Tufts Medical Center - Genetic Risk Assessment

Approximately 5-10% of all cancer is due to inherited gene changes (mutations) that predispose people to certain types of cancer. Genes are pieces of DNA code that regulate cell growth and replication. If these genes have abnormal code, a person may have an increased predisposition to cancer in a lifetime.

Inheritance

Gene changes that predispose to cancer are usually inherited (passed down) in an autosomal dominant fashion. This means that each time a person with a cancer predisposition gene has a child, there is a 50 percent chance (one out of two) that the child will inherit this trait. Therefore, we expect to see certain types of cancers within families, generation after generation, affecting about half of the offspring of each affected parent.

Inherited Predisposition to Cancer Indicators

o Cancer before 50 years of age

o Two types of cancer in the same person

o Two episodes of the same type of cancer in one person

o Several generations affected by one type of cancer

o Cancer in certain combinations within a family

o Colon, uterine, stomach, ovarian, intestinal, biliary, renal, brain (link to pg.2)

o Breast, ovarian, prostate, pancreatic , melanoma (link to p.3)

o Melanoma, pancreatic-link

o And others-link

Genetic Risk Assessment

A genetics profession will review your personal medical history as well as your family’s medical history back through several generations. The geneticist will then discuss your risk of having a genetic predisposition to cancer, whether genetic testing is indicated, and information regarding preventative cancer screening and surgeries.

Cancer Genetics Clinic

Genetic risk assessment and testing is available at:

Tufts Medical Center, Floating Hospital for Children

800 Washington St, 3^rd Floor

Boston, MA 02111

Appointments: (617) 636-8100

Questions: (617) 636-7790

Our Experts:

Laurie Demmer, MD

Jaclyn Douyard, ScM, CGC

Jodi D. Hoffman, MD

Hereditary Colon Cancer Syndromes

About 5-10% of all colorectal cancer is hereditary. There are several different genetic syndromes with increased risk for colon cancer. The following are some of the most common colorectal cancer syndromes. Scroll down the page to read complete information on:

Lynch Syndrome/HNPCC

Familial Adenomatous Polyposis (FAP)/AFAP/MYH

Peutz Jeghers Syndrome

Lynch Syndrome/HNPCC

Lynch syndrome, also known as hereditary non-polyposis colorectal cancer syndrome, accounts for approximately 3-5% of all cases of colon cancer. It is caused by mutations in more than 4 genes. This cancer syndrome can increase one’s lifetime risk for colon cancer to approximately 80% (without screening) and the risk for uterus cancer to about 60%. It may also increase the risk for other cancers such as stomach, ovarian, intestinal, biliary, brain, renal and skin cancer.

Genetic Testing

If you are determined to be at increased risk for Lynch syndrome, a blood sample can be drawn and sent for analysis of the four most common known genes to cause Lynch syndrome called MLH1, MSH2, MSH6, and PMS2. New genetic tests for Lynch syndrome are being developed.

Tumor Testing

Your doctor may perform a preliminary test on your polyps or colon cancer to help determine whether a genetic cause is likely. Two methods currently used are called MSI (microsatellite instability) and IHC (immunohistochemistry).

Insurance Coverage

This testing is often covered by medical insurance, as medical insurers encourage their members to avail themselves of care that will improve their health and lifespan.

Why should I consider genetic testing?

Interventions are available for people with Lynch Syndrome. Your doctor will discuss interventions that might be right for you such as:

o Colonoscopies to screen for polyps and early colorectal cancers

o Consideration of uterine ultrasounds and scrapings

o Consideration of upper GI scopes

o Consideration of removal of portion of the bowel, uterus or ovaries

Genetic testing results are also important for family members who may not know that they are at increased risk for cancer. Screening and early detection of cancer can save lives.

Who should be tested for Lynch Syndrome?

People who have a personal or family history of early onset or multiple colon, uterine, and related cancers may benefit from genetic testing.

Testing is generally performed after the age of consent (18 years), as there is little medical intervention available for people prior to age 20-25.

Please speak to your cancer specialist or primary care physician to determine if referral to a genetics clinic would be useful for you.

For more information visit: http://ghr.nlm.nih.gov/condition/lynch-syndrome

Familial Adenomatous Polyposis (FAP)

FAP is an inherited cancer predisposition syndrome that causes the formation of hundreds to thousands of colon polyps early in life. FAP accounts for approximately 1% of all cases of colon cancer. This cancer syndrome increases one’s lifetime risk for colon cancer to 100% without surgical intervention by 38 years of age. It may also increase the risk for other cancers and non-cancer findings such as jaw growths, pigment in the eyes, and extra or missing teeth.

Genetic Testing

If you are determined to be at increased risk for FAP, a blood sample can be drawn and sent for analysis of the most common known gene that causes FAP called APC.

A less severe form of FAP called Attenuated Familial Adenomatous Polyposis (AFAP) can also be caused by mutations in the APC gene.

A closely related syndrome with autosomal recessive inheritance (both copies of the gene have changes) is due to mutations in a gene called MYH. Testing for this syndrome is warranted when a person has tens to hundreds of polyps and no family history of colon cancer other than siblings with colon cancer.

Insurance Coverage

This testing is often covered by medical insurance, as medical insurers encourage their members to avail themselves of care that will improve their health and lifespan.

Why should I consider genetic testing?

Interventions are available for those people with mutations in the APC and MYH genes. You doctor will discuss interventions that might be right for you such as:

o Colonoscopies to screen for polyps and early colorectal cancers

o Upper GI scopes

o Consideration of removal of portion of the bowel early in life

Genetic testing results are also important for family members who may not know that they are at increased risk for cancer. Screening and early detection of cancer can save lives.

Who should be tested for FAP?

People who have a personal or family history of early onset colon cancer with tens to thousands of polyps may benefit from genetic testing.

Although genetic testing is generally performed after the age of consent (18 years), due to the need for early surveillance and surgical interventions for FAP, genetic testing is often discussed at approximately 10-12 years of age, and sometimes even younger.

Please speak to your cancer specialist or primary care physician to determine if referral to a genetics clinic would be useful for you.

For more information visit: http://ghr.nlm.nih.gov/condition/familial-adenomatous-polyposis

Peutz-Jeghers Syndrome (PJS)

Peutz-Jeghers syndrome is an inherited cancer predisposition syndrome that causes hamartomatous polyps throughout the small intestine along with dark pigment on the lips, inside the mouth, and on the fingertips. The polyps can cause bowel obstruction early in life. Later in life, people with Peutz-Jeghers syndrome are at significantly increased risk for colon, breast, pancreatic, stomach, ovarian, lung and bowel tumors.

Genetic Testing

If you are determined to be at increased risk for Peutz-Jeghers syndrome, a blood sample can be drawn and sent for analysis of the gene that causes PJS called STK11.

Insurance Coverage

This testing is often covered by medical insurance, as medical insurers encourage their members to avail themselves of care that will improve their health and lifespan.

Why should I consider genetic testing?

Interventions are available for those people with mutations in the STK11. You doctor will discuss interventions that might be right for you such as:

o Colonoscopies to screen for polyps and early colorectal cancers

o Upper GI scopes to look for polyps in the stomach and intestines

o Screening for breast and reproductive organ cancers

Genetic testing results are also important for family members who may not know that they are at increased risk for cancer. Screening and early detection of cancer can save lives.

Who should be tested for Peutz-Jeghers Syndrome?

People who have a personal or family history of blue to brown spots of the lips, cheeks, and fingertips, people with hamartomatous polyps, and people with a family history of these findings may benefit from genetic testing.

Although genetic testing is generally performed after the age of consent (18 years), due to the need for early surveillance PJS, genetic testing is often discussed at approximately 8 years of age.

Please speak to your cancer specialist or primary care physician to determine if referral to a genetics clinic would be useful for you.

For more information visit: http://ghr.nlm.nih.gov/condition/peutz-jeghers-syndrome

Hereditary Breast and Ovarian Cancer

About 5-10% of all breast and ovarian cancer is hereditary. There are several different genetic syndromes with increased risk for these cancers. The following are some of the most common breast and ovarian cancer syndromes. Scroll down the page to read complete information on:

Hereditary Breast and Ovarian Cancer Syndrome

PTEN Hamartomatous Tumor Syndrome (Cowden)

Li Fraumeni Syndrome

Lynch Syndrome

Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

HBOC syndrome is a genetic predisposition syndrome that increases the likelihood of breast and/or ovarian cancer in a lifetime, often at a younger age. Breast cancer lifetime risk may be as high as 87%. Ovarian cancer lifetime risk ranges may be as high as 44%.

Genetic Testing

If you are determined to be at increased risk for HBOC, a blood sample can be drawn and sent for analysis of the two most common known genes to cause HBOC called BRCA1 and BRCA2.

Insurance Coverage

This testing is often covered by medical insurance, as many medical insurers encourage their members to avail themselves of care that will improve their health and lifespan.

Why should I consider genetic testing?

Interventions are available for those with HBOC. You doctor will discuss interventions that might be right for you such as:

o Imaging of the breasts at an earlier age than provided for the general population

o Consideration of imaging of the ovaries

o Use of medications that may decrease the risk of breast and/or ovarian cancer

o Consideration of prophylactic removal of breast and/or ovarian tissue, especially after the completion of childbearing

Genetic testing results are also important for family members who may not know that they are at increased risk for cancer. Screening and early detection of cancer can save lives.

Who should be tested for HBOC?

People who have a personal or family history of early onset breast and/or ovarian cancer may benefit from genetic testing. Your doctor can help determine whether genetic risk assessment is appropriate for you.

Testing is generally performed after the age of consent (18 years), as there is little medical intervention available for people prior to age 25.

Men may also benefit from testing for HBOC, as HBOC may increase the risk for prostate cancer as well as male breast cancer. Both men and women with HBOC may have an increased risk for pancreatic cancer and melanoma in addition to breast and ovarian cancer (in women).

Please speak to your cancer specialist or primary care physician to determine if referral to a genetics clinic would be useful for you.

For more information visit: http://ghr.nlm.nih.gov/condition/breast-cancer

PTEN Hamartomatous Tumor Syndrome (PHTS)

PHTS is a genetic predisposition syndrome that includes Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. Both syndromes cause the growth of benign tumors in many areas of the body and increase the likelihood of certain cancers.

Cowden syndrome causes large head size, skin growths, as well as in an increased risk for multiple benign and malignant tumors including:

Breast cancer lifetime risk ranges from 25-50%

Thyroid cancer (usually follicular, occasionally papillary) ~10%

Endometrial cancer risk ranges from 5-10%

Bannayan-Riley-Ruvalcaba syndrome causes large head size, fatty growths (lipomas), gastrointestinal hamartomatous polyps, penile freckling, but is less likely to result in cancer.

Genetic Testing

If you are determined to be at increased risk for a PHTS, a blood sample can be drawn and sent for analysis of the most common known gene to cause PHTS called PTEN.

Insurance Coverage

This testing is often covered by medical insurance, as many medical insurers encourage their members to avail themselves of care that will improve their health and lifespan.

Why should I consider genetic testing?

Interventions are available for those with PHTS. You doctor will discuss interventions that might be right for you such as:

o Imaging of the breasts at an earlier age than provided for the general population

o Imaging of the thyroid gland at an early age

o Surveillance of the bowel and uterus

o Regular complete physical exams and urinalysis

Genetic testing results are also important for family members who may not know that they are at increased risk for cancer. Screening and early detection of cancer can save lives.

Who should be tested for PHTS?

People who have a personal or family history of large heads and skin lesions in combination with breast, thyroid, and uterus cancer may benefit from genetic testing. Your doctor can help determine whether genetic risk assessment is appropriate for you.

Testing is generally performed after the age of consent (18 years), as there is little medical intervention available for people prior to this age.

Please speak to your cancer specialist or primary care physician to determine if referral to a genetics clinic would be useful for you.

For more information visit: http://ghr.nlm.nih.gov/condition/cowden-syndrome

Other Cancer Predisposition Syndromes

Although the majority of all cancers are sporadic (by chance), approximately 5-10% of all cancers are due to a genetic predisposition. If diagnosed, increased screening and surveillance of associated cancers are available for each condition. Your physician can help determine whether genetic consultation would be beneficial for you.

Below are brief descriptions of some of the rarer cancer predisposition syndromes. Scroll down the page to read more about these cancer syndromes.

Birt-Hogg-Dubé Syndrome

Familial Atypical Multiple Mole Melanoma

Hereditary Diffuse Gastric Cancer Syndrome

Hereditary Leiomyomatosis and Renal Cell Cancer

Hereditary Retinoblastoma

Juvenile Polyposis

Li Fraumeni Syndrome

Multiple Endocrine Neoplasia

von-Hippel-Lindau

Birt-Hogg-Dubé Syndrome includes three main issues: 1) multiple flesh colored skin growths, 2) lung blebs and predisposition to pneumothorax, and 3) predisposition to several types of renal tumors. This is autosomal dominant and passed on in a 50:50 fashion. Genetic testing for mutations in the Birt-Hogg Dubé gene called FLCN is available.

For more information visit: http://ghr.nlm.nih.gov/condition/birt-hogg-dube-syndrome

Familial Atypical Multiple Mole Melanoma causes multiple dysplastic nevi that can become melanomas as well as an increased risk of pancreatic cancer. This syndrome increases the lifetime risk of cancer to over 90%. This is autosomal dominant and passed on in a 50:50 fashion. Genetic testing for the most common known gene to cause FAMMM called p16 is available.

Hereditary Diffuse Gastric Cancer Syndrome predisposes to stomach cancer and lobular breast cancer. This is autosomal dominant and passed on in a 50:50 fashion. The most common known gene to cause hereditary gastric cancer is called CDH1. Individuals with a CDH1 mutation have an average lifetime risk of gastric cancer of 67% in men and 83% in women, and women have an average lifetime risk of 39% for lobular breast cancer. Genetic testing of CDH1 is available.

For more information click visit: http://ghr.nlm.nih.gov/gene/CDH1.

Hereditary Leiomyomatosis and Renal Cell Cancer predisposes to cutaneous leiomyomas, uterine fibroids, and renal cell cancer in 10-16% due to mutations in the FH gene. This is autosomal dominant and passed on in a 50:50 fashion. Genetic testing for this condition is available. For more information visit: http://ghr.nlm.nih.gov/condition/hereditary-leiomyomatosis-and-renal-cell-cancer.

Hereditary Retinoblastoma is characterized by retinoblastoma that can be unilateral unifocal, unilateral multifocal, or bilateral. Individuals are also at increased risk for other cancers later in life. This is autosomal dominant and passed on in a 50:50 fashion. Hereditary retinoblastoma is due to mutations in the RB1 gene and genetic testing is available. For more information visit: http://ghr.nlm.nih.gov/condition/retinoblastoma.

Juvenile Polyposis is characterized by multiple hamartomatous polyps of the colon that present early in life. People with these polyps have an increased risk of colon cancer (39%) and other gastrointestinal tract cancers (21%). This is autosomal dominant and passed on in a 50:50 fashion due to mutations in two genes, SMAD4 and BMPR1A. Genetic testing for this condition is available. For more information visit: http://ghr.nlm.nih.gov/condition/juvenile-polyposis-syndrome.

Li Fraumeni Syndrome (LFS) predisposes to early onset breast cancer (often <30 years), bone and soft tissue cancers, brain tumors, and adrenocorticol carcinoma as well as other cancers. Li Fraumeni increases the lifetime risk of cancer to approximately 100% in women and about 73% in men. This is autosomal dominant and passed on in a 50:50 fashion. The most common known gene to cause LFS is called TP53 and genetic testing is available. For more information visit: http://ghr.nlm.nih.gov/condition/li-fraumeni-syndrome.

Multiple Endocrine Neoplasia Syndrome (MEN) is divided into several types. Type 1 includes increased risk for multiple types of neuroendocrine tumors. Type 2 includes increased risk for medullary thyroid cancer (MTC), with type 2a also including pheochromocytoma and parathyroid adenomas, and type 2b including pheochromocytoma, a tall, lanky body habitus, mouth growths, and gastrointestinal growths, and type 3 called familial medullary thyroid carcinoma only involving MTC. These are autosomal dominant and passed on in a 50:50 fashion. MEN 1 is due to mutations in the MEN1 gene and MEN2 is due to mutations in the RET gene. Genetic testing is available. For more information visit: http://ghr.nlm.nih.gov/condition/multiple-endocrine-neoplasia.

von-Hippel-Lindau (VHL) predisposes to renal cell carcinoma, hemangioblastomas, and pheochromocytomas, as well as other tumors and cysts. Almost everyone who has VHL will develop features of the condition. This is an autosomal dominant condition due to mutations in the gene VHL. Genetic testing is available. For more information visit: http://ghr.nlm.nih.gov/condition/von-hippel-lindau-syndrome