk assessment, and even genetic testing in these circumstances. The U.S. Preventive Services Taskforce recommendations47 may be overly restrictive and fail to recognize the potential bias against individuals with small families, limited knowledge of their family history, or families with relatives who have not lived long enough to express a hereditary cancer pattern. The NCCN and some insurers have explicitly acknowledged the special circumstance of limited family structure.85, 116

Patient-related Barriers

Understanding and acting on genetic/genomic information is a critical rate-limiting step for both clinicians and patients in the translation of this information to preventive practice.7 To make informed decisions about genetic counseling/testing, risk reduction interventions and lifestyle choices, and to promote effective dissemination of information within families, it is essential that patients understand how genetics/genomics information influences their personal and family’s health. A challenge for providers in effectively conveying risk information is to ensure that patients understand numeric and graphical representations used to discuss risk, which may be difficult even for highly educated patients.178179 Providing written information may aid comprehension of complex health information and decision-making,180181 and is especially warranted for persons with poor health literacy.182 Further, women undergoing evaluation for hereditary breast cancer risk have expressed the need for time to assimilate the volume and complexity of information provided during genetic counseling with the need to make timely decisions.179, 183 Decision aids can help these women contemplate their options, decrease decisional conflict and increase decision satisfaction,184 allowing more time for addressing the emotional elements essential to effective genetic counseling.185

Additional barriers to uptake of GCRA services include lack of awareness of these services or the reason for referral,186 limited knowledge of one’s family cancer history, genetic discrimination, privacy and confidentiality concerns, and fear of stigma and medical consequences associated with a genetic mutation being identified. As noted above, perception of high out-of-pocket costs may also interfere with presenting for GCRA as well as proceeding with recommended genetic testing.187 While many insured individuals will have genetic consultation and testing coverage, some may be unable or unwilling to pay for co-payment or deductible expenses. Additionally, patients referred at the time of cancer diagnosis may find the inter-current stress of the diagnosis and multiple medical appointments deters full engagement in the GCRA process.

Similar to other healthcare services, minority populations are less likely to have access to or uptake of GCRA, partly due to lack of adequate insurance coverage and discrimination fears.166, 188189 Mistrust in the medical system,190 anticipated guilt about passing on a mutation to children and stigma associated with having a genetic condition also contribute to negative perception of breast cancer risk counseling and testing among African-American women.191 Access to care may be hampered by few ethnically sensitive and culturally competent healthcare providers, unfamiliarity with the U.S. health care system, and linguistic isolation.192194 Some studies have suggested that lower level of acculturation for Latinas and African-Americans influences uptake of genetic testing for cancer risk.195197 Although studies have found that race/ethnicity198199 and socioeconomic status (SES) influence uptake of genetic testing, a recent study suggests that regional differences account for lack of awareness of genetic testing for disease risk and attitudes towards this testing more so than ethnicity or SES.200 Nonetheless, the use of bilingual/bicultural cancer risk counselors and Spanish language counseling aides can result in good uptake and effectiveness of GCRA,166, 201 suggesting a positive impact of the availability of culturally tailored services.

Family Communication

A primary motivator for GCRA is concern for and perceived duty to inform relatives of cancer risk.202207 Several studies have found that genetic test results are often shared with at least first degree relatives.202209 Little is known about communications to potentially at-risk distant relatives or what information is communicated beyond the test result. Various factors, including lack of confidence in communicating complex information, gender and age differences, relationship issues (e.g., estrangement/loss of contact), and cultural norms affect risk communications and the quality of the information shared.202203, 205, 210211 Studies also indicate that positive test results are shared more often than uninformative results.207 The lower uptake of genetic counseling/testing for identified BRCA mutations among at-risk paternal relatives and men212 may reflect lack of understanding of the healthcare implications.

Despite the described challenges and barriers to care, the central clinical utility and efficacy of GCRA in promoting risk appropriate cancer screening, prevention and targeted therapy warrants efforts to develop and expand access to competent clinical services.

Current Models for Delivery of GCRA Services

The initial delivery models for cancer risk assessment services emerged out of the academic health care setting, where GCRA is conducted by a multidisciplinary team that includes genetic counselors, advanced practice nurses, one or more physician (generally a medical geneticist or oncologist), and often a mental health professional.46, 213 Rapidly-evolving knowledge of the genetic basis of cancer, national policy mandates and direct-to-consumer and provider marketing by commercial genetic testing vendors has catapulted the onslaught of cancer genetic services offered in the community setting.63, 214219 A number of alternative practice models, such as those described in Table 4, have evolved to extend GCRA services beyond the confines of the academic healthcare delivery system to the broader community. A community-of- practice model that leverages the experience and multidisciplinary nature of academic programs in partnership with community-based providers has many attractive features.220221

Table 4
Evolving Models of Practice for Genetic Cancer Risk Assessment (GCRA)

It is important to note that all of the models described in Table 4 involve some degree of professional mediation of the GCRA process by clinicians with cancer genetics training and experience. Some of these models, particularly those that employ an interdisciplinary team-based approach, combine efficient patient care with best practices in GCRA, while others may not adequately address important nuances inherent in the GCRA process that inform several aspects of patient care, such as optimal testing strategies, appropriate interpretation of uninformative test results, consideration of alternate genetic etiologies, and psychosocial and family communication dynamics. Despite efforts to expand community-based best practices in GCRA, market forces are compelling an increasing number of clinicians with no training or expertise in GCRA to prescribe and interpret predictive genetic tests.34, 215216, 219, 222226 Problems related to absent or inadequate counseling range from genetic testing issues, including inappropriate or incomplete testing and misinterpretation of test results by both patients and clinicians (e.g., considering a variant of uncertain significance to have implications for patients/relatives’ cancer risks; believing that a “negative” result equates to no risk in families where a causative mutation has not been identified) to inappropriate cancer screening/prevention recommendations and psychological issues.2, 227228 Moreover, direct-to-consumer genetic testing has created a third rail of access to personal genetic information that completely circumvents professional mediation, including access to high-risk genetic traits for which there is known clinical utility as well as emerging low-penetrance genomic variants. As highlighted in the recent ASCO policy update,2 creating appropriately-supported models for delivery and interpretation of genomic information and defining clinical utility for emerging moderate and low penetrance variants pose major challenges (Figure 3).

FIGURE 3
Clinical utility of genetic and genomic tests. When considering the future development of germline genetic testing in oncologic care, it is useful to think of tests with regard to their position along two axes. The first axis identifies whether or not ...

Genomic Discovery: The Next Generation of Personalized Medicine

One of the concerns accompanying the emergence of genomics in oncology is the risk of “premature translation” of genomic tests to clinical practice. Indeed, as discussed in the prior sections, the majority of both cancer and non-cancer-associated common variants discovered by whole genome association studies are not believed to be medically “actionable.”2, 160 Unlike the genetic mutations discovered during the past decade, new cancer-associated “genomic” variants are, for the most part, not associated with readily identifiable syndromes or sufficient risk thresholds to spur preventive interventions. During the genetics era, the use of linkage or “reverse genetics” led to discoveries of the basis of single gene disorders, such as breast cancer229 prompting further scientific research into the mechanisms of disease causation, as well as proof of clinical efficacy of interventions. Nonetheless, more than 15 years after the advent of testing for BRCA1, its numerous cellular roles continue to be defined,230 complicating prediction of the functional (hence clinical) significance of some of the mutations (those resulting in single amino acid changes) routinely detected.231

This same pattern is unfolding in the clinical translation of genomic research exploring the functional role of the estimated 50,000 to 200,000 SNPs, which may contribute to disease.232 As in the genetics era, these genomic studies have revealed novel pathways of disease causation, such as the complement pathway in adult onset blindness due to macular degeneration.233 As mechanistic research continues, translation to practice will also occur. For example, it may soon be possible to offer testing for risk modifying variants affecting BRCA2 penetrance,234235 even in the absence of knowledge of their function. As shown in Figure 4, while most of the findings of genome-wide association studies have produced relative risks too low for actionability; in at least two examples, familial testicular cancer and familial myeloproliferative disorders, the point estimates of risk are high enough to consider notifying patients within a research context.39 In the case of other SNPs, it is also true that a very small subset of the population will be at significantly higher risk if they carry two copies of multiple disease-associated variants, and that multiplicative interactions between SNPs may eventually approach thresholds for actionability.236 Analogous to the translation of genetics into clinical practice, translation of newly-discovered cancer genomic risk markers into practice should be carried out in the context of longitudinal research studies, leading to the promulgation and embrace of evidentiary standards.237

FIGURE 4
Genome Wide Association Studies for Cancer. The left axis represents the odds ratio (OR). The horizontal axis depicts the frequency of minor alleles. As shown, the OR associated with developing cancer for most of the alleles is low. Exceptions are the ...

While the proof of clinical utility of genetic or genomic disease predictive markers does not depend on a complete understanding of the biological function of the genetic variant in question, such an understanding remains critical for pharmacologic targeting. The lack of functional models for most disease associated SNPs remains a significant impediment to development of “preventive” drugs. Ultimately, a mechanistic understanding of all the genomic as well as epigenomic changes affecting the germline will be required to accurately predict cancer risk.35, 238 Epigenetic phenomena such as “silencing” of genes by addition of methyl groups which affect critical control regions (“promoter methylation”) do not change the DNA sequence and are not detected on first generation genome scans. Similarly the emerging role of small RNA molecules that also regulate gene expression (micro RNA’s) will also need to be taken into account as part of personalized cancer genomic profiles, since both of these epigenetic and genetic mechanisms may affect risk for diseases such as cancer.

As next-generation sequencing technologies are now being deployed to analyze tumor and constitutional genomes, an impending “data deluge” has descended on cancer genomics. The cost of “next generation” sequencing technologies continues to decrease, facilitating the availability of terabytes of genomic data per patient in the next decade. At the current rate of technological developments, human whole genome sequencing could cost $1,000 by the year 2014, and as little as U.S. $100 by the year 2020.6 However, efforts to deduce potentially pathogenic mutations from the genome of just a single 40-year-old male took over a year of work by a multidisciplinary team at one center.239 The challenges facing routine translation of genomics to practice include: the limitations of current sequencing platforms (e.g., failure to detect structural genomic changes or to distinguish mutations on the same or different chromosomes), the absence of a central repository of rare and disease-causing variants, and the need for longitudinal follow-up to update counseling based on new information.240 It is now estimated that 50 to 100 variants implicated in inherited disorders are identifiable in the “personal genome” of the average individual.241 The interpretation of these findings will require a vastly improved human reference sequence annotation, which are needed as a comparison group to deduce clinical significance from the data.242 It has been observed that the conventional clinical GCRA model of 2-hour multi-visit counseling for a single gene disorder must scale up for counseling for dozens or hundreds of genetic markers of risk.240 One needed resource for counselors and patients will be interactive computer-assisted aids to transmit components of the genomic risk assessment.

Even with advances in computer-assisted risk assessment and counseling, therapeutic and reproductive aspects of genomic counseling will continue to require interpersonal interaction, support, and follow-up. The therapeutic implications of genomic information are becoming well established in cancer medicine.6 A new class of drugs already appears to be of particular benefit to oncology patients with germline BRCA mutations.69, 156157 The current practice of clinical oncology is being transformed by the growing number of pharmacologic agents targeted to specific tumor-derived genomic alterations.6 This is only the first ripple in the tsunami of genomic information that will inform oncology practice. While the Cancer Genome Atlas project has led to new scientific insights, the translation of these findings to personalized therapeutics requires an ability to scan gigabytes of genome sequence and remains a research-in-progress.243244 It is also important to emphasize the parallel yet distinct progress in germline and somatic (tumor-associated) genetics in oncology. At present, tailoring cancer treatment to either germline (e.g., pharmacogenetic) or somatic tumor profiles (e.g., Oncotype Dx, EGFR, BRAF) is a process distinct from GCRA, although the same oncogenic signaling pathways may be involved in disease susceptibility as well as targeted therapy.

Interpreting and counseling about the medical implications of individual germline or cancer-derived genome sequences will likely entail greater investment of human capital and more potential liability than was required in the genetic era.242 Given that it will be easier to generate genomic data than to counsel about it, new approaches to genomic risk notification will require paradigm shifts in both the models of delivery of information to consumers in a medical context and education of health care professions. However, the core principles of GCRA, based on a foundation of evidence-based counseling regarding the clinical utility of testing, should remain a pre-requisite for the responsible translation of genomic technologies. The successful implementation of personalized genomics will also hinge on the continued training of a multidisciplinary work force.

Preparing an Expanded Genomics Workforce

Advances in genetic technology and market-driven pressures notwithstanding, leading stakeholders in medicine strongly recommend that predictive genetic testing be conducted in the context of pre- and post-test counseling, conducted by suitably trained health care providers.2, 4, 116, 159, 245 This recommendation is supported by the nuanced nature of hereditary disease patterns, complex genetic and genomic test information, appropriate prescription of personalized risk management procedures, and the growing body of evidence that documents the emotional and psychosocial needs of the patients who undergo GCRA.43, 85, 175, 183, 207, 246251

As there is no subspecialty practice credential in cancer genetics, a comprehensive roster of experienced GCRA professionals is not available. Currently, most experienced physician GCRA practitioners are licensed and/or credentialed in oncology or genetics. Among allied health professionals who practice GCRA, most are genetic counselors or advanced practice nurses. As of March 2011, the NCI listed 563 cancer genetics specialists on its Cancer Genetics Services database,213 representing an approximate 70% increase in self-registrants who met the criteria for inclusion in this clinical service resource since March of 2006. Although similar increases have also been observed in recent years on other clinical service registries (such as www.genetests.org) and among such professional memberships as the cancer genetics special interest groups of the NSGC and the ONS, there is still a dearth of professionals with interdisciplinary training and expertise in GCRA.

Despite priorities set forth by policy and leadership stakeholders emphasizing the need for cancer genetics education.45, 184, 252261 GCRA education and training resources remain limited. Professional societies and some academic institutions offer cancer genetics seminars, workshops and Web-based GCRA resources, and the ASCO Cancer Genetics & Cancer Predisposition Testing Curriculum is a self-teaching resource for oncologists and other health care providers.38, 262 Toward the goal of promoting practitioner-level competence in GCRA, a multimodal course (supported in part by NCI R25 grant funding) developed by several authors of this monograph combines 12 weeks of distance and face-to-face interdisciplinary-team training followed by ongoing practice-based support for community-based clinicians.89, 220221 To date, 220 community-based clinicians from 47 U.S. states and 7 countries outside the U.S. have completed the course, and despite its rigorous participation requirements, each course offering generates four times more applicants than can be accommodated for training.

It is in this setting of limited GCRA professional workforce, education and training resources that we face the challenge of integrating genomics information into clinical care. Beyond the core interdisciplinary knowledge and skills currently employed in the practice of GCRA, translating complex genomic information into clinically meaningful applications will require understanding the inference of gene-gene and gene-environment risk interactions, epidemiologic, non-cancer risk information, and other nuanced genomic factors that will contribute to the practice of genomically-informed personalized medicine.

It would be close to impossible for the individual healthcare practitioner to master and apply this expanding range of knowledge and skills. Thus, similar to the pivotal role of multidisciplinary team to the integration of genetic discovery into clinical practice, training and promoting multidisciplinary clinical/research teams, comprised of genetics/genomics and oncology specialists, pathologists, biostatisticians, informatics/computational specialists, epidemiologists, behavioral scientists, pharmacists, etc., will be essential to support the effective and responsible translation of genomic information into clinical utility.

Discussion

It is now widely anticipated that the rapid progress in genome science over the past decade, coupled with the declining cost of sequencing technologies, will hasten the arrival of new tools for personalized medicine, with an immediate impact in the field of cancer medicine.6, 263 The computational and counseling challenges resulting from the emerging deluge of next generation sequencing data constitutes a barrier that will need to be surmounted to translate genomics research to practice, and to surmount the approaching eventuality of what one senior geneticist has termed the era of “the $1,000 genome and $100,000 analysis.”264

Just as the rapid progress in genome technologies has outstripped the pace of clinical practice, these genomic breakthroughs now are requiring new regulatory and ethical anticipation and accommodation. For example, in the past year, the House Committee on Energy and Commerce Subcommittee on Oversight and Investigations issued a report on direct-to-consumer marketing of genomics, and held open hearings. Following concerns about the need for new regulatory efforts in this area, device notification letters were sent by the U.S. Food and Drug Administration.44 It can be anticipated over the next decade that commercial genetic testing companies will work with laboratories that are Clinical Laboratory Improvement Amendments (CLIA) approved and seek evidentiary proof of clinical validity and utility of tests offered. The for-profit pressure to directly market genomic tests for disease risk will continue to recede in the face of perceived economic inefficiencies and regulatory requirements for clinical utility, as well as consumer risks inherent in uncoupling medical tests from a context of medical support and follow-up. Federal efforts to support the creation of an evidentiary database for genomic medicine have included the Working Group for the Evaluation of Genomic Applications in Practice and Prevention.265266 However, in the face of continued debate and limited budgets, the future of these vital “impartial brokers” of genomic information may be threatened.

It is important to promote translational behavioral research on factors influencing uptake and responses to genetic/genomic counseling/testing as well as uptake of recommended primary or secondary preventive interventions following risk assessment. As the pace of genomic technologies also tests ethical precepts, the current emerging consensus in the bioethical community is that the issue is no longer if genomic information should be returned to consenting individuals, but how to do this while avoiding harm.267 As mentioned in the course of this discussion, a pressing issue limiting the translation of genomics to personalized medicine is equity and access; there is the risk that these technologies will be available only to the affluent.242 These same concerns have accompanied the clinical dissemination of preimplantation genetic diagnosis for cancer predisposition syndromes.7, 268

The rational and appropriate use of genomic technologies in cancer medicine can be based on several decades of experience in the use of genetics in cancer medicine.2, 7 To a great extent, the challenges facing the practitioner of genomic medicine are similar in substance but far greater in scale when genomic technologies are involved. The model of GCRA outlined here offers a solid blueprint for the foundation of genomic applications in cancer prevention and management. This model will need to be supplemented with next-generation interactive teaching and counseling aids, more efficient means to collect and interpret family history as well as genomic and environmental risk information, a new synthesis of these approaches in training multi-disciplinary cancer genomic risk assessment and management teams, and continuing education to promote a genomically-informed healthcare workforce. Further, the predictive landscape is likely to be augmented in the future by allied sciences such as metabolomics and environmental exposure monitoring.

Efforts to reform public and private healthcare policy and coverage are needed to address gaps in insurance coverage for genetic/genomic analyses as a component of preventive care, and to improve reimbursement relative to the time required for adequate risk counseling, particularly for physicians outside of an academic setting. Additionally, licensure for genetic counselors (currently available in some states) is likely to help facilitate insurer/counselor contracting.

Thus, continued translational research, regulatory protection, as well as professional efforts to educate both providers and consumers will be required to most effectively apply recent advances in genomic research to personalized cancer care and prevention.

TABLE 7
Resources and Activities to Help Clinicians Learn More About Cancer Genetics and Genomics

Supplementary Material

Acknowledgments

We are grateful to Peter Thom, MS, for his help with designing Figure 1, to Dr. Stephen Gruber for his critical reading of the manuscript, and to Tracy Sulkin and Shawntel Payton for assistance with preparation of the manuscript. We also thank participants in the City of Hope Community Cancer Genetics and Research Training Intensive Course (NCI #R25CA112486 PI: JNW) for providing insights about the challenges and rewards of providing genetic cancer risk assessment in community-based practices and the Cancer Genetics Community of Practice.

Financial Support: Supported in part by National Cancer Institute grant #R25CA112486, and grant #RC4CA153828 from the National Cancer Institute and the Office of the Director, National Institutes of Health to Jeffrey Weitzel and City of Hope, and also by support to Kenneth Offit from the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Sharon Levine Corzine Fund at MSKCC, the Lymphoma Foundation, and the Esther and Hyman Rapport Philanthropic Trust.

Glossary

Alleles
Alternate forms of the same gene. Humans typically inherit one copy of each gene (allele) from each parent. Different alleles produce variations in inherited characteristics such as eye color or blood type.
De novo
A mutation present for the first time in a family member. De novo mutations result from a mutation in a germ cell (egg or sperm) of one parent, or a mutation that occurs early in embryogenesis.
Epigenetic
A modification in gene expression that is not due to a change in the DNA sequence of a gene (e.g., DNA methylation).
Exome
The 1% of the human genome that is the most functionally relevant and most likely to cause noticeable phenotypes (physical, biochemical or physiological expression). Comprised of short segments of DNA called exons. The exome provides the genetic blueprint for proteins.
Expressivity
Refers to the variation in phenotype (expression) of one’s genotype (genetic make-up). For example, two individuals may be affected by the same condition with one expressing the condition more severely than the other, due to genetic, epigenetic, environmental, aging, or other factors. Differs from penetrance, defined below.
Genetic heterogeneity
Variation in expression of a specific condition due to either different alleles (allelic heterogeneity, e.g., different mutations in BRCA1 confer high risk for breast and ovarian cancer) or mutations in different genes (locus heterogeneity, e.g., risk for breast and ovarian cancer with either a BRCA1 or BRCA2 mutation).
Genetic isolates
A population that has a similar genetic background because of common ancestry, often due to geographical isolation, cultural selection, or other mechanisms. This sometimes leads to “founder” mutations (mutations common in a specific population, such as the 3 specific BRCA gene mutations that account for most BRCA-related breast and ovarian cancer in persons of Ashkenazi Jewish heritage).
Genome
An organism’s entire set of genetic material (instructions) containing all information necessary to build and maintain the organism.
Genomics
The study of whole-genome structure and function, including the characterization and architecture of genes and their mRNA and protein products, the relationships between genes and proteins of different species, epigenomic mechanisms, and pharmacogenetics.
Genome wide association studies (GWAS)
An approach that examines genetic markers across the entire human genome, with the aim of developing strategies to detect, treat, and prevent disease.
Genotype-phenotype correlations
The association between a specific genetic trait (genotype) and the resulting physical trait, abnormality, or pattern of abnormalities (phenotype).
Germline (aka, constitutional) DNA
Technically refers to the DNA sequence in germ cells (egg and sperm). However, in practice also refers to DNA extracted from nucleated blood cells as germline DNA is the source of DNA for all other cells in the body. Germline DNA is heritable and becomes incorporated into the DNA of every cell in the body of offspring.
Heterozygous
Two different alleles of a particular gene occupying the gene's position on the homologous (similar) chromosomes.
HL-7
Abbrieviated from Health Level Seven (http://www.hl7.org/), is the global authority for developing a standardized framework for the exchange, integration, sharing, and retrieval of electronic health information.
Homologues
The chromosome of a particular pair, one inherited from the mother and one from the father, containing the same genetic loci in the same order
Imprinting
The process by which maternally and paternally derived chromosomes are chemically modified leading to different expression of a certain gene or genes on a chromosome, depending on whether the chromosome is of maternal or paternal origin.
Locus
The position of a gene or copy of a gene (allele) on a chromosome. Plural = loci.
Mendelian
Referring to the Austrian biologist Gregor Mendel (1822–84) who is credited with the basic laws of classical genetic inheritance. The modes of Mendelian inheritance are autosomal dominant, autosomal recessive, X-linked dominant and X-linked recessive.
Metabolomics
The study of complete collection of metabolites present in a cell or tissue under a particular set of conditions that generate a biochemical profile.
MicroRNA (miRNA)
A short piece of RNA (about 22 bases in length) that binds to complementary sequences on target messenger RNA pieces and generally suppresses production of the corresponding protein.
Pedigree
A diagram representing the genetic relationships and relevant health history of members of a family. Pedigree symbols and nomenclature have been standardized (Bennett, French, Resta, & Doyle, 2008) to allow clinicians and researchers to readily identify pertinent details about inherited traits and patterns of disease.
Penetrance
The proportion of individuals with a gene trait who will exhibit the associated trait or phenotype (e.g., Ret gene mutations are nearly 100% penetrant, so nearly all mutation carriers will develop thyroid cancer without prophylactic intervention [thyroidectomy]).
Pharmacogenetics/genomics
Genetically/genomically informed approach to designing drugs and vaccines.
Promoter methylation
An epigenetic modification of a DNA sequence that results from disruption in gene expression by attachment of a methyl group to the DNA at cytosine bases upstream from the gene coding region. For example, non-expression of MLH1on immunohistochemistry (IHC) staining may be a result of methylation rather than a mutation in the DNA sequence. Methylation is also considered the main mechanism in imprinting.
Single nucleotide polymorphisms (SNPs; pronounced “snips”)
A DNA variation occurring when a single nucleotide — A, T, C, or G — in the genome sequence differs from the usual nucleotide at that position. Some SNPs are associated with disease whereas many others are normal variations of the genome.

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