Hereditary Cancer Syndromes

Hereditary Gynecologic Cancer Syndromes
Cancers arise due to accumulation of damage to genes involved in controlling cell growth and DNA repair. In contrast to “sporadic” cancers, in which all mutations are acquired after birth, hereditary cancers arise in individuals who have inherited a mutation in a cancer-causing gene. These individuals generally develop cancer at a younger age than those with sporadic cancers and often develop multiple cancers. Approximately 5-10 percent of cancers arise due to inherited mutations in genes responsible for hereditary cancer syndromes. The most common hereditary cancer syndromes that cause gynecologic cancers are hereditary breast-ovarian cancer syndrome, and Lynch syndrome, and these are discussed below. Other inherited gene mutations may predispose to gynecologic cancers to a lesser degree, but would not typically manifest as a hereditary cancer syndrome.

Hereditary Breast-Ovarian Cancer Syndrome
In the United States, approximately 10 percent of women will develop breast cancer and 1.5 percent will develop ovarian cancer. Inherited mutations in the BRCA1 and BRCA2 genes dramatically increase the risk of breast, ovarian, fallopian tube and peritoneal cancers. The lifetime risk of having one of the gynecologic cancers is 39-46% in BRCA1 carriers and 12-20% in BRCA2 carriers. These gene mutations also markedly increase breast cancer risk, causing a lifetime risk of 40-85% compared to 12% in the general population. BRCA1 and BRCA2 associated cancers often occur at much earlier ages than most ovarian and breast cancers and it is also common to find multiple women with these cancers in affected families. Approximately 1 out of every 500 individuals in the general population has a mutation in one of the BRCA genes. In certain ethnic groups the mutation frequency is much higher (for example, one out of every 40 Ashkenazi Jewish individuals carry mutations). Both men and women can carry BRCA mutations and have a 50 percent chance of passing the mutation on to each of their children.

If you have a personal or family history of any of the following medical criteria, you may be at risk for a hereditary cancer syndrome. Speak to your doctor, genetic counselor, or other qualified healthcare professional to determine if you are at risk for a hereditary cancer syndrome (Hereditary Breast and Ovarian Cancer Syndrome or Lynch syndrome). They will know best how to proceed with hereditary risk assessment and genetic testing if necessary.

  • A close blood relation (i.e. mother, sister, daughter, grandmother, granddaughter, aunt or niece), on either your mother’s or father’s side of the family, who has had ovarian cancer at any age.
  • Personally had breast cancer before age 45.
  • Personally had breast cancer before age 50 and have at least one close relative who has had breast cancer prior to age 50, or ovarian cancer at any age, or a male relative with breast cancer at any age.
  • Two or more close relatives on the same side of the family (either your mother’s or father’s) that have had breast cancer before age 50 or ovarian cancer at any age.
  • Eastern European (Ashkenazi) Jewish ancestry, and you or a close relative, on either side of your family, has had breast cancer before age 50, or ovarian cancer at any age, or male breast cancer at any age.

In addition, regardless of family history, genetic testing should be considered in women with high grade serous ovarian cancer, which comprises about two-thirds of cases, as about 20% will be found to have BRCA mutations. Genetic testing is performed using a blood sample and generally begins by focusing on a family member who has been diagnosed with breast or ovarian cancer. If a mutation in either BRCA1 or BRCA2 is found, other family members can then be tested to see if they also inherited the same mutation. For women who are at high risk on the basis of a strong family history or a positive BRCA gene test, a spectrum of options exist, including clinical monitoring (mammograms, CA125 blood test, pelvic ultrasound), preventive medications such as oral contraceptives and Tamoxifen, and prophylactic (preventive) surgery. Because of the lack of a reliable screening test for ovarian cancer, prophylactic removal of the ovaries and fallopian tubes is generally recommended after completion of childbearing and also reduces breast cancer risk. The risk of uterine cancer is not increased, but hysterectomy is often performed as well, particularly if there is coexistent uterine pathology, such as fibroids or endometriosis.

Lynch Syndrome
Lynch syndrome was named after Henry Lynch, who first described familial clustering of early onset colorectal cancer. This syndrome is due to inherited mutations in DNA mismatch repair genes, most often MSH2 and MLH1, but mutations may also occur in MSH6, PMS1 and PMS2. About 1 in 1000 individuals in the US carry a Lynch syndrome mutation. There is also an increased incidence of several other types of cancers in Lynch syndrome—most notably endometrial cancer risk is 40-60%. About 3-5% of all endometrial cancers are attributable to Lynch syndrome, and these cancers usually are confined to the uterus and rarely are fatal. The risk of ovarian cancer is also significantly increased to about 10%, but this accounts for only about 1% of all ovarian cancers. Ovarian cancers in women with Lynch syndrome also generally present at an early stage. The risk of stomach, small intestine, liver, brain, and urinary system cancers is also increased.

The Amsterdam criteria for diagnosis of Lynch syndrome include: (1) three or more relatives with Lynch syndrome associated cancers; (2) two affected relatives in successive generations, (3) one affected relative is a first-degree relative of the other two, and (4) one or more relatives with Lynch syndrome-associated cancer diagnosed before the age of 50 years. In the context of a concerning family history, genetic testing from a blood sample can be performed to detect the gene mutations that cause Lynch syndrome. In addition, screening for Lynch syndrome can be performed using cancer tissue by looking for loss of one of the mismatch repair genes or for a change know as microsatellite instability. Screening of all colorectal and endometrial cancers for Lynch syndrome has been advocated by some experts, but this practice has not been widely implemented.

Women with Lynch syndrome should be monitored carefully by their health care provider. Current recommendations include frequent evaluation of the colon by colonoscopy starting in the 20s. Women should also be advised to consider having the CA125 blood test and transvaginal ultrasound annually to evaluate the ovaries and a biopsy of the lining of the uterus (endometrium) annually beginning at age 25 to 35 years. Colorectal cancer is the main cause of cancer mortality in Lynch syndrome. If a woman with Lynch syndrome requires surgical removal of the colon (colectomy) because of cancer or pre-cancer changes, then it is also appropriate to remove the uterus and ovaries at the same time to reduce the risk of ovarian and endometrial cancer. Generally, this can be delayed until after childbearing is complete because Lynch syndrome associated gynecologic cancers are infrequent prior to age 40 and are usually curable.

The discovery of the genes responsible for hereditary gynecologic cancer syndromes represents an exciting advance. Although there have been concerns about the possibility of genetic discrimination against BRCA1/2 and Lynch syndrome mutation carriers with respect to employment and insurance, genetic non-discrimination laws have been enacted and this has not occurred. The ability to perform genetic testing allows the women at highest risk to consider options for prevention and early detection that can reduce the risk of dying from cancer. It is essential for each woman to discuss her family history and other cancer risk factors with her physician that can be translated into a personalized cancer risk assessment and prevention strategy.


The Foundation gratefully acknowledges Myriad Genetics, Inc. for sponsorship of the Hereditary Cancer Syndrome section of the website.  Sponsorship excludes editorial input.


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