Genetic Counseling - Commonwealth Hematology-Oncology

An affiliate of Beth Israel Deaconess Medical Center. A teaching hospital of Harvard Medical School

Helping You Make The Right Choices

Genetic Counseling

Many patients with cancer often wonder if they inherited their cancer or if they can pass that cancer risk on to their children. It’s a common concern. You should know that most cancer risk is NOT inherited and occurs through a combination of lifestyle, environmental, and age-related factors.

However, a small number of families will have an identifiable genetic risk for cancer. At Commonwealth Hematology-Oncology, a comprehensive genetic counseling program can help you determine if genetic testing is appropriate for you. Before a test is obtained, you will have the opportunity to meet with a provider who specializes in genetic cancer syndromes and who will determine your risk of carrying a gene that may result in cancer.

The benefits of knowing whether you carry a gene mutation will be explained, and your legal and insurance rights will be explained. After the testing is done, regardless of the result, you will be provided with an individual written risk reduction plan and a follow-up plan.

Before a genetic counseling visit you may wish to speak with family members to gain as much information as possible about the medical histories of your parents, grandparents, aunts and uncles to help determine your individual risk.

Genetic Testing: Why Be Tested?

All cancer is genetic. Cancer develops when genes that control the orderly replication of cells become damaged and allow cells to reproduce without restraint. Most cancer is not inherited. Most cancers are sporadic and result from damage during replication due to a mistake during cell division or in response to environmental injuries. Approximately 5% to 10% of cancer is inherited.

An accurate genetic test can tell if a genetic defect is present, but it does NOT guarantee the disease will develop. The American Society of Clinical Oncology recommends that genetic testing be offered when 1) an individual has a personal or family history that suggests a genetic cancer susceptibility and 2) the test can be adequately interpreted and its results will influence diagnosis or management of the individual or family members at risk for hereditary cancer.

Some individuals use their test results to make medical decisions that may prevent cancer from potentially developing or use their test results to have procedures done to help detect cancer at an early, more treatable stage. If you have a personal or family history of cancer, genetic testing may have important benefits for your health care and the health care of members of your family. Choosing to be tested is a personal decision. We hope to help you make an informed decision that has the best possible outcome for you and your family. (April 2008)

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DNA: The Hereditary Stuff of Humans

DNA (deoxyribonucleic acid) is the hereditary material of humans and almost all other organisms. DNA is made up of chemical bases: adenine (A), thymine (T), cytosine (C), and guianine (G). The order of these paired bases determines the information available for building and maintaining organisms and their function. Each base pair is called a unit. Each unit is attached to a sugar molecule and a phosphate molecule. Collectively, a base unit, sugar molecule, and phosphate molecule are called a nucleotide. Nucleotides are arranged in pairs to form two long strands that spiral together and become a double helix. (April 2008)

Every human cell contains the same DNA. One important function of DNA is that it can replicate itself. Each strand of the double helix of DNA serves as a pattern for duplicating the sequence of bases. Because of this property, when cells divide, each new cell has an exact copy of the DNA present from the old cell. (April 2008)

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Understanding the Function and Dysfunction of Genes

A gene is the basic physical and functional unit of heredity. Genes are any given segment along DNA carrying a specific set of instructions. Each gene produces a specific product—typically a protein, such as an enzyme. (April 2008)

A sound body depends upon the harmonious interplay of thousands of proteins. Most diseases have their roots in our genes. Greater than 4000 diseases stem from altered genes we inherited from either our mother or father. Common diseases such as heart disease and most cancers arise from a complex interaction between multiple genes and our environment. (April 2008)

Genes can be altered in many ways. The most common way involves a single base mismatch. Other times a base may be added or deleted. Sometimes large pieces of DNA are erroneously repeated or deleted. Gene mutations can either be inherited or acquired. (April 2008)

Each human cell contains two sets of chromosomes: one set from your mother and one set from your father. Each set has twenty-three single chromosomes (autosomes) and one sex determining chromosome (XX for women and XY for men). (April 2008)

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Patterns of Inheritance

Genes come in pairs with one copy inherited from each parent. Alleles are alternative forms of a gene that are on a specific location on a chromosome.

In dominant genetic disorders, one parent has a disease producing alledominants, its counterpart. (April 2008)

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Hereditary Breast and Ovarian Cancer Syndrome (HBOCS)

The U.S. Preventive Services Task Force (2005) states that germline mutations in BRCA1 and BRCA2 have been associated with an increased risk for breast and ovarian cancer. HBOCS is an inherited condition that results in an increased risk for breast (often before age 50) and ovarian cancer. The majority of hereditary breast and ovarian cancer is due to a mutation in either the BRCA1 or BRCA2 genes. For women with a potentially deleterious BRCA mutation, the probability of developing breast or ovarian cancer by 70 years of age is estimated to be 35% to 84% for breast cancer and 10% to 50% for ovarian cancer.

Characteristics Associated with an Increased Risk of BRCA Mutations
  • Breast cancer diagnosed at an early age
  • Bilateral breast cancer
  • History of both breast and ovarian cancer
  • Presence of breast cancer in 1 or more male family members
  • Multiple cases of breast cancer in the family
  • Both breast and ovarian cancer in the family
  • One or more family members with 1 or more primary cases of cancer
  • Ashkenazi Jewish background

(April 2008)

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Management of HBOCS

Increased Surveillance:

According to U.S. Preventive Services Task Force, evidence on the efficacy of intensive surveillance to decrease morbidity and mortality is insufficient. However, expert groups recommend intensive screening for breast cancer in patients with BRCA mutation.

Mammogram versus MRI:

Descriptive studies report increased risk for cancer occurring between mammograms in BRCA positive patients with and without previous cancer who were receiving annual mammographic screening.

Strong evidence shows that an MRI has a higher sensitivity for detecting breast cancer among women with a BRCA1 or BRCA2 mutation than does mammography, clinical breast exam, or ultrasonography

Use of MRI, ultrasonography, and mammography in combination had the highest sensitivity.

The evidence is also insufficient to determine the morbidity and mortality effects of intensive screening for ovarian cancer.

1610 women with a family history of ovarian cancer were screened with transvaginal ultrasonography. The study showed a high rate of false-positive results.

Chemoprevention:

Tamoxifen, a selective estrogen receptor modulator, may decrease incidence of estrogen receptor-positive breast cancer in women without previous breast cancer.

Side effects include, but are not limited to, pulmonary embolism, deep venous thrombosis, and endometrial cancer.

Most breast cancer associated with BRCA1 mutations is estrogen receptor negative and, therefore, not prevented by tamoxifen use.

Preventive Surgery:

Four published studies (2 of fair quality and 2 that did not meet USPTF quality criteria) of prophylactic bilateral mastectomy in high-risk women show a consistent 85% to 100% reduction in risk for breast cancer despite differences among study designs and comparison groups. (April 2008)

Prophylactic oopherectomy reduced ovarian cancer risk outcomes by 85% to 100% and reduced breast cancer risk by 53% to 68%. (April 2008)

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Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

According to Genetics Home Reference, a service of the U.S. National Library of Medicine, HNPCC or Lynch Syndrome, is a type of inherited cancer of the digestive tract that usually affects the large intestine and rectum. Individuals with HNPCC syndrome have an increased risk of cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, and prostate. Women who have this syndrome are also at increased risk of developing endometrial and ovarian cancer. Individuals with this disorder may also have occasional noncancerous growths called colon polyps, despite the name which implies a nonpolyposis syndrome. Although the polyps do not occur in greater number than in the general population, they are more likely to become cancerous. HNPCC syndrome is responsible for approximately 2 to 7 percent of all diagnosed cases of colorectal cancers. HNPCC syndrome is inherited in an autosomal dominant inheritance pattern.

The genes responsible for HNPCC syndrome include variations of MLH1, MSH2, MSH6, and PMS2. MLH1 and MSH2 mutation carrriers have an estimated risk of between 70% and 82% of developing colorectal cancer by age 70 versus the general population whose risk is estimated to be at 2%. Endometrial cancer risk in those with this specific genetic mutation is estimated between 42% and 61% versus the general population with a 1.5% risk by age 70. Stomach cancer risk is estimated around 13% in MLH1 and MSH2 mutation carriers versus a less than 1% risk in the general population by the age of 70. Finally, ovarian cancer risk in MLH1 and MSH2 is estimated to be at 12% versus a 1% risk by age 70 in the general population. (April 2008)

Characteristics Associated with an Increased Risk of HNPCC
  • Personal history of colorectal cancer or endometrial cancer diagnosed before age 50
  • First-degree relative with colorectal cancer diagnosed before age 50
  • Colorectal cancer occurring in two or more generations, on the same side of the family
  • Two or more relatives with colorectal cancer or HNPCC-associated cancer (including endometrial, ovarian, gastric, hepatobiliary, small bowel, ureter), with one who is a first-degree relative of the other
  • Personal history of colorectal cancer and a first-degree relative with adenomas disagnosed before age 40
  • An affected relative with a known genetic mutation (MSH2, MLH1, MSH6, PMS2)

(April 2008)

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Management of HNPCC

The American Society of Clinical Oncology, the American Cancer Society, the American Gastroenterology Association, and the National Cancer Center Network have developed recommendations and practice guidelines for surveillance and management of individuals with hereditary colorectal cancer syndromes. The following is a summary of their recommendations:

Increased Surveillance

Colonoscopy should begin between the ages of 20 to 25 years (or 5 years earlier than the youngest colorectal cancer in the family, whichever occurs first) and should be repeated every 1 to 2 years.

Gynecologic exam: annual transvaginal ultrasound (to measure the thickness of the endometrium), endometrial tissue sampling/aspirate, and CA-125 should be initiated between the ages of 25 to 35 years and repeated every 1 to 2 years.

Screening for other HNPCC-associated cancers (stomach, kidney/urinary tract, biliary tract, brain, small bowel) may be considered based on the presence of that cancer in a family member.

Surgical Management

The American Society of Clinical Oncology recommends that subtotal colectomy be considered in HNPCC gene mutation carriers at the time of first diagnosis of a colon cancer.

Preventive removal of the endometrium and/or ovaries reduces the risk of endometrial and ovarian cancer and may be an option when childbearing is complete.

Unaffected mutation carriers not willing or unable to undergo screening colonoscopies may consider removal of the colon.

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The Adenomatous Polyposis Syndromes (FAP, AFAP, MYH)

Familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis, and MYH-associated polyposis (MA) account for less than 1% of all colon cancers.

Familial Adenomatous Polyposis (FAP)

Diagnosis is made clinically by the presence of greater than 100 colon polyps. Patients presenting with these many polyps should be referred for genetic testing. The adenomatous polyposis coli (APC) gene is responsible due to a mutation on chromosome 5 (at 5q21). The pattern of inheritance is autosomal dominant. It is estimated that one fourth to one third of cases are de novo which means there is no family history.

The following are characteristics associated with FAP:
  • Colon is carpeted with polyps
  • Appearance of polyps may occur as early as 20 years of age
  • 100% penetrance of this genetic mutation
  • Other related cancers include: ampulle of Vater, bile duct, small intestine, non-medullary thyroid cancer, childhood hepatoblastoma, stomach cancer
  • Other related nonmalignant tumors: sebaceous cysts, lipomas, demoid tumors, fibromas, osteomas of the jaw, epidermoid cysts

Attenuated Familial Adenomatous Polyposis (AFAP)

AFAP is also caused by a mutation on the APC gene. It is also a clinical diagnosis but presents with fewer colorectal polyps and has a later onset than classic FAP. Multiple extracolonic polyps may also be present.

By age 50, the risk of developing colorectal cancer is 0.2%, however with a mutation on the APC gene, the risk becomes 93%.

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MYH-Associated Polyposis (MAP)

MYH mutations account for 1% of all hereditary colorectal cancers. The pattern of inheritance is autosomal recessive, therefore an individual must have 2 copies of the mutated gene to be affected. Patients often have little or no family history of colon adenomas or cancer. They may present with extracolonic disease similar to FAP (see above). MYH mutations can be seen in patients present with classic FAP but is more likely the cause of adenomas seen in AFAP. MYH mutations can be present in cases with as few as 4 colonic adenomas to as many as 1000. Testing for this syndrome should be offered to patients with multiple colorectal adenomas (with or without cancer) and no clear family history. Testing for the 2 most common mutations on MYH (Y165C, G382C) or full sequencing of MYH gene is available commercially.

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Reducing the Risk of Cancer in the Adenomatous Polyposis Syndromes

FAP
  • Annual flexible sigmoidoscopy beginning between ages 10-12
  • Prophylactic colectomy is advised
  • Following a subtotal colectomy, flexible sigmoidoscopy of the remaining ileal pouch and rectum every 6 months to 3 years, depending on the number of polyps found on the previous exam
AFAP
  • Colonoscopy every 1 to 3 years beginning in the late teens or mid-twenties
  • Following a prophylactic subtotal colectomy (if necessary), flexible sigmoidoscopy of the remaining ileal pouch and rectum every 6 months to 3 years, depending on the number of polyps found on the previous exam
  • Prophylactic colectomy may not be necessary but should be considered on an individual basis
MAP
  • Risk reduction should be similar to FAP or AFAP depending on the number of polyps present

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Interpreting Results

An accurate genetic test can tell if a genetic defect is present, but it does NOT guarantee the disease will develop.

POSITIVE
  • A positive result signifies an increased cancer risk.
NEGATIVE
  • Single Site Analysis (when a mutation has previously been identified in the family): A negative result signifies no increased cancer risk and medical management is based on general population cancer screening recommendations.
  • Comprehensive Analysis (when no mutation has been previously identified in the family): A negative result signifies that the cancer risk for the individual is not fully defined and medical management is based upon personal and family history of cancer.
UNCERTAIN VARIANT
  • According to the U.S. Preventive Services Task Force, approximately 13% of tests report mutations of unknown significance (uncertain variant). An uncertain variant signifies that the cancer risk is not fully defined and medical management is based on personal and family history of cancer.

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Genetic Testing and Its Impact on the Workplace, Health Insurance, and Disability Insurance

According to Myriad Genetic Laboratories, over 100,000 people have been tested since the 1990s and to date there are no documented cases of health insurance discrimination. Experts in the government, scientific community, and insurance companies agree that the risk of genetic discrimination is very small.

HIPPA (The Health Insurance Portability and Accountability Act of 1996)

The Health Insurance Portability and Accountability Act of 1996 provided the first federal protections against genetic discrimination in the health insurance arena. In general, the act prevented health insurers from excluding individuals from group coverage due to past or present medical problems including genetic syndromes which may predispose them to certain diseases. HIPPA limited exclusions to group plans for preexisting conditions for 12 months and did not allow exclusions for those individuals who had been covered previously for that condition previously for 12 months. And the law specifically stated that the knowledge of genetic information did not constitute a preexisting condition. The following are some of the shortcomings of HIPPA as it relates to the potential for genetic discrimination:

  • Does not prevent health insurers from charging a higher rate to individuals based on their genetic makeup
  • Does not prevent health insurers from collecting genetic information or limit the disclosure of genetic information about individuals to insurers
  • Does not prevent insurers from requiring applicants to undergo genetic testing

ADA (Americans with Disabilities Act)

According to the National Human Genome Research Institute, a sector of the National Institutes of Health, the ADA is the most likely current source of protection against genetic discrimination in the workplace. However, the ADA and other similar disability-based anti-discrimination laws do not explicitly address genetic information. They do serve to provide some protections against disability-related genetic discrimination in the workplace. Outlined by the ADA, individuals with symptomatic genetic disabilities have the same protections against discrimination as individuals with other disabilities. Also, under the protection of the ADA, an employer generally may not make medical inquiries about a job applicant prior to extending a conditional offer of employment. The following are some of the potential areas of concern with the ADA as it relates to genetic discrimination:

  • Individuals with unexpressed genetic conditions that do not fall within clear disability-based discrimination prohibitions of the ADA will not be protected.
  • Once a conditional offer of employment has been made, the employer may obtain extensive medical information about the applicant, including genetic information.

GINA (Genetic Information Nondiscrimination Act of 2007)

GINA was passed in the U.S. House of Representatives by a vote of 420-3. The act will protect individuals against discrimination based on their genetic information when it comes to health insurance and employment. These protections are intended to encourage Americans to take advantage of genetic testing when appropriate as part of their medical care.

For more information about how these laws apply to you, please visit the National Human Genome Research Institute at: http://www.genome.gov/PolicyEthics/LegDatabase/pubMapSearch.cfm (April 2008)

RED FLAGS FOR CONSIDERING GENETIC COUNSELING AND TESTING
  • Breast cancer under age 50
  • Bilateral breast cancer
  • Ovarian cancer at any age
  • More than 10 polyps on a colonoscopy
  • More than 20 polyps over a lifetime
  • Kidney cancer
  • Medullary thyroid cancer
  • Pediatric sarcoma in a family history
  • Multiple family members with cancer in successive generations
  • Early onset of cancer
  • Unusual cancer or a common cancer in an unusual site

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