Caring for Patients at Risk for Hereditary Colorectal Cancer

February 5, 2007

About 6% of colorectal cancers are caused by genetic mutations associated with hereditary colorectal cancer syndromes. The most common hereditary cancer syndromes nurses are likely to encounter include hereditary nonpolyposis colon cancer or Lynch syndrome, familial adenomatous polyposis, attenuated familial adenomatous polyposis, and MYH polyposis. Current colorectal cancer recommendations for risk management, screening, and surveillance are complex and based on level of colorectal cancer risk and whether an individual carries a genetic mutation associated with a hereditary colorectal cancer syndrome. Caring for patients with hereditary colorectal cancer syndromes requires nurses to understand how to identify individuals and families at risk for hereditary colorectal cancer, refer to appropriate resources, and provide accurate information regarding screening, surveillance, and management. Nurses play a critical role in assessing colorectal cancer risk, obtaining an accurate family history of cancer, and providing information concerning appropriate cancer screening and surveillance.

ABSTRACT: About 6% of colorectal cancers are caused by genetic mutations associated with hereditary colorectal cancer syndromes. The most common hereditary cancer syndromes nurses are likely to encounter include hereditary nonpolyposis colon cancer or Lynch syndrome, familial adenomatous polyposis, attenuated familial adenomatous polyposis, and MYH polyposis. Current colorectal cancer recommendations for risk management, screening, and surveillance are complex and based on level of colorectal cancer risk and whether an individual carries a genetic mutation associated with a hereditary colorectal cancer syndrome. Caring for patients with hereditary colorectal cancer syndromes requires nurses to understand how to identify individuals and families at risk for hereditary colorectal cancer, refer to appropriate resources, and provide accurate information regarding screening, surveillance, and management. Nurses play a critical role in assessing colorectal cancer risk, obtaining an accurate family history of cancer, and providing information concerning appropriate cancer screening and surveillance.

Colorectal cancer occurs as a result of the uncontrolled growth and spread of abnormal cells in the colon or rectum. Colorectal cancer is the third most common cancer in both men and women, and incidence rises with age.[1] In 2006, an estimated 106,680 persons were diagnosed with colorectal cancer and an estimated 41,930 died of the disease. Having a personal or family history of colorectal cancer, polyps, chronic ulcerative colitis, Crohn's disease, or inflammatory bowel disease also increases risk. Personal risk factors for colorectal cancer include obesity, physical inactivity, smoking, heavy alcohol consumption, and a diet high in red meat.[1] This disease is asymptomatic in the early stages, which makes screening particularly important. Symptoms include rectal bleeding, blood in the stool, change in bowel habits, and abdominal cramping. Increased age and having a personal or family history of colorectal cancer or polyps are significant risk factors.

Impact of Cancer Genomics on Cancer Care

The Human Genome Project served as a catalyst for incredible advances in genetics and genomics knowledge and technology, which are changing how oncology services are defined and delivered. The goal of the Human Genome Project, which was launched in 1990 and completed in 2003, was the formidable task of sequencing all the genes in the human body. There are about 30,000 genes in the human genome, a much smaller number than expected. Why was it important to sequence the human genome? Understanding the role of genomics in human health and disease is a tremendous step toward developing better prevention, treatment, and potential cures for common diseases and health problems such as cancer.

This genetic revolution resulted in a paradigm shift from genetics to genomics. Genetics refers to the examination and understanding of genes and their effects. Genomics is the study of all the genes in the human genome together, including their interactions with each other and the environment. Although the greatest advances in human genetics have been associated with variation in a single gene, most common diseases such as cancer are more complex in origin, involving the interplay between multiple genetic factors and nongenetic factors such as environmental influences.[2]

Genomics and Oncology Nursing Practice

Oncology nurses are challenged with developing and implementing nursing interventions that take into account the influence of a person's genotype when providing care. Cancer predisposition genetic testing and tumor genotyping have become much more widespread, resulting in more tailored interventions for cancer screening, surveillance, risk reduction, and treatment.

Scientific discoveries and advancements have improved our ability to predict cancer susceptibility through genetic testing, predict cancer risk, provide tailored preventive, screening, and risk reduction interventions, and individualize cancer treatment. More than 20 different hereditary cancer syndromes have now been identified that can be attributed to specific germline mutations in inherited cancer susceptibility genes.[3] Cancer susceptibility genetic testing has the potential to identify whether a person is at increased risk for a particular cancer or cancers based on their genotype.

About 5% to 10% of cancers are related to hereditary factors.[4] Most major hereditary cancer syndromes follow an autosomal dominant pattern of inheritance, [3] which means that the altered gene can be transmitted by either parent to its offspring. A person needs to inherit only one altered copy of the gene to be at risk for the cancers associated with that particular genetic change, and there is a 50% chance of passing this same altered gene on to one's children. The majority of altered genes associated with hereditary cancer syndromes act as tumor suppressor genes when they are functioning properly.[3] Tumor suppressor genes regulate or stop the growth of damaged cells. A defective or mutated tumor suppressor gene cannot stop cells from proliferating wildly and therefore is not able to suppress cellular changes that lead to cancer.

Genetic testing for colorectal cancer susceptibility is an example of how genetic information is changing oncology nursing practice. Health-care recommendations for cancer surveillance and risk management can be very different for someone who has undergone genetic testing for cancer susceptibility and is found to carry a genetic mutation associated with a hereditary colorectal cancer syndrome compared to someone without that genotype.

Hereditary Colorectal Cancer

It is estimated that about 6% of colorectal cancers are caused by genetic mutations associated with hereditary colorectal cancer syndromes.[5] The most common hereditary cancer syndromes likely to be encountered include hereditary nonpolyposis colon cancer (HNPCC) or Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), and MYH polyposis (Table 1).[6-8]

Hereditary Colorectal Cancer in Older Adults

Not all hereditary cancers have an early age of onset; older persons are also at risk for hereditary colorectal cancer syndromes. Very little attention has been given to the needs of those aged 65 and older who have a hereditary colorectal cancer syndrome or are at risk for one. As life expectancy increases, the number of older persons who seek genetics services will continue to increase. Increased age is associated with an increased risk of both colorectal cancer and polyps. Individuals over the age of 65 are also more likely to have survived more than one cancer. As individuals diagnosed with hereditary colorectal cancer age, it will be important for nurses to provide age-appropriate care tailored to their individual needs.

Since the elderly are often diagnosed with cancer, it is not uncommon for individuals over the age of 65 to be the first in their families to undergo genetic testing. It is always best to test the person in the family with a cancer diagnosis associated with the suspected genetic mutation before testing unaffected at-risk family members. Research has shown that colonoscopy surveillance should be continued after age 65 even if previous examinations have been negative.[9] Cancer risk assessment and obtaining an accurate family history in an older patient with polyps or colorectal cancer are essential in determining whether they are at risk for a hereditary colorectal cancer syndrome.

Hereditary nonpolyposis colorectal cancer or Lynch Syndrome

About 2% to 5% of colorectal cancers are attributable to HNPCC or Lynch syndrome.[5,10] HNPCC is an autosomal dominant condition characterized by an increased risk of colorectal and other cancers. Individuals with HNPCC have about an 80% risk of being diagnosed with colorectal cancer by age 75. Two-thirds of these cancers occur in the proximal or right side of the colon. Women with HNPCC have a lifetime risk of developing endometrial cancer of about 41% to 60%. There is also an increased risk of developing cancers of the stomach, ovary, bladder and urinary tract, kidney, gallbladder, and brain.[5,10]

Risk factors for HNPCC include having a personal or family history of colorectal cancer, especially a cancer diagnosed before age 50. A common method for diagnosing HNPCC is to use the Amsterdam II Criteria listed in Table 2. These are research criteria for defining HNPCC families that were established by the International Collaborative Group at a meeting in Amsterdam in 1990 and later revised.[10,11]

Genetic Testing for HNPCC

The genes that cause HNPCC are called mismatch repair genes or DNA repair genes and are listed in Table 1. In HNPCC, an individual has inherited one mutated copy of a DNA repair gene. If the remaining nonmutated copy of that DNA repair gene becomes mutated, a cell cannot repair damaged DNA, mutations accumulate, and a tumor may be the result. Current data suggest that about 95% of HNPCC diagnoses can be accounted for by mutations in MLH1 (about 40%), MSH2 (about 40%), MSH6 (about 10%), and PMS2 (about 5%).[12] Genetic testing is commercially available for HNPCC for MLH1, MSH2, and MSH6. It is important to keep in mind that not all individuals who meet Amsterdam criteria will test positive for a mutation associated with HNPCC.

There are several ways to determine whether or not genetic testing for HNPCC is indicated. One method is to offer genetic testing to individuals who meet Amsterdam II criteria (discussed previously). Another strategy is to perform an MSI assay on the affected family member's colorectal tumor. In HNPCC, mutations in the DNA repair genes cause another phenomenon called microsatellite instability (MSI). Microsatellites are repeated sequences of DNA, which are a set length for a given individual. Some of these sequences accumulate errors and become abnormally longer or shorter; this is referred to as microsatellite instability. About 90% of tumors from individuals who have HNPCC show MSI. However, only about 15% of individuals without HNPCC show MSI.[13] If the tumor is found to exhibit MSI, then the patient or family can be offered genetic testing. The Bethesda guidelines were developed and revised to identify when tumors from individuals should be tested for MSI and can be found in Table 2.

Risk Assessment Models for HNPCC

As our understanding of HNPCC increases, the methods for identifying those at risk continue to evolve and become more accurate. A new tool that recently became available is the MMRpro, which is a computerized risk prediction tool that estimates the probability of carrying a deleterious mutation in MLH1, MSH2, and MSH6. It also estimates the probability of unaffected individuals to develop colorectal or endometrial cancer.[14] The model's prediction is based on each individual's family history of colorectal and endometrial cancer and on tumor characteristics including microsatellite instability. This model can be used whether or not tumor samples are available for MSI testing. The authors report a high model accuracy with a ratio of observed to expected cases (O/E ratio) of 0.94 and a concordance index of 0.83 with MSI testing, and an O/E ratio of 0.97 and concordance index of 0.79 without MSI testing.[14] The link for BayesMendel Lab, where this software can be downloaded free of charge, is http://astor.som.jhmi.edu/BayesMendel/mmrpro.html (please note that address is case-sensitive.)

Familial Adenomatous Polyposis

Up to 1% of colorectal cancers are attributable to FAP, which is an autosomal dominant condition characterized by hundreds to thousands of colorectal polyps and a risk of colorectal cancer that approaches 100% by age 50.[5,8,10] FAP should be suspected in any individual with greater than 100 adenomatous polyps in the colon and rectum. These polyps start developing after the first decade of life with a mean age of 16 years. By age 35 years, 95% of individuals with FAP have polyps and without colectomy will likely develop colorectal cancer in their 30s or 40s.[15] Individuals with FAP can also have polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft-tissue (desmoids) tumors, and associated cancers such as thyroid, small bowel, hepatoblastoma, pancreas, and brain (particularly medulloblastoma).[10,15] The combination of colonic polyposis typical of FAP with osteomas and sebaceous cysts is often referred to as Gardner syndrome. Another variation of FAP is Turcot syndrome, which is the association of colonic polyposis and central nervous system tumors.[15]

Every nurse needs to be familiar with FAP. Although FAP represents only a small percentage of colorectal cancers, early diagnosis and treatment is essential. The hallmark of FAP is greater than 100 adenomatous polyps and individuals with a personal or family history of numerous polyps should be referred for FAP screening. Surveillance may begin as early as age 10. Individuals with a personal or family history of 10 or more colorectal polyps should be referred to a genetics professional to determine if a hereditary cancer syndrome may be present.

Attenuated Familial Adenomatous Polyposis

Attentuated familial adenomatous polyposis (AFAP) is an autosomal dominant condition characterized by the presence of fewer polyps than with FAP, usually 20 to 100 colorectal polyps, with an average number of about 30.[15] The risk of colorectal cancer is about 69% by age 80. The diagnosis of colorectal cancer is about 10 to 15 years later than with classic FAP, with an average age of 52, and tends to occur on the right side of the colon. Polyps are more likely to be located on the right side of the colon. Upper gastrointestinal polyps and cancers are often present, and many of the adenomas may be morphologically flat in appearance. Extra colonic manifestations of FAP may also be present but are less common and desmoids tumors or congenital hypertrophy of the retinal pigment epithelium (CHRPE) are rare.[16,17]

MYH-Associated Polyposis

Mutations in the MYH gene have recently been associated with what appears to be a recessive form of polyposis. The average age of presentation is about 46 and individuals usually have from 10 to 100 polyps, although more than 100 polyps can be present. MYH polyposis can resemble FAP or AFAP.[18] About two-thirds of individuals with MYH-associated polyposis (MAP) developed colorectal cancer, 62% right-sided, and about one-third developed upper gastrointestinal lesions. In this same study 4 out of 22 women with MAP had breast cancer diagnoses, two of which were bilateral.[19] Individuals who carry only one MYH mutation may carry an increased risk for colorectal cancer later in life.[20]

Genetic Testing for FAP and AFAP

Genetic testing is available for FAP and AFAP and is usually performed using a blood sample. Most diagnoses of FAP and AFAP are due to mutations in the adenomatous polyposis coli (APC) gene, and involve a truncated or shortened protein. APC is a tumor suppressor gene located in chromosome 5. Sensitivity is about 80% using either protein truncation or gene sequencing to detect APC mutations.[10] Individuals with a phenotype resembling FAP or AFAP when no clear vertical transmission is present should be referred for MYH genetic counseling and testing.[18] As with any genetic testing, genetic counseling prior to testing and after test results have been received is recommended. This is especially important with FAP, since genetic testing is recommended as early as age 10 and the testing of minors is associated with numerous ethical and psychosocial issues.

Screening and Surveillance for Hereditary Colorectal Cancer

One set of cancer screening recommendations no longer applies to almost everyone in a particular age group. We have entered an era of risk stratification and individualized screening based on sophisticated algorithms that take into account genomic and other risk factors. Screening recommendations for colorectal cancer have become very complex. For example, current National Comprehensive Cancer Network colorectal cancer screening guidelines include 18 pages of algorithms related to colorectal cancer screening.[21] Nurses need to have a basic understanding of colorectal screening guidelines for average-risk, increased-risk, and high-risk individuals (Table 3).

HNPCC Screening and Surveillance

There is general agreement that individuals with HNPCC need to have a colonoscopy every 1 to 2 years starting at age 20 to 25 or 10 years earlier than the youngest age of diagnosis in the family (Table 4).[7] There is less evidence for screening women annually for endometrial and ovarian cancer. One study reports that endometrial or ovarian cancer can precede the development of colon cancer in women with HNPCC and recommends screening women with HNPCC annually for gynecologic cancer. The study also recommends that hysterectomy and bilateral salpingo-oophorectomy be considered after childbearing is finished.[22] Subtotal colectomy with ileorectal anastomosis may be indicated in individuals with HNPCC mutation carriers diagnosed with colorectal cancer.[7]

Screening and Surveillance for FAP, AFAP, and MAP

Familial adenomatous polyposis begins in the teens, so screening needs to start early. Recommendations are for sigmoidoscopy annually starting at age 10 to 12 and colectomy in the late teens to early twenties. Colectomy is considered essential since the risk of colorectal cancer by age 50 is nearly 100% in individuals without this surgery.[23] Recommendations also include front- and side-viewing endoscopies of the stomach, duodenum, and periampullary region.[24]

Both AFAP and MAP are associated with a high number of right-sided colorectal cancers; therefore colonoscopy every 1 to 2 years starting at age 20 to 25 is recommended. Screening of the upper gastrointestinal tract with endoscopy is recommended every 6 months to 4 years for AFAP depending on number of polyps found and pathology. For MAP upper endoscopy and side-viewing duodenoscopy are recommended every 3 to 5 years starting at age 30 to 35.[21] Colectomy should be considered for individuals with AFAP.[16] Individuals with MAP with large numbers of polyps may want to consider a subtotal colectomy.[19]

The Nurse's Role

Colorectal Cancer Risk Assessment

Cancer risk assessment is a term that usually refers to the evaluation of individual's cancer risk based on information related to heredity, lifestyle, dietary, hormonal, environmental and other factors that have been associated with an increased risk for certain cancers. Nurses play a critical role in the cancer risk assessment process. Without an accurate risk assessment, it is impossible for an individual to make good choices about genetic testing, cancer prevention practices, and cancer detection strategies. A good cancer risk assessment involves obtaining a detailed patient and family history of cancer and constructing a pedigree. A detailed pedigree is a visual representation of a family history and should be constructed involving at least three generations.[25] It is important to note the type of cancer, age at diagnosis, and age at death on the pedigree. Each generation is a different level, which makes it easier to identify patterns of cancer that pass down through several generations. It is important to use standardized pedigree symbols and nomenclature.[26]

When conducting a colorectal cancer risk assessment, it is important to ask the individual about personal and family history of gastrointestinal polyps, dental abnormalities, soft-tissue (desmoids) tumors, CHRPE, and sebaceous cysts or osteomas (bony growths, usually found on the jaw), which can indicate Gardner syndrome. Cancer risk assessment also includes asking about nonhereditary colorectal cancer risk factors including chronic ulcerative colitis, Crohn's disease, inflammatory bowel disease, physical activity, tobacco and alcohol use, and consumption of dietary fat and red meat.

All individuals need to receive an age-appropriate cancer risk assessment and a plan for cancer risk reduction, surveillance, and frequency of early detection tests based on that information. During the cancer risk assessment process it is important for the nurse to identify and recognize key indicators or red flags that an individual may be at risk for a hereditary colorectal cancer syndrome (Table 4). The family history and pedigree make it much easier to identify these key indicators. Communicating risk information to patients and addressing the psychological issues related to that information are an important component of nursing care.

Individuals at risk for a hereditary colorectal cancer syndrome need to be offered referral to a genetics professional for genetic counseling and to determine if genetic testing is appropriate. Individuals diagnosed with or at risk for hereditary colorectal cancer also may need to be referred to a gastroenterologist for appropriate surveillance and management. Nurses are instrumental in identifying when referrals are needed and facilitating the referral process.

Genetic Counseling and Testing

All nurses play a role in providing genetics education, performing cancer risk assessment and facilitating genetics referrals. Cancer genetic counseling includes education about the basic principles of cancer genomics, information about relevant cancer syndromes, assessment, interpretation, and communication of cancer risk information, discussion of the risks and benefits of cancer genetic testing, discussion of cancer screening, surveillance and risk reduction options, and addressing the psychosocial issues related to genetic information.[27] There are advanced practice oncology nurses who provide cancer genetic counseling and testing. Oncology nurses are well suited to assume this expanded role; however, they need to be advanced practice nurses with specialized education and training in genetics.[28] Individuals who undergo cancer risk assessment and do not meet the criteria for genetic testing or are not at risk for a hereditary cancer syndrome need to receive cancer screening, surveillance, and risk reduction information based on their family history of cancer and other cancer risk factors. This is a role ideally suited for nurses (see page 36 for an overview of discussion points for talking with patients and their families).

Genetic testing to identify cancer susceptibility genes is now much more common in clinical practice. When there is a strong family history of cancer, suggesting a cancer-predisposing mutation may be present, it is always best to first test a person in the family with a cancer diagnosis associated with the suspected genetic mutation.[27] It is important to keep in mind that interpretation of genetic test results is somewhat complex since not all persons with a hereditary cancer syndrome will have a positive test result.

Genetic testing is different from most laboratory blood tests in clinical practice. When looking for a genetic mutation on a specific gene, there can be hundreds of different mutations on one gene that can be associated with a particular hereditary cancer syndrome. A simple analogy is looking for a typographical error in a book. There can be many errors, yet not all errors will be detrimental. Explaining how genetic testing works and what the results mean is part of genetic counseling. It is important to remember that genetic information has implications for other family members. If a family member tests positive for a mutation that is autosomal dominant, then each of their first-degree relatives has a 50% chance of having the same mutation.

Identification of a cancer-predisposing mutation associated with a hereditary colorectal cancer syndrome can alter cancer medical management, screening, and surveillance recommendations. In addition, cancer chemoprevention measures and even prophylactic surgery may be indicated in individuals found to carry cancer-predisposing mutations.[21]

Summary

Caring for patients with hereditary colorectal cancer syndromes requires nurses to understand how to identify individuals and families at risk for hereditary colorectal cancer, refer to appropriate resources, and provide accurate information regarding screening, surveillance, and management. Cancer predisposition genetic testing and tumor genotyping have become much more widespread, resulting in more tailored interventions for cancer screening, surveillance, risk reduction, and treatment. Nurses play a critical role in assessing colorectal cancer risk, obtaining an accurate family history of cancer, and providing information concerning appropriate cancer screening and surveillance.

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Cancer Facts and Figures 2006, pp 1-64. Atlanta, American Cancer Society, 2006.

2. Collins FS, Green ED, Guttmacher AE, et al: A vision for the future of genomics research: A blueprint for the genomic era. Nat Genet 422:835-847, 2003.

3. Fearon ER: Human cancer syndromes: Clues to the origin and nature of cancer. Science 278(5340):1043-1050, 1997.

4. Heredity and Cancer. Atlanta, American Cancer Society, 2006.

5. Jeter JM, Kohlmann W, Gruber SB: Genetics of colorectal cancer. Oncology 20(3):269-276, 2006.

6. Greco KE, Mahon S: Common hereditary cancer syndromes. Semin Oncol Nurs 20(3):164-177, 2004.

7. Lindor NM, Petersen GM, Hadley DW, et al: Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: A systematic review. JAMA 296(12):1507-1517, 2006.

8. Vasen HSA: Clinical diagnosis and management of hereditary colorectal cancer syndromes. J Clin Oncol 18(21s):81s-92s, 2000.

9. Feingold DL, Forde KA: Colorectal cancer surveillance after age 65 years. Am J Surg 185(4):297-300, 2003.

10. Genetics of Colorectal Cancer. National Cancer Institute, 2006.

11. Vasen HF, Watson P, Mecklin JP, et al: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterol 116(6):1453-1456, 1999.

12. Umar ABC, Terdiman JP, Syngal S, et al: Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Nat Cancer Inst 96(4):261-268, 2004.

13. Komaromy M: Microsatellite instability testing. Genetic Health, 2000.

14. Chen S, Wang W, Lee S, et al: Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 296(12):1479-1487, 2006 (see comment).

15. Solomon C, Burt RW: APC-associated polyposis conditions. Seattle, Gene Reviews, 2005.

16. Knudsen AL, Bisgaard ML, Bulow S: Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer 2(1):43-55, 2003.

17. Lynch HT, Smyrk T, McGinn T, et al: Attenuated familial adenomatous polyposis (AFAP). A phenotypically and genotypically distinctive variant of FAP [see comment.] Cancer 76(12):2427-2433, 1995.

18. Sampson JR, Dolwani S, Jones S, et al: Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 362(9377):39-41, 2003 (see comment).

19. Nielsen M, Franken PF, Reinards TH, et al: Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). J Med Gen 42(9):e54, 2005.

20. Tenesa A, Farrington SM, Dunlop MG: Re: Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. J Natl Cancer Inst 97(4):320-322, 2005 (see comment).

21. NCCN: Colorectal cancer screening. National Comprehensive Cancer Network, 2006.

22. Lu KH, Dinh M, Kohlmann W, et al: Gynecologic cancer as a "sentinel cancer" for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol 105(3):569-574, 2005.

23. Winawer S, Fletcher R, Rex D, et al: Colorectal cancer screening and surveillance: Clinical guidelines and rationale-Update based on new evidence. Gastroenterol 124(2):544-560, 2003.

24. Galiatsatos P, Foulkes WD: Familial adenomatous polyposis. Am J Gastroenterol 101(2):385-398, 2006.

25. Spahis J: Human genetics: Constructing a family pedigree. Am J Nurs 102(7):44-50, 2002.

26. Bennett RL, Steinhaus KA, Uhrich SB, et al: Recommendations for standardized human pedigree nomenclature. Pedigree Standardization Task Force of the National Society of Genetic Counselors. Am J Human Genet 56(3):745-752, 1995 (see comment).

27. Greco K: How to provide genetic counseling and education, in Masney A, Strauss Tranin A, Jenkins J (eds): Guidelines for Cancer Genetics Nursing Practice and Education, pp 189-219. Pittsburgh, Oncology Nursing Press, 2003.

28. ISONG/ANA, Genetics and Genomics Nursing: Scope and Standards of Practice. Washington DC, American Nurses Association, 2006.

29. Smith RA, Cokkinides V, Eyre HJ: American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin 56(1):11-25, 2006.