DNA Tests and Risk Assessment
Special Feature
DNA Tests and Risk Assessment
By Joann Bodurtha, MD, MPH, FACMG, and Thomas J. Smith, MD, FACP
Five years have elapsed since the announcement of the discovery of the BRCA1 gene. The science of testing is getting more complicated. The gene is large and many different mutations can occur. The differences between pathogenic mutations and "neutral" changes, or polymorphisms, may not be clearcut. Other genes for hereditary breast cancer susceptibility (e.g., BRCA2) have also been found.
The implementation of testing is complicated. Patents, and a limited array of research protocols, have discouraged a one-stop shopping approach. Physicians have variable comfort and skill in addressing family history and time-consuming informed consent. They share women’s concerns about emotional distress, employment and discrimination issues, cost, and the "so what can I do differently with this information?" question. We address five related questions here.
How likely am I to find a BRCA1 mutation in a patient with breast cancer?
More than 80% of women with breast cancer do not have a family history. The presence of multiple occurrences of breast and ovarian cancer before age 50 in a family increases the chances that a mutation will be found. Estimates of the prevalence of mutations in BRCA1 and BRCA2 from series of patients with breast or ovarian cancers, registries of families with multiple episodes of these cancers, and community samples are shown in Table 1. (See Table 1.) Three founder mutations in BRCA1 and BRCA2 occur frequently enough among Ashkenazi Jews to enable consideration of this specific testing. Community samples of 5318 Jewish women and men in the Washington DC area found that 2.3% carried one of these mutations. Among 297 women with breast or ovarian cancer, 9.1% carried a mutation.1
Table 1 | |
Germline BRCA1 Mutations in Select Populations___________________ | |
Population Studied |
|
High-risk Families |
|
Early-onset breast cancer
Non-Jewish women Jewish women |
6.2 - 13 21 - 50 |
Population-based |
|
Clinic-based |
|
Adapted from: Hartge P, et al. Am J Hum Genet 1999;64:963-970. ______________________________________________________________________ |
How likely is a person with a BRCA1 or BRCA2 gene change to develop cancer?
The Breast Cancer Linkage Consortium has estimated the risks of breast cancer conferred by BRCA1 mutations to be about 50% by age 50 years and about 85% by age 70 years. In the Washington Ashkenazi Study, the risk of developing breast cancer by age 70 was estimated to be 13% in non carriers of the three common mutations and 56% in carriers.
Cumulative risks at age 70 years were 13% for ovarian cancer and 16% for prostate cancer in carriers. The interaction of these genes with other genes and environmental risk factors is likely to make individualized risk prediction complex.
How are people deciding to refer for genetic counseling and testing?
The recently NCI-funded Cancer Genetics Network hopes to understand better what is actually happening in oncology practice, not only what is occurring in research protocols. In part because genetic counseling and testing are variably covered by insurance, some amount of self-selection and limitation of access exists a priori.
Some health maintenance organizations have developed triage plans for referral. The Permanente Medical Group criteria for referral for genetic screening include:
• persons with a known clinically-significant BRCA gene change in a relative
• persons with multiple primary breast tumors
• persons with breast and ovarian cancer
• Ashkenazi Jewish descent and ovarian cancer, or having breast cancer at younger than 40 years and Ashkenazi Jewish descent and having breast cancer at younger than 30 years.2
For women younger than 50 years with breast cancer, they suggest that one or more first- or second-degree relatives with breast cancer diagnosed younger than age 50 be present. Additional parts of their algorithm address other family history issues, men, significant anxiety, and ovarian cancer (Permanente Medical Group). All individuals are required to have genetic counseling and sign a formal informed consent document prior to genetic testing.
Any list is acknowledged to become dated, but the ASCO curriculum for Cancer Genetics and Cancer Predisposition Testing (1998) considers three groups in its guidelines for testing. (See Table 2.)3
Table 2 |
ASCO Cancer Genetics and Predisposition Guidelines by Group__ |
Group 1. Genetic test result will change medical care and is standard management. Examples: familial adenomatous polyposis, multiple endocrine neoplasia 2, multiple endocrine neoplasia 1, retinoblastoma, Von Hippel-Lindau disease. Group 2. Possible medical benefit in the identification of a germline mutation. Examples: hereditary nonpolyposis colorectal cancer, hereditary breast and ovarian cancer, Li-Fraumeni syndrome, Cowden syndrome. Group 3. Tests in which the significance of the detection of a germline mutation is not clear; or for which mutations have been identified only in a small number of families. Examples: melanoma and associated syndromes, Wilms tumor, familial papillary renal carcinoma, Peutz-Jeghers syndrome. Adapted from: ASCO,1998.
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Where do I find a genetic counselor to refer my patients?
Several resources are available for finding cancer genetics professionals. They include: The National Cancer Institute’s Cancer Genetics Professional Directory at http://cancernet.nci.nih.gov/wwwprot/genetic/generch. html, and the National Society of Genetic counselors at http://www.nsgc.org/Resource_link.html. The Cancer Information Service (1-800-4-CANCER) is also developing as a resource for information about cancer genetics professionals and cancer genetic research. The National Society of Genetic Counselors can also be reached at 610-872-7608 and by e-mail [email protected].
Our prediction is that most oncologists will opt not to do this in the office (it will be too time-consuming, scientifically challenging, and not reimbursed like chemotherapy).
What is on the horizon for cancer susceptibility testing?
The DNA chip offers the potential for automated multiple mutation testing. It seems likely that it will first be used for individuals with a particular cancer or genetic condition to screen more efficiently for their specific mutation. Relatives could decide when to order their chip home test kit as can now happen for cystic fibrosis mutation testing in England.
The history of genetic screening, for example with metabolic conditions like phenylketonuria (PKU) in newborns and alpha-fetoprotein in pregnant women, suggests that some specific interventions need to have broad public support before the screening is adopted widely.
We foresee that offering testing to women younger than 50 years of age who present with breast cancer may effect surgical and chemotherapy choices as data from ongoing clinical trials becomes available. Maybe those who are BRCA1 or 2 positive will be able to go on tamoxifen as one way of successfully preventing new cancers. Genetic cancer susceptibility testing might be incorporated with the annual Pap exam, stool blood test, or mammography screening.
References
1. Hartge P, et al. Am J Hum Genet 1999;64:963-970.
2. Permanente Medical Group (1997). Clinical Practice Guidelines for Referral for Genetic Counseling for Inherited Susceptibility for Breast and Ovarian Cancer. Copies available by calling 510-987-2950.
3. American Society of Clinical Oncology curriculum information may be obtained through ASCO, 225 Reinekers Lane, Suite 650, Alexandria VA 22314.
4. Couch F, Hartman L. JAMA 1998;279:955-957.
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