Cancer Predisposition Program

CMMRD is a genetic condition in which individuals are born with a predisposition to develop many different types of childhood and adult-onset cancers. The average age of cancer diagnosis in patients with this syndrome is age 7.

Cancers most often diagnosed in children with CMMRD include:

• Leukemia and lymphoma (especially non-Hodgkin lymphoma)
• Glioblastoma multiforme and high-grade gliomas
• Colon cancer

CMMRD syndrome is caused by genetic changes in both copies of a mismatch repair gene. These include MLH1, MSH2, MSH6, PMS2 and EPCAM. An individual must inherit a nonworking copy of a gene from each of his or her parents in order to be affected by this syndrome. In most cases, the parents themselves will not be diagnosed with cancer; the child with cancer is most often the first patient identified in the family. Each parent of a child with CMMRD has an adult-onset syndrome called Lynch syndrome, which increases lifetime risk of colon, endometrial and other types of cancers.

The incidence of CMMRD syndrome is unknown and thought to be very rare. Fewer than 500 patients with CMMRD syndrome have been reported in the medical literature.

CMMRD syndrome can be diagnosed through genetic testing that is facilitated by a genetic counselor or genetics services provider.

Children and adults with CMMRD syndrome should receive care at centers with expertise in this syndrome.

DICER1 syndrome, also known as DICER1-pleuropulmonary blastoma familial tumor predisposition syndrome, is a condition in which an individual is born with genetic changes that predispose him or her to develop benign and malignant tumors during childhood, through adolescence and, rarely, as an adult.

In childhood, these most often include:

• Pleuropulmonary blastoma
• Ovarian sex cord stromal tumors
• Cystic nephroma
• Genitourinary rhabdomyosarcomas
• Increased risk for familial nodular goiter
• Pineoblastomas
• Pituitary blastomas
• Ciliary body medulloepitheliomas
• Renal sarcomas

The genetic changes that cause this syndrome are found in the DICER1 gene, a tumor suppressor gene. When working normally, both copies of this gene help suppress the development of cancer. However, individuals with DICER1 syndrome are born with one working copy and one nonworking copy.

This genetic change is passed down from either parent 80% of the time. However, 20% of the time, this genetic change occurs on its own in an oocyte or sperm cell prior to fertilization.

DICER1 syndrome can only be diagnosed after genetic testing. This process is facilitated by a genetic counselor, who will discuss family history, complete a risk assessment, and explain testing benefits and options.

Not all individuals with a diagnosis of DICER1 syndrome will develop tumors or cancer. Surveillance strategies are important because if cancer does develop, it can be caught and treated as early as possible.

FAP syndrome is a genetic syndrome that predisposes individuals to develop hundreds to thousands of adenomatous polyps, in addition to colorectal cancer, papillary thyroid cancer and other cancers. Every patient with FAP will develop colorectal cancer, typically by age 40, unless screening and preventive measures are taken.

In childhood, patients with FAP are at risk for developing:

• Hepatoblastoma (a type of liver cancer), typically before age 5
• Medulloblastoma (a type of brain cancer)
• Thyroid cancer
• Gastrointestinal (especially colorectal) polyps
• Desmoid tumors (typically noncancerous)
• Extra/additional teeth

FAP is caused by inherited genetic changes in the APC gene. A child of a parent diagnosed with FAP has a 50% chance of inheriting this condition. While the majority of cases are passed down to a child from a parent, nearly 20% of cases of FAP occur for the first time in the affected child and are not inherited.

The incidence of FAP is estimated to be 1 in 14,000.

FAP can be diagnosed through genetic testing, which is typically performed by a genetic counselor. Family history of polyposis, “carpeted colon” appearance on a colonoscopy or colon cancer diagnosed at an early age (20 to 40 years old) can also increase the likelihood of this diagnosis.

Guidelines and recommendations for the care and surveillance of children and adults with FAP include:

• Annual colonoscopy screening beginning between ages 10 and 15.
• Cervical palpation of thyroid.
• Abdominal ultrasound and labs.
• Annual physical exam by pediatric hematologist/oncologist with expertise in caring for patients with FAP.

HPPS includes a number of different genetic syndromes that predispose individuals to develop paragangliomas (tumors that form from neuroendocrine tissue) and pheochromocytomas (similar tumors that form in the adrenal medulla). These tumors may or may not secrete hormones, and while the majority are benign (nonmalignant), a few of them can go on to become cancerous (malignant).

Patients with HPPS are also at an increased risk of developing the following, depending on the specific genetic syndrome:

• Renal cell carcinoma (a type of kidney cancer)
• Gastrointestinal stromal tumors
• Papillary thyroid carcinoma, pituitary adenomas and other neuroendocrine tumors

HPPS is caused by genetic changes in the following genes, which act as tumor suppressor genes:

• SDHx (SDHA, SDHB, SDHC, SDHD, SDHAF2)
• TMEM27
• MAX
• VHL
• NF1
• RET

A tumor suppressor gene, when working properly, encodes proteins that prevent the growth and development of tumors in the human body. The incidence of HPPS is unknown.

HPPS can be diagnosed through genetic testing that is facilitated by a genetic counselor or genetics services provider. Any patient diagnosed with a paraganglioma or a pheochromocytoma should be referred to genetic counseling or medical genetics to discuss genetic testing and be evaluated for HPPS.

The medical monitoring of children and adults with HPPS should start between ages 6 and 8 and often includes:

• Annual lab work (e.g., plasma metanephrines).
• Whole-body MRIs (skull to pelvis) once every two years.
• Blood pressure checks at all clinical visits.
• Physical exam (annually).

LFS is a syndrome that predisposes individuals to develop several types of benign and malignant tumors. In childhood, this most often includes:

• Choroid plexus carcinoma, a type of brain tumor
• Adrenocortical carcinoma, which is present in the adrenal glands located on top of the kidneys
• Osteosarcoma, or bone tumor
• Rhabdomyosarcoma, or soft tissue tumor

LFS is caused by genetic changes that occur in the TP53 gene, which is often called the guardian of the genome and has several vital functions, including preventing tumor development and controlling the cell cycle. In 7-20% of cases, LFS may occur on its own, without being passed down from either parent. However, in most cases, genetic alterations, or changes in the TP53 gene that cause LFS, are inherited from one parent. This means that a patient’s full siblings also have a 50% chance of having Li-Fraumeni syndrome.

Not everybody with LFS will develop cancer in childhood, though almost 100% of women and 85-90% of men with this syndrome will go on to develop cancer in their lifetimes. In large groups of patients with LFS, 22% received a cancer diagnosis by age 5, and 40% developed their first cancer by age 18.

Diagnosis of LFS occurs through genetic testing, which is often facilitated by a genetic counselor or a clinical oncology team.

Due to the increased risk of cancer, monitoring is recommended for both children and adults with LFS. This is best done at a center where physicians, genetic counselors and geneticists have expertise in LFS.

A diagnosis of LFS may change treatment plans for existing cancers, as well as medical management and future surveillance or monitoring plans, as individuals with LFS are extremely sensitive to radiation and at increased risk for secondary cancers.

Research has shown that patients with LFS who undergo regular surveillance have a significantly higher overall survival than those who do not undergo regular surveillance.

Once an individual has been identified as having LFS, a genetic counselor can help identify family members who may be at risk for LFS. All family members at risk may choose to pursue genetic counseling and testing.

Rhabdoid predisposition syndrome is a genetic condition in which individuals are born with an increased likelihood of developing soft tissue tumors called rhabdoid tumors. These develop primarily in the kidneys and brain but can also develop elsewhere in the body, such as in the ovaries. In the brain, they are called atypical teratoid rhabdoid tumors.

Most often, these tumors are diagnosed before a child’s fifth birthday, but they can also present in older individuals.

This syndrome is caused by genetic changes in the SMARCA4 and SMARCB1 genes. Both of these genes act as organizers of the genome, specifically with regard to chromatin structuring and packing, or chromatin remodeling.

Individuals with rhabdoid predisposition syndrome are born with these changes, and in about 40% of cases, the changes are passed down from one parent. Not everybody born with rhabdoid tumor predisposition syndrome will go on to develop these types of tumors.

Rhabdoid predisposition syndrome can be diagnosed through genetic testing, which is often facilitated by a genetic counselor or genetics services provider.

Guidelines for monitoring of children and adults with rhabdoid predisposition syndrome include:

• Brain MRI every three months until age 5.
• Ultrasound of abdomen every six months.
• Physical exams by pediatric hematologist/oncologist once a year.

VHL syndrome is a genetic condition in which individuals are born with a predisposition to develop a range of benign and malignant tumors. These include:

• Renal cell carcinoma (a type of kidney cancer)
• Tumors of the liver, pancreas and adrenal gland (pheochromocytomas)
• Hemangioblastomas (brain and spine) and retinal angiomas
• Endolymphatic sac tumors that may cause hearing loss
• Epididymal and broad ligament cystadenomas

VHL syndrome is caused by genetic changes in the VHL gene, which acts as a tumor suppressor. A tumor suppressor gene, when working properly, encodes proteins that prevent the growth and development of tumors in the human body.

The incidence of VHL syndrome is estimated to be 1 in 30,000.

VHL syndrome can be diagnosed through genetic testing that is facilitated by a genetic counselor or genetics services provider.

Some families have had a diagnosis of VHL syndrome without any previous genetic testing, based on multiple hemangioblastomas and other tumor types that are associated with this syndrome.

Guidelines for the medical monitoring of children and adults with VHL syndrome often include:

• Annual lab work (e.g., plasma metanephrines).
• Annual eye exams by an ophthalmologist familiar with this syndrome.
• Biannual brain, spine and abdominal MRIs.
• Blood pressure checks at all medical visits.