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Cancer Genetics Risk Assessment and Counseling (PDQ®)

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Components of the Risk Assessment Process

        Psychosocial assessment
        Risk perception
Clinical Evaluation
        Personal health history
        Physical examination
        Family history
Determining Cancer Risk
        Analysis of the family history
        Methods of quantifying cancer risk

This section provides an overview of critical elements in the cancer risk assessment process.

A number of professional guidelines on the elements of cancer genetics risk assessment and counseling are available, such as the National Comprehensive Cancer Network Practice Guidelines for Genetic/Familial High Risk Assessment: Breast and Ovarian Cancer.[1-7] Except where noted, the discussion below is based on these guidelines.

The cancer risk assessment and counseling process, which may vary among providers, requires one or more consultative sessions and generally includes the following:

  • A detailed, multifaceted assessment.
  • A determination of the risk of cancer and/or indication for genetic testing based on evidence of an inherited cancer syndrome.
  • Education and counseling.
  • Establishment of a cancer risk management plan.

At the outset of the initial counseling session, eliciting and addressing the consultand's perceptions and concerns about cancer and his or her expectations of the risk assessment process helps to engage the consultand in the session. This also helps inform the provider about practical or psychosocial issues and guides the focus of counseling and strategies for risk assessment.

Psychosocial assessment

The counseling process that takes place as part of a cancer risk assessment can identify factors that contribute to the consultand's perception of cancer risk and motivations to seek cancer risk assessment and genetic testing. It can also identify potential psychological issues that may need to be addressed during or beyond the session. Information collected before and/or during the session may include the following:

  • Motivations for seeking cancer risk assessment.
  • Beliefs about the causes of cancer.
  • Experiences with cancer and feelings, perceptions, concerns, or fears related to those experiences.
  • The influence of cancer experiences and perceptions on health behaviors and cancer screening practices.
  • Cultural, religious, and socioeconomic background.
  • General psychological issues, such as depression or anxiety.
  • Coping mechanisms.
  • Support systems.

Either alone or in consultation with a mental health provider, health care providers offering cancer risk counseling attempt to assess whether the individual's expectations of counseling are realistic and whether there are factors suggesting risk of adverse psychological outcomes after disclosure of risk and/or genetic status. In some cases, referral for psychotherapeutic treatment may be recommended prior to, or in lieu of, testing.[8]

One study has shown that the addition of a colored ecogenetic relationship map (CEGRM) to the psychosocial assessment is feasible for assessing the social milieu in which an individual resides.[9] The CEGRM is a psychosocial assessment tool that expands the family pedigree to include a family systems genogram and ecomap.[10]


Assessing the concept of personal cancer risk and its relationship to genetics is complex and not completely understood. However, the evidence continues to accumulate that a set of evolving factors influences a person’s concept of his or her risk, which may not be congruent with evidence-based quantitative calculations. This assessment includes the following:

  • Experiential and empathetic knowledge.
  • People's beliefs regarding the basis for the occurrence of cancer in themselves and/or their relatives.
  • Sources of information and inaccuracies and/or misperceptions.
  • Literacy level, including health and numeracy.[11,12]
  • Personal theories of inheritance.
  • Patterns of decision making (deliberate vs. experiential).[13,14]

A thorough understanding of these issues can greatly inform genetic education and counseling. These factors influence the processing of risk information and subsequent health behaviors.[14]

Risk perception

The communication of risk involves the delivery of quantitative information regarding what the data indicate about the likelihood of developing illness given various preventive actions. More broadly, however, risk communication is an interactive process regarding the individual’s knowledge, beliefs, emotions, and behaviors associated with risk and the risk message conveyed. Accordingly, the goal of risk communication may be to impact the individual’s knowledge of risk factors, risk likelihoods, potential consequences of risk, and the benefits and drawbacks of preventive actions.

Even before the provision of risk information, the provider may anticipate that the individual already has some sense of his or her own risk of cancer. The individual may have derived this information from multiple sources, including physicians, family members, and the media.[15] This information may be more salient or emotional if a family member has recently died from cancer or if there is a new family diagnosis.[16,17] Additionally, individuals may have beliefs about how genetic susceptibility works in their family.[18,19] For example, in a family where only females have been affected with an autosomal dominant cancer susceptibility syndrome thus far, it may be difficult to convince the consultand that her sons have a 50% risk of inheriting the disease-related mutation. The social-ecological context through which risk beliefs develop and are maintained are important as potential moderators of individuals’ receptivity to the cancer risk communication process and also represent the context in which individuals will return to continue ongoing decision making about how to manage their risk.[20,21] As such, individuals’ beliefs, and the social context of risk, are important to discuss in education and genetic risk counseling.

Perceived risk can play an important role in an individual’s decision to participate in counseling,[22] despite the fact that perceived risk often varies substantially from statistical risk estimates.[23-25]

Clinical Evaluation

Personal health history

Consideration of the consultand's personal health history is essential in cancer risk assessment, regardless of whether the individual has a personal history of cancer. Important information to obtain about the consultand's health history includes the following:

  • Current age.
  • Race and ethnicity.
  • History of benign or malignant tumors, surgeries, biopsies, major illnesses, medications, and reproductive history (for women, this includes age at menarche, parity, age at first live birth, age at menopause, and history of exogenous hormone use).
  • Environmental exposures.
  • Diet and exercise practices.
  • Complementary and alternative medicine practices.
  • Past and current alcohol intake and tobacco use.
  • Screening practices and date of last screening exams, including imaging and/or physical examinations.[4,6,26]

For consultands with a history of cancer, additional information collected includes the following:

  • Site of primary tumor.
  • Age at diagnosis.
  • Tumor pathology.
  • Treatment (e.g., surgery, chemotherapy, and radiation therapy).
  • Bilaterality of disease, if applicable.
  • Current surveillance plan.[4]
Physical examination

In some cases, a physical exam is conducted by a qualified medical professional to determine whether the individual has physical findings suggestive of a hereditary cancer predisposition syndrome or to rule out evidence of an existing malignancy. For example, a medical professional may look for the sebaceous adenomas seen in Muir-Torre syndrome, measure the head circumference or perform a skin exam to rule out benign cutaneous features associated with Cowden syndrome, or perform a clinical breast and axillary lymph node exam on a woman undergoing a breast cancer risk assessment.

Family history

Documenting the family history

The family history is an essential tool for cancer risk assessment. The family history can be obtained via interview or written self-report; both were found to result in equivalent information in a study that utilized a sample (N = 104) that varied widely in educational attainment.[27] Studies suggest that paper-based family history questionnaires completed before the appointment provide accurate family history information [28] and that the use of these questionnaires is an acceptable and understandable family history collection method.[29] However, questionnaire-based assessments may lead to some underreporting of family history; therefore, a follow-up interview to confirm the reported information and to capture all relevant family history information may be required.[30] Details of the family health history are best summarized in the form of a family tree, or pedigree. The pedigree, a standardized graphic representation of family relationships, facilitates identification of patterns of disease transmission, recognition of the clinical characteristics associated with specific hereditary cancer syndromes, and determination of the best strategies and tools for risk assessment.[31,32] Factors suggesting inherited cancer risk were previously discussed.

Both multimedia-based (e.g., Internet) and print-based (e.g., family history questionnaires) tools are currently available to gather information about family history. In the United States, many are written at reading grade levels above 8th grade, which may reduce their effectiveness in gathering accurate family history information. On average, print-based tools have been found to be written at lower reading grade levels than multimedia-based tools.[33]

Standards of pedigree nomenclature have been established.[31,32] Refer to Figure 1 for common pedigree symbols.

Standard pedigree nomenclature; diagram shows common symbols used to draw a pedigree.
Figure 1. Standard pedigree nomenclature. Common symbols are used to draw a pedigree (family tree). A pedigree shows relationships between family members and patterns of inheritance for certain traits and diseases.

Documentation of a family cancer history typically includes the following:

  • A minimum of three generations of relatives on both the maternal and paternal sides of the family. Information on multiple generations helps to demonstrate inheritance patterns. Hereditary cancer can be inherited from either the maternal or paternal side of the family and is often an adult-onset disease.

  • Race, ancestry, and ethnicity of all grandparents. This may influence decisions about genetic testing because specific mutations in some genes are known to occur with increased frequency in some populations (founder effect).

  • Information about seemingly unrelated conditions, such as birth defects, atypical skin bumps, or other nonmalignant conditions of children and adults that may aid in the diagnosis of a cancer susceptibility syndrome.

  • Notation of adoption, nonpaternity (the biologic father should be included in the pedigree), consanguinity, and use of assisted reproductive technology (e.g., donor egg or sperm), when available.

A three-generation family history includes the following:

  • First-degree relatives (e.g., children, brothers and sisters, and parents).
  • Second-degree relatives (e.g., grandparents, aunts and uncles, nieces and nephews, grandchildren, and half-siblings).
  • Third-degree relatives (e.g., first cousins, great aunts, and great uncles).
  • Additional distant relatives are included if information is available, especially when there are known cancer histories among them.

For any relative with cancer, collect the following information:[34]

  • Primary site of each cancer, with supportive documentation of key cancers (if available) to confirm primary site and histology (e.g., pathology reports, clinical documents, and death certificates).
  • Age at diagnosis for each primary cancer.
  • Where the relative was diagnosed and/or treated.
  • History of surgery or treatments that may have reduced the risk of cancer. For example, bilateral salpingo-oophorectomy in a premenopausal woman significantly reduces the risk of ovarian and breast cancers. This may mask underlying hereditary predisposition to these cancers.
  • Current age (if living).
  • Age at death and cause of death (if deceased).
  • Carcinogenic exposures (e.g., tobacco use and radiation exposure).
  • Other significant health problems.

For relatives not affected with cancer, collect the following information:

  • Current age or age at death.
  • Cause of death (if deceased).
  • History of any surgeries or treatments that may have reduced the risk of cancer.
  • Cancer screening practices.
  • Any nonmalignant features associated with the syndrome in question.
  • Carcinogenic exposures.
  • Other significant health problems.
Accuracy of the family history

The accuracy of the family history has a direct bearing on determining the differential diagnoses, selecting appropriate testing, interpreting results of the genetic tests, refining individual cancer risk estimates, and outlining screening and risk reduction recommendations. In a telephone survey of 1,019 individuals, only 6% did not know whether a first-degree relative had cancer; this increased to 8.5% for second-degree relatives.[35] However, people often have incomplete or inaccurate information about the cancer history in their family.[31,32,34,36-42] A population-based survey of 2,605 first- and second-degree relatives and confirmed proband reports of cancer diagnoses found that the accuracy of reported cancer diagnoses in relatives was low to moderate, while reports of no history of cancer were accurate.[41] Accuracy varies by cancer site and degree of relatedness.[41,43] Reporting of cancer family histories may be most accurate for breast cancer [41,44] and less accurate for gynecologic malignancies [41,44] and colon cancer.[41] Self-reported family histories may contain errors and, in rare instances, could be fictitious.[39,44,45] It is important to confirm the primary site of cancers in the family that will affect the calculation of hereditary predisposition probabilities and/or estimation of empiric cancer risks, especially if decisions such as risk-reducing surgery will be based on this family history.[45] The most reliable documentation of cancer histology is the pathology report. Verification of cancers can also be made through other medical records, tumor registries, or death certificates.

It is also important to consider limited, missing, or questionable information when reviewing a pedigree for cancer risk assessment. It is more difficult to identify features of hereditary disease in families with a truncated family structure due to loss of contact with relatives, small family size, or deaths at an early age from unrelated conditions. When there are few family members of the at-risk gender when considering a particular syndrome with primarily male or female specific disease manifestations, the family history may be difficult to assess (e.g., few female members in a family at risk of hereditary breast and ovarian cancer syndrome). In addition, information collected on risk-reducing surgical procedures, such as oophorectomy, could significantly change prior probability estimation and the constellation of cancers observed in a family.[46] Other factors to clarify and document whenever possible are adoptions, use of donor egg or sperm, consanguinity, and uncertain paternity.

Additionally, family histories are dynamic. The occurrence of additional cancers may alter the likelihood of a hereditary predisposition to cancer, and consideration of differential diagnoses or empiric cancer risk estimates may change if additional cancers arise in the family. Furthermore, changes in the cancer family history over time may alter recommendations for earlier or more intense cancer screening. A descriptive study that examined baseline and follow-up family history data from a U.S. population-based cancer registry reported that family history of breast cancer or colorectal cancer becomes increasingly relevant in early adulthood and changes significantly from age 30 years to age 50 years.[47] Therefore, it is important to advise the consultand to take note of, confirm, and report cancer diagnoses or other pertinent family health history that occurs after completion of the initial risk assessment process. This is especially important if genetic testing was not performed or was uninformative.

Finally, the process of taking the family history has a psychosocial dimension. Discussing and documenting discrete aspects of family relationships and health brings the family into the session symbolically, even when a single person is being counseled. Problems that may be encountered in eliciting a family history and constructing a pedigree include difficulty contacting relatives with whom one has little or no relationship, differing views between family members about the value of genetic information, resistance to discussion of cancer and cancer-related illness, unanticipated discovery of previously unknown medical or family information, and coercion of one relative by another regarding testing decisions. In addition, unexpected emotional distress may be experienced by the consultand in the process of gathering family history information.

Determining Cancer Risk

Analysis of the family history

Because a family history of cancer is one of the important predictors of cancer risk, analysis of the pedigree constitutes an important aspect of risk assessment. This analysis might be thought of as a series of the following questions:

  • What is the evidence that a cancer susceptibility syndrome is present in this family?
  • If a syndrome is present, what is the most probable diagnosis?
  • What could make this family history difficult to interpret?
  • What is the most likely mode of inheritance, regardless of whether a specific syndrome diagnosis can be established?
  • What is the chance of a member of this family developing cancer, if an inherited susceptibility exists?
  • If no recognizable syndrome is present, is there a risk of cancer based on other epidemiological risk factors?

The following sections relate to the way that each of these questions might be addressed:

  1. What is the evidence that a cancer susceptibility syndrome is present in this family?

    The clues to a hereditary syndrome are based on pedigree analysis and physical findings. The index of suspicion is raised by the following:

    • Multiple cancers in close relatives, particularly in multiple generations.
    • Early age of cancer onset (younger than age 40 to 50 years for adult-onset cancers).
    • Multiple cancers in a single individual.
    • Bilateral cancer in paired organs (e.g., breast and kidney).
    • Recognition of the known association between etiologically related cancers in the family.
    • Presence of congenital anomalies or precursor lesions that are known to be associated with increased cancer risk (e.g., presence of atypical nevi and risk of malignant melanoma).
    • Recognizable Mendelian inheritance pattern.

    Clinical characteristics associated with distinctive risk ranges for different cancer genetic syndromes have been clarified by the Society of Gynecologic Oncologists Education Committee.[48]

  2. If a syndrome is present, what is the most probable diagnosis?

    Hundreds of inherited conditions are associated with an increased risk of cancer. These have been summarized in texts [49-51] and a concise review.[52] Diagnostic criteria for different hereditary syndromes incorporate different features from the list above, depending on the original purpose of defining the syndrome (e.g., for gene mapping, genotype -phenotype studies, epidemiological investigations, population screening, or clinical service). Thus, a syndrome such as Lynch syndrome (also called hereditary nonpolyposis colorectal cancer [HNPCC]) can be defined for research purposes by the Amsterdam criteria as having three related individuals with colorectal cancer, with one person being a first-degree relative of the other two; spanning two generations; and including one person who was younger than age 50 years at cancer diagnosis, better known as the 3-2-1 rule. These criteria have limitations in the clinical setting, however, in that they ignore endometrial and other extracolonic tumors known to be important features of Lynch syndrome. Revised published criteria that consider extracolonic cancers of Lynch syndrome have been subsequently developed and include the Amsterdam criteria II and the revised Bethesda guidelines.

  3. What could make the family history difficult to interpret?

    Other factors may complicate recognition of basic inheritance patterns or represent different types of disease etiology. These factors include the following:

    • Small family size.
    • Gender imbalance (e.g., few women in a family suspected of hereditary breast cancer).
    • Deaths at particularly early ages.
    • Removal of the at-risk organ, either for risk reduction or as a result of a medical condition (e.g., total abdominal hysterectomy due to history of uterine fibroids or endometriosis).
    • Misidentified parentage.
    • Late or variable onset.
    • Nonpenetrance.
    • Variable expression.
    • Genetic heterogeneity.
    • Genomic imprinting.
    • De novo mutation.
    • Mosaicism (somatic or germline).
    • Mitochondrial inheritance.
    • Consanguinity.
    • Assisted reproductive technology (e.g., donor egg or sperm or in vitro fertilization).
  4. What is the most likely mode of inheritance, regardless of whether a syndrome diagnosis can be established?

    The mode of inheritance refers to the way that genetic traits are transmitted in the family. Mendel’s laws of inheritance posit that genetic factors are transmitted from parents to offspring as discrete units known as genes that are inherited independently from each other and are passed on from an older generation to the following generation. The most common forms of Mendelian inheritance are autosomal dominant, autosomal recessive, and X-linked. Non-Mendelian forms of inheritance include chromosomal, complex, and mitochondrial. Researchers have learned from cancer and other inherited diseases that even Mendelian inheritance is modified by environmental and other genetic factors and that there are variations in the ways that the laws of inheritance work.[53-55]

    Most commonly, Mendelian inheritance is established by a combination of clinical diagnosis with a compatible, but not in itself conclusive, pedigree pattern.[56] Below is a list of inheritance patterns with clues to their recognition in the pedigree, followed by a list of situations that may complicate pedigree interpretation.

    Autosomal dominant

    • Autosomal dominant inheritance refers to disorders that are expressed in the heterozygote (i.e., the affected person has one copy of a mutated allele and one allele that is functioning normally). Autosomal dominant inheritance is characterized by the following:
      • Vertical occurrence (i.e., seen in successive generations).
      • Usually seen only on one side of the family (i.e., unipaternal or unimaternal).
      • Males and females may inherit and transmit the disorder to offspring.
      • Male-to-male transmission may be seen.
      • Offspring have a 50% chance of inheriting a mutation and a 50% chance of inheriting the normal allele.
      • The condition may appear to skip a generation due to incomplete penetrance, early death due to other causes, delayed age of onset, or paucity of males or females when the at-risk organ is gender-specific (e.g., prostate and ovary).
      • Most currently known cancer susceptibility syndromes follow an autosomal dominant inheritance pattern. Examples include hereditary breast and ovarian cancer syndrome, Lynch syndrome, familial adenomatous polyposis, and von Hippel Lindau disease.
      • It is possible for an individual to have a mutation in a gene that has not previously been expressed as an autosomal dominant family history of cancer due to a variety of factors discussed above (see question #3).
      • It is possible for an individual to have a de novo (new) mutation. This person would be the first affected member of his or her family but could transmit this trait in the usual autosomal dominant manner to their offspring.

    Autosomal recessive

    • Autosomal recessive inheritance refers to an inheritance pattern in which an affected person must be homozygous (i.e., carry two copies of a mutant gene, one from each parent). Autosomal recessive inheritance is characterized by the following:
      • Horizontal occurrence (i.e., seen in one generation only [affected siblings in the absence of affected parents]); generally not seen in successive generations.
      • Mutated genes must come from both sides of the family (i.e., biparental inheritance).
      • Parents are heterozygous carriers; each carries one mutated copy of the gene and one functional copy.
      • Parents usually do not express the trait or the full syndrome; in some cases, parents may show a mild version of some features.
      • Two heterozygous parents together have a 25% recurrence risk for future offspring being affected.
      • Some well-defined cancer susceptibility syndromes with an autosomal recessive inheritance pattern include Bloom syndrome, Ataxia Telangiectasia, MYH-associated polyposis, and Fanconi anemia.


    • X-linked inheritance refers to inheritance of genes located on the X chromosome. Because males carry one Y and one X chromosome, genes on their X chromosome are hemizygous and may be expressed, regardless of whether the trait is dominant or recessive in females. X-linked recessive inheritance is more common than X-linked dominant and is characterized by the following:
      • Male and female offspring have a 50% chance of inheriting the mutated allele from a female carrier.
      • Males in the maternal lineage (brothers and maternal uncles) are affected.
      • Females are rarely affected, but when they are, the effects are usually milder than the effects in males.
      • No father-to-son transmission of the mutation occurs (i.e., a father cannot transmit an X-linked condition to his son because he gives the son his Y chromosome and not his X).
      • It is unusual for a cancer susceptibility syndrome to show X-linked transmission. One rare example is X-linked lymphoproliferative disorder.


    • Chromosomal disorders generally are not inherited conditions, except in rare cases of chromosomal translocations. Rather, they occur as a de novo error in meiosis at the time of conception of a given individual. Certain chromosomal anomalies confer a risk of malignancy; thus, inquiries about birth defects and intellectual disability are important for thorough pedigree construction and interpretation. Examples of chromosomal disorders with increased risk of malignancy include leukemia associated with Down syndrome (trisomy 21) and breast cancer associated with Klinefelter syndrome (47,XXY karyotype).


    • Complex or multifactorial disease inheritance is used to describe conditions caused by genetic and environmental factors. Thus, a condition may be caused by the expression of multiple genes or by the interaction of genes and environmental factors. Therefore, a single genetic locus is not responsible for the condition. Rather, the net effect of genetic, lifestyle, and environmental factors determines a person’s liability to be affected with a condition, such as cancer.

      Susceptibility or resistance shows a more or less normal distribution in the population. Most people have an intermediate susceptibility, with those at the tails of the distribution curve having unusually low or unusually high susceptibility. Affected individuals are presumably those who are past a point of threshold for being affected due to their particular combination of risk factors. Outside of the few known Mendelian syndromes that predispose to a high incidence of specific cancer, most cancers are complex in etiology.

      Clustering of cancer among relatives is common, but teasing out the underlying causes when there is no clear pattern is more difficult. With many common malignancies, such as lung cancer, an excess of cancers in relatives can be seen. These familial aggregations are seen as being due to combinations of exposures to known carcinogens, such as tobacco smoke, and to mutations in high penetrance genes or alterations in genes with low penetrance that affect the metabolism of the carcinogens in question.[57]

      The general practitioner is likely to encounter some families with a strong genetic predisposition to cancer and the recognition of cancer susceptibility may have dramatic consequences for a given individual's health and management. Although mutations in major cancer susceptibility genes lead to recognizable Mendelian inheritance patterns, they are uncommon. Nonetheless, cancer susceptibility genes are estimated to contribute to the occurrence of organ-specific cancers from less than 1% to up to 15%.[58] Mutations in these genes confer high relative risk and high absolute risk. The attributable risk is low, however, because they are so rare.

      In contrast, scientists now know of polymorphisms or alterations in deoxyribonucleic acid that are very common in the general population. Each polymorphism may confer low relative and absolute risks, but collectively they may account for high attributable risk because they are so common. Development of clinically significant disease in the presence of certain genetic polymorphisms may be highly dependent on environmental exposure to a potent carcinogen. People carrying polymorphisms associated with weak disease susceptibility may constitute a target group for whom avoidance of carcinogen exposure may be highly useful in preventing full-blown disease from occurring.

      For more information about specific low-penetrance genes, please refer to the summaries on genetics of specific types of cancer.

      Complex inheritance might be considered in a pedigree showing the following:

      • Males and females affected (unless the target organ is gender-specific).
      • A few cancers, without clear-cut vertical transmission or sibship clusters.
      • No set pattern of inheritance.
      • May appear to skip generations.
  5. What is the chance of developing cancer if an inherited susceptibility exists?

    These probabilities vary by syndrome, family, gene, and mutation, with different mutations in the same gene sometimes conferring different cancer risks, or the same mutation being associated with different clinical manifestations in different families. These phenomena relate to issues such as penetrance and expressivity discussed elsewhere.

  6. If no recognizable syndrome is present, is there a risk of cancer based on other epidemiological risk factors?

    A positive family history may sometimes provide risk information in the absence of a specific genetically determined cancer syndrome. For example, the risk associated with having a single affected relative with breast or colorectal cancer can be estimated from data derived from epidemiologic and family studies. Examples of empiric risk estimates of this kind are provided in the PDQ summaries on Genetics of Breast and Ovarian Cancer and Genetics of Colorectal Cancer.

Methods of quantifying cancer risk

The overarching goal of cancer risk assessment is to individualize cancer risk management recommendations based on personalized risk. Methods to calculate risk utilize health history information and risk factor and family history data often in combination with emerging biologic and genetic/genomic evidence to establish predictions.[59] Multiple methodologies are used to calculate risk, including statistical models, prevalence data from specific populations, penetrance data when a documented deleterious mutation has been identified in a family, Mendelian inheritance, and Bayesian analysis. All models have distinct capabilities, weaknesses, and limitations based on the methodology, sample size, and/or population used to create the model. Methods to individually quantify risk encompass two primary areas: the probability of harboring a deleterious mutation in a cancer susceptibility gene and the risk of developing a specific form of cancer.[59]

Risk of harboring a deleterious mutation in a cancer susceptibility gene

The decision to offer genetic testing for cancer susceptibility is complex and can be aided in part by objectively assessing an individual's and/or family's probability of harboring a mutation.[60] Predicting the probability of harboring a mutation in a cancer susceptibility gene can be done using several strategies, including empiric data, statistical models, population prevalence data, Mendel’s laws, Bayesian analysis, and specific health information, such as tumor-specific features.[60,61] All of these methods are gene specific or cancer-syndrome specific and are employed only after a thorough assessment has been completed and genetic differential diagnoses have been established.

If a gene or hereditary cancer syndrome is suspected, models specific to that disorder can be used to determine whether genetic testing may be informative. (Refer to the PDQ summaries on the Genetics of Breast and Ovarian Cancer; Genetics of Colorectal Cancer; or the Genetics of Skin Cancer for more information about cancer syndrome-specific probability models.) The key to using specific models or prevalence data is to apply the model or statistics only in the population best suited for its use. For instance, a model or prevalence data derived from a population study of individuals older than 35 years may not accurately be applied in a population aged 35 years and younger. Care must be taken when interpreting the data obtained from various risk models because they differ with regard to what is actually being estimated. Some models estimate the risk of a mutation being present in the family; others estimate the risk of a mutation being present in the individual being counseled. Some models estimate the risk of specific cancers developing in an individual, while others estimate more than one of the data above. (Refer to NCI's Risk Prediction Models Web site or the disease-specific PDQ cancer genetics summaries for more information about specific cancer risk prediction and mutation probability models.) Other important considerations include critical family constructs, which can significantly impact model reliability, such as small family size or male-dominated families when the cancer risks are predominately female in origin, adoption, and early deaths from other causes.[61,62] In addition, most models provide gene and/or syndrome-specific probabilities but do not account for the possibility that the personal and/or family history of cancer may be conferred by an as-yet-unidentified cancer susceptibility gene.[63] In the absence of a documented mutation in the family, critical assessment of the personal and family history is essential in determining the usefulness and limitations of probability estimates used to aid in the decisions regarding indications for genetic testing.[60,61,63]

When a deleterious mutation has been identified in a family and a test report documents that finding, prior probabilities can be ascertained with a greater degree of reliability. In this setting, probabilities can be calculated based on the pattern of inheritance associated with the gene in which the mutation has been identified. In addition, critical to the application of Mendelian inheritance is the consideration of integrating Bayes Theorem, which incorporates other variables, such as current age, into the calculation for a more accurate posterior probability.[4,64] This is especially useful in individuals who have lived to be older than the age at which cancer is likely to develop based on the mutation identified in their family and therefore have a lower likelihood of harboring the family mutation when compared with the probability based on their relationship to the mutation carrier in the family.

Even in the case of a documented mutation on one side of the family, careful assessment and evaluation of the individual’s personal and family history of cancer is essential to rule out cancer risk or suspicion of a cancer susceptibility gene mutation on the other side of the family (maternal or paternal, as applicable).[65] Segregation of more than one mutation in a family is possible (e.g., in circumstances in which a cancer syndrome has founder mutations associated with families of particular ancestral origin).

Risk of developing cancer

Unlike mutation probability models that predict the likelihood that a given personal and/or family history of cancer could be associated with a mutation in a specific gene(s), other methods and models can be used to estimate the risk of developing cancer over time. Similar to mutation probability assessments, cancer risk calculations are also complex and necessitate a detailed health history and family history. In the presence of a documented deleterious mutation, cancer risk estimates can be derived from peer-reviewed penetrance data.[4] Penetrance data are constantly being refined and many gene mutations have variable penetrance because other variables may impact the absolute risk of cancer in any given patient. Modifiers of cancer risk in mutation carriers include the mutation's effect on the function of the gene/protein (e.g., mutation type and position), the contributions of modifier genes, and personal and environmental factors (e.g., the impact of bilateral salpingo-oophorectomy performed for other indications in a woman who harbors a BRCA mutation).[66] When there is evidence of an inherited susceptibility to cancer but genetic testing has not been performed, analysis of the pedigree can be used to estimate cancer risk. This type of calculation uses the probability the individual harbors a gene mutation and gene mutation-specific penetrance data to calculate cancer risk.[4]

In the absence of evidence of a hereditary cancer syndrome, several methods can be utilized to estimate cancer risk. Relative risk data from studies of specific risk factors provide ratios of observed versus expected cancers associated with a given risk factor. However, utilizing relative risk data for individualized risk assessment can have significant limitations: relative risk calculations will differ based on the type of control group and other study-associated biases, and comparability across studies can vary widely.[64] In addition, relative risks are lifetime ratios and do not provide age-specific calculations, nor can the relative risk be multiplied by population risk to provide an individual's risk estimate.[64,67]

In spite of these limitations, disease-specific cumulative risk estimates are most often employed in clinical settings. These estimates usually provide risk for a given time interval and can be anchored to cumulative risks of other health conditions in a given population (e.g., the 5-year risk by the Gail model).[64,67] Cumulative risk models have limitations that may underestimate or overestimate risk. For example, the Gail model excludes paternal family histories of breast cancer.[61] Furthermore, many of these models were constructed from data derived from predominately Caucasian populations and may have limited validity when used to estimate risk in other ethnicities.[68]

Cumulative risk estimates are best used when evidence of other underlying significant risk factors have been ruled out. Careful evaluation of an individual's personal health and family history can identify other confounding risk factors that may outweigh a risk estimate derived from a cumulative risk model. For example, a woman with a prior biopsy showing lobular carcinoma in situ (LCIS) whose mother was diagnosed with breast cancer at age 65 years has a greater lifetime risk from her history of LCIS than her cumulative lifetime risk of breast cancer based on one first-degree relative.[69,70] In this circumstance, recommendations for cancer risk management would be based on the risk associated with her LCIS. Unfortunately, there is no reliable method for combining all of an individual's relevant risk factors for an accurate absolute cancer risk estimate, nor are individual risk factors additive.

In summary, careful ascertainment and review of personal health and cancer family history are essential adjuncts to the use of prior probability models and cancer risk assessment models to assure that critical elements influencing risk calculations are considered.[60] Influencing factors include the following:

  • Differential diagnosis that is consistent with the personal and cancer family history.
  • Consideration of factors that influence how informative the family history may be.
  • Population that is best suited for the use of the model.
  • Tumor-specific features that may be suspicious for an inherited predisposition or modify individual cancer risk predictions.
  • Model-specific limitations that can overestimate or underestimate calculations.[63]

A number of investigators are developing health care provider decision support tools such as the Genetic Risk Assessment on the Internet with Decision Support (GRAIDS),[71] but at this time, clinical judgment remains a key component of any prior probability or absolute cancer risk estimation.[60]

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