Cancer Genetics

Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant familial cancer syndrome associated with an increased risk for various types of cancer including; sarcomas, breast cancer, brain cancer, leukemia, adrenal cortical carcinoma, melanoma, colon cancer and pancreatic cancer. This syndrome was originally referred to as sarcoma, breast, leukemia, adrenal gland (SBLA) syndrome, however research has noted that the spectrum of tumors associated with Li-Fraumeni is broader than originally thought. Li-Fraumeni Syndrome is a highly penetrant syndrome, with a 50% risk for cancer by age 40, and a 90% risk for cancer by the age of 60. Individuals with Li-Fraumeni are also at risk to develop multiple primary tumors.

Clinical Criteria

The classic definition of Li-Fraumeni in a family requires:

Genetics

Li-Fraumeni is diagnosed based on the established clinical criteria listed above. More than 50% of individuals meeting the diagnostic criteria will have an identifiable mutation in the TP53 gene (also known as the p53 gene). The p53 gene is located at 17p13.1 and most of the mutations that have been identified occur in exons 5-8 of the gene. p53 is a well-known tumor-suppressor gene. Normally p53 exists in an inactive state. When there is damage to the DNA, p53 is activated and halts the cell cycle. When activated, p53 forms a transcription factor as a tetramer, and binds to several gene promoters. These genes cause disruption of the cell cycle to allow time for DNA repair, or if the damage is too severe, trigger the steps leading to apoptosis (programmed cell death). If p53 is damaged or mutated, it will remain in the inactive state allowing DNA damage to accumulate within a cell, thus increasing the risk for cancer formation.

Some families with Li-Fraumeni or Li-Fraumeni-like Syndrome who have tested negative for mutations in the p53 gene have been identified as having a mutation in the CHEK2 gene. The CHEK2 gene is a tumor suppressor gene that is within the p53 pathway and is located on chromosome 22 at locus q12.1. The CHEK2 gene is typically activated in the event of DNA damage. CHEK2 encodes for a serine threonine protein kinase that is required as a DNA checkpoint. Mutations in CHEK2 appear to inhibit its ability to stop the cell cycle when DNA damage is present. There have been only a few families who have been identified with a CHEK2 mutation, therefore it is unknown whether CHEK2 mutations are associated with the same cancer risks attributed to p53 mutations.

Surveillance

There are no current screening recommendations for individuals with Li-Fraumeni that have been proven to decrease the mortality associated with Li-Fraumeni, with the exception of breast cancer screening. Proposed screening recommendations for children at risk for Li-Fraumeni include complete blood count (CBC), urinalysis, complete physical exam, abdominal ultrasound, and additional surveillance based on family history. It is recommended that women at risk for Li-Fraumeni receive twice yearly clinical breast exams and annual mammograms (or ultrasound/MRI) beginning around the ages of 20-25. Additional surveillance based on family history is recommended for all adults at risk for Li-Fraumeni Syndrome.

MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 (MEN1)
Wermer's Syndrome

MEN1 is an autosomal dominant disorder affecting the endocrine system (including the pituitary, parathyroid, pancreas). Hyperparathyroid is the presenting symptom or diagnosed simultaneous with the presenting symptom in approximately 94% of cases. Individuals with MEN1 may have several endocrine glands become overactive at the same time.

Hyperparathyroidism

The parathyroid glands are the earliest and most commonly affected endocrine system in MEN1. Elevated levels of parathyroid hormone may cause fatigue, weakness, kidney stones, and other symptoms, and if left untreated could lead to kidney damage.

Pancreas

MEN1 can lead to oversecretion of gastrin by the pancreas. Elevated levels of gastrin in the bloodstream can cause stomach uclers, diarrhea, and tumors in the pancreas (gastrinomas) which may ultimately cause the rupture of the stomach or small intestine.

Pituitary Gland

An overactive pituitary gland leads to elevated levels of prolactin which may cause infertility, decreased sex drive, and excessive production of breast milk in women. Medicine, surgery or radiation may be required to shrink the benign tumor that causes the overactive pituitary gland.

Other complications of MEN1

Other benign tumors may develop in MEN1 which can result in overactive hormone levels in the body and may require surgery to be removed. Individuals with MEN1 may also develop lipomas, and other skin findings such as multiple angiofibromas (previously thought to be pathognomic for Tuberous Sclerosis). Approximately half of individuals with MEN1 will develop a cancerous tumor in the pancreas.

Genetics

Multiple Endocrine Neoplasia Type 1 is associated with a genetic mutation in a gene appropriately titled MEN1. MEN1 is a tumor suppressor gene located on chromosome 11q13.

Surveillance

Screening individuals who are at high risk for MEN1 generally includes testing for hyperparathyroidism. Blood screening for signs of hyperparathyroidism will frequently diagnosis the hyperparathyroidism many years before any symptoms of hyperparathyroidism develop. Although genetic testing of minors is strongly discouraged for many conditions, genetic testing for MEN1 (with a mutation identified in the family) is recommended since treatable tumors may develop as young as age 5. In addition, annual evaluation is recommended for known gene carriers (or at risk individuals) beginning at the age of 15. Screening should include testing for prolactin, cortisol, glucose, calcium and phosphorus. Careful physical examination and endocrine system review are also warranted. Periodic (every 3-5 years) MRI of the pituitary and the pancreas should be considered, although the efficacy of these screening recommendations is not yet known.

MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 (MEN2)

MEN2 can be divided into three subsets, MEN2A, Familial Medullary Thyroid cancer (FMTC) and MEN2B. All three conditions confer an increased risk of medullary thyroid cancer (MTC). MEN2A and MEN2B are also associated with an increased risk of pheochromocytoma. In addition, MEN2A is associated with parathyroid adenoma or hyperplasia. The onset of medullary thyroid cancer differs in each syndrome, onset of MTC in MEN2B is in early childhood, MEN2A in early adulthood, and FMTC in middle adulthood.

MEN2B

MEN2B is clinically diagnosed by the presence of mucosal neuromas on the lips and tongue. Individuals with MEN2B also present with a body habitus similiar to that seen with Marfan Syndrome (long limbs, tall, thin stature), medullary thyroid cancer, medullated corneal nerve fibers and a distinctive facial appearance. Only 5% of MEN2 cases are MEN2B. Characteristically MEN2B is associated with an aggressive form of medullary thyroid carcinoma in all patients. Patients with MEN2B who do not undergo a prophylactic thyroidectomy by the age of 1 are likely to develop metastatic MTC. Individuals with MEN2B have approximately a 50% risk of developing a pheochromocytoma, and parathyroid disease is not common in this subset of individuals. Approximatley 40% of patients have diffuse ganglioneuromatosis of the gastrointestinal tract, and 75% of MEN2B patients will have a Marfanoid habitus.

MEN2A

MEN2A is diagnosed clinically in individuals with two or more endocrine tumors (pheochromocytoma, parathyroid adenoma, medullary thyroid carcinoma) or in families who have several close relatives affected with the endocrine tumors. MEN2A comprises approximately 60-90% of all MEN2 cases. Individuals with MEN2A have approximately a 95% risk of MTC, a 50% risk for pheochromocytoma, and a 20-30% risk to develop hyperparathyroidism. Typically individuals with MEN2A present with MTC, followed later by the diagnosis of a pheochromocytoma, if present.

FMTC

FMTC is diagnosed in families with four cases of medullary thyroid cancer in the absence of pheochromocytoma or parathyroid adenoma or hyperplasia. Individuals with FMTC comprise approximately 5-35% of cases of MEN2. In this subset of MEN2, medullary thyroid carcinoma is the only presentation.

Genetics

MEN2 is caused by mutations in the RET oncogene. Only 5-10% of all thyroid cancers are medullary, and 20% of those MTC are due to germline mutations in the RET gene. More than 95% of individuals with MEN2A and MEN2B have an identifiable mutation in the RET gene. Approximately 88% of individuals with FMTC will have identifiable mutations in the RET gene. The de novo mutation rate for MEN2A is approximately 5%, whereas the new mutation rate for MEN2B is about 50%.

Surveillance and Prophylactic Surgery

Genetic testing for germline mutations in the RET gene should be offered to all individuals clinically diagnosed with MEN2 (any subtype). In families with MEN2A, RET testing should be offered to children at risk prior to the age of 5 years since MTC has been documented in childhood. Families with FMTC are also recommended to offer genetic testing to at risk children prior to 5 years of age. Prophylactic thyroidectomy should be performed before 2 years of age if possible in children identified with a RET mutation. In MEN2B families, RET genetic testing should be offered as soon as possible after birth in all at risk children in the family. Children identified with a RET mutation should have prophylactic thyroidectomy performed within the first six months of life (preferably before 1 month). Prophylactic thyroidectomy with autotransplantation of the parathyroids is the primary prophylactic option for all subtypes of MEN2. Annual biochemical screening for pheochromocytoma at least until the age of 35 is also recommended. Screening for parathyroid adenoma or hyperplasia is also recommended for patients who do not have a parathyroidectomy. Other screening studies such as abdominal ultrasounds or CT scans may be warranted in some patients.

HEREDITARY MELANOMA

Skin Structure

The epidermis, or outer layer of skin, is comprised of three different types of cells: squamous cells (flat cells), basal cells (round cells) and melanocytes (create melanin). Moles (or nevi) are benign clusters of melanocytes that can develop secondary to sun exposure. There are three main types of skin cancer: basal cell carcinoma, squamous cell carcinoma, and melanoma. Basal cell carcinoma and squamous cell carcinoma are the most common forms of skin cancer, and can typically be treated with simple surgery. Melanoma accounts for approximately 4% of skin cancers and may require more intensive treatment than the non-melanoma skin cancers.

Moles

Moles are extremely common. Most individuals have between 10 and 40 moles that are generally uniform in color and one quarter inch in diameter. Melanoma is most likely to develop from a dysplastic moles that may exhibit several of the following features:

Individuals with lighter skin color are more likely to develop melanoma than individuals who have darker skin tones. The only other crucial risk factor for melanoma is a personal or family history of melanoma.

Inherited Risk Factors

Currently experts believe that only 1%-2% of all skin cancer due to melanoma are due to inherited mutations in a single gene that predispose individuals to develop melanoma. It is likely that genetics and environmental factors affect the risk for melanoma. However since a genetic link has been identified, it is recommended that relatives of individuals who have been diagnosed with melanoma have their skin examined regularly.

Presently, several genes have been identified with an increased risk of melanoma. CDKN2A is a cyclin dependent kinase that is located on chromosome 9p21. CDKN2A acts as a tumor suppressor gene by inhibiting the actions of Cyclin D1, which typically functions to promote passage through the cell cycle. Mutations in the CDKN2A gene (also referred to as p16) have been discovered in approximately 20-40% of families with multiple (more than three) affected first-degree relatives. In addition to an increased risk for melanoma, studies suggest some individuals with CDKN2A mutations are also an increased risk of pancreatic cancer. Mutations in the CDKN2A gene have also been noted in approximately 10% cases of sporadic melanoma, although is should be noted that the frequency of CDKN2A mutations in the general population is not known.

Familial Atypical Mole Malignant Melanoma Syndrome (FAMMM)

FAMMM syndrome is characterized by the familial occurrence of melanomas and atypical precursor nevi. FAMMM syndrome increases the risk of melanoma, may increase the risk of pancreatic cancer, and is known to be associated with specific mutations within CDKN2A. Individuals with any of the following features may benefit being evaluated for FAMMM:

Another gene, CDK4 is on chromosome 12q13, has been linked to several families affected with melanoma and is believed to act as a dominant oncogene. Mutations in codon 24 occur at the binding site for p16, thus inducing loss of cell cycle regulation. Currently this mutation has only been identified in three families worldwide, thus is not expected to account for a large proportion of familial melanoma.

Research on CDKN2A also points to the p14ARF (alternate reading frame) gene that is believed to be involved in cell cycle regulation and apoptosis. Other genes, including the CDK6 gene, CDKN2B gene, CDKN2C gene , and CDKN2D gene are currently being examined as potential candidate genes for melanoma prone families.

Screening and Surveillance

Individuals who are considered to be at increased risk for melanoma, either due to personal (skin) history, a family history of melanoma, or based on genetic test results should consider the following screening options:

Cowden Syndrome is considered to be a multiple hamartoma syndrome since affected individuals often have hamartomatous polyps within the gastroinestinal system, including the colon and stomach. Individuals with Cowden Syndrome are at increased risk for benign and malignant tumors of the breast, thyroid and endometrium. There is approximately 25-50% risk for breast cancer, up to a 10% risk for thyroid cancer (usually follicular type, though occasionally papillary), and a 5-10% risk for endometrial cancer. Affected individuals also have macrocephaly, trichilemmomas, and papillomatous papules. Cowden Syndrome is inherited in an autosomal dominant pattern with relatively high penetrance in both sexes, though there are moderate differences in the expressivity of many of the symptoms. The majority of affected individuals appear to be isolated cases- only 10-15% of individuals with Cowden Syndrome report a parent who also has Cowden Syndrome.

Clinical Criteria

Clinical criteria have been established to aid healthcare professionals to make the diagnosis of Cowden Syndrome. These criteria may be considered in three categories, including pathognomonic, major criteria and minor criteria. Pathognomonic criteria of Cowden Syndrome include mucocutaneous lesions such as facial trichilemmomas, acral keratoses, papillomatous lesions, or mucosal lesions. Major criteria for Cowden Syndrome include diagnoses of breast, endometrial or thyroid cancer, macrocephaly, or cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease). Minor criteria include other types of thyroid lesions, mental retardation, hamartomatous polyps, fibrocystic breast disease, lipomas, fibromas, or other genito-urinary tumors (such as uterine fibroids).

Genetics of Cowden Syndrome

Cowden Syndrome has been mapped to the PTEN gene on chromosome 10q22-23 along with other genetic conditions such as Bannayan-Riley-Ruvalcaba Syndrome, and may be considered under the umbrella of the PTEN Hamartoma Tumor Syndrome. Bannayan-Riley-Ruvalcaba Syndrome is a congenital autosomal dominant developmental disorder that is associated with different clinical features than Cowden Syndrome. The PTEN gene acts as a tumor suppressor gene by regulating both cell cycle arrest and apoptosis. Approximately 80% of individuals who meet the strict clinical criteria for Cowden Syndrome will have an identifiable mutation in the PTEN gene.

Surveillance

The component tumors, specifically the breast, endometrial, non-medullary thyroid cancers, as well as the potential for renal cell carcinoma and melanoma dictate the screening recommendations for individuals with Cowden Syndrome. Comprehensive physical exams are recommended beginning at the age of 18 or five years younger than the youngest diagnosis of cancer in the family, including careful examination of the neck and thyroid area. Women should begin annual clinical breast exam and self-breast exams at the age of 25. Annual mammography should begin at 30, or five years younger than the youngest breast cancer diagnosis in the family. Recommendations also include endometrial biopsies for premenopausal women, and annual urinalysis for the presence of blood.

Von Hippel Lindau (VHL) is a rare disorder characterized by the presence of angiomas (knot of distended blood vessels typically and irregularly arranged) in certain parts the body. Angiomas may develop in the central nervous system, including the brain or the retina of the eye. The size or location of the angioma may impede normal functioning by exerting pressure within the central nervous system. Cysts may form around the angiomas also resulting in increased pressure or blockages and symptoms such as headaches, dizziness, high blood pressure, vision problems, etc. Other types of tumors may develop in the adrenal glands, the kidneys, liver or the pancreas. Individuals with VHL are also at increased risk for certain types of cancer, including kidney cancer.

Symptoms

Individuals with VHL within the same family may experience a wide variability of symptoms. Because of the variability in symptoms, any at-risk or affected family member should be screened for all of the potential manifestations of VHL. The primary manifestations of VHL occur in varying frequencies among the patient population, including pheochromocytosis (7-18%), hemangioblastom of the retina (43-60%), cysts and tumors of the kidney (24-45%), pancreatic cysts and tumors (8-37%), hemangioma of the brain of spinal cord (21-72%). Individuals with VHL often experience multiple primary tumors, and the tumor type may vary based on ethnicity. Individuals from French families are more likely to develop CNS lesions, German families are more likely to have pheochromocytomas, and Japanese families are more likely to have kidney tumors. Renal cell carcinoma occurs in about 40% of patients and is the leading cause of mortality.

Genetics

Von Hippel Lindau disease is caused by mutations in the VHL gene located on chromosome 3p25-3p26. The VHL gene is a tumor suppressor gene that has been implicated in a variety of functions such as transcription regulation. Molecular genetic testing of the VHL gene is clinically available and detects mutations in nearly 100% of patients clinically affected with VHL. VHL is inherited in an autosomal dominant pattern meaning the offspring of affected individuals have a 50% of also developing VHL. New mutations of the VHL gene are estimated to occur in about 20% of probands, therefore a negative family history should not rule out the diagnosis of VHL.

Screening and Treatment

Individuals with VHL need careful monitoring by a physician or medical team familiar with the disorder. Treatment for VHL typically depends on the size and location of the tumor or cyst. The objective of screening and treatment in VHL is to detect growths before they cause any permanent problems by exerting pressure on the brain or spine. Treatments for most of the symptoms of VHL involve surgery to remove the tumor before it becomes problematic. Genetic testing of minor children at risk for VHL is beneficial because early detection of at-risk individuals affects medical management. Children at increased risk for VHL based on family history should be evaluated by the age of 6 utilizing non-invasive methods such as a detailed eye exam, a complete physical exam including blood pressure, and a neurological examination. If any symptoms develop, or by the age of 10-12, imaging of the brain, ultrasound of the abdomen, and urine catecholamine analysis is also recommended. This screening protocol may need to continued throughout an individual's lifetime if genetic testing is not informative since some individuals with VHL do not develop symptoms of the disorder until adulthood.

NEUROFIBROMATOSIS TYPE 1

Neurofibromatosis Type 1 (NF Type 1) is an autosomal dominant condition associated with an increased risk of benign and malignant tumors. NF Type 1 is generally a clinical diagnosis based on several diagnostic criteria that were put forth by the NIH Consensus Development Conference.

The diagnostic criteria for NF Type 1 include having two or more of the following:

Genetics

The only gene currently associated with NF Type 1 is the NF1 gene, located at chromosome 17q11. More than 500 different mutations have been identified in the NF1 gene, most of which are unique to individual families. NF1is a large gene that codes for the protein neurofibromin. The function of neurofibromin is not clearly understood, although reports suggest that it activates ras GTPase, resulting in control of cellular proliferation. Neurofibromatosis is believed to be the result of a loss of function mutation since most of the germline mutations cause protein truncation. DNA analysis of the NF1 gene will identify about 70% of NF Type 1 mutations and theoretically can be offered to family members at risk if a familial mutation is identified. However, the primary means of diagnosing a patient with NF Type 1 is still based on clinical exam.

Approximately 50% of patients clinically affected with NF Type 1 will have a positive family history, and 50% of the time the condition will arise de novo in an individual. It is important to keep in mind that although NF Type 1 is highly penetrant, it is characterized by clinical variability, even within the same family, thus a thorough medical examination of both parents of a clinically affected individual is warranted.

Increased cancer risks in NF Type 1:

The majority of symptoms in a patient with NF Type 1 are not associated with malignancy. The most common presentation of NF Type 1 is multiple café au lait spots and inguinal/axillary freckling. Adults with NF Type 1 often have numerous cutaneous or subcutaneous neurofibromas, or less commonly a plexiform neurofibroma. However, in addition to these and other symptoms (such as those listed above), there also appears to be a relative increased risk for some types of malignancy in individuals diagnosed with NF Type 1.

The most frequent malignancy associated with NF Type 1 are peripheral nerve sheath tumors (PNST/malignant schwannomas) that occur in approximately 10% of NF Type 1 patients. Half of all PNST are diagnosed in patients with a clinical diagnosis of NF Type 1, and tend to be highly aggressive in these individuals.

Children with NF Type 1 tend to develop leukemias (especially CML and myelodysplastic syndromes) more frequently than children who do not have NF Type 1, although the actual frequency of leukemia in children with NF Type 1 is relatively low.

Retinoblastoma is a condition in which malignant tumors develop in the retina of the eye, and occurs most frequently in children. The malignant tumors in Retinoblastoma develop from the retionblast cells, and may develop unilaterally or bilaterally. Retinoblastoma is more common in childhood because the retinoblast cells are precursors to the cone cells in the retina of the eye, and they no longer divide after the cells differentiate, which occurs during childhood.

Clinical Presentation

The most common presenting sign of RB is leukocoria (white pupillary reflex). Another common presentation of Retinoblastoma is strabismus, which may or may not present simultaneously with the leukocoria. Most affected children are diagnosed before 5 years of age.

Genetics

Retinoblastoma is caused by mutations in the RB1 gene located on chromosome 13q14.1-q14.2. RB1 is a tumor suppressor gene that normally functions to regulate cell division. Two "hits" in the RB1 gene in a single cell result in a loss of function as a tumor suppressor, resulting in the tumor formation characteristic of Retinoblastoma.

Retinoblastoma may occur in the germline (in 40% of cases) or may develop sporadically (in 60% of cases). Individuals with germline mutations in the RB1 gene tend to either have a positive family history, or develop the germline mutation de novo. The germline form of Retinoblastoma may manifest itself as unilateral or bilateral disease. All bilateral disease is due to a germline mutation, whereas unilateral disease may occur due to a germline mutation, or sporadically in nature. Germline tumors tend to occur at a younger age than sporadic tumors.

Genetic testing for germline mutations in the RB1 gene is available. Approximately 80% of individuals with a hereditary predisposition to Retinoblastoma will have an identifiable germline mutation. A germline mutation in the RB1 gene is inherited in an autosomal dominant pattern. Offspring of individuals who carry a germline mutation in the RB1 gene will have a 50% chance of also inheriting the same RB1 mutation.

Two-hit hypothesis

Dr. Alfred Knudson predicted the existence of tumor suppressor genes in 1971. Dr. Knudson came up with the two-hit hypothesis based on the disease history of Retinoblastoma. Retinoblastoma is more common in childhood because the retinoblast cells are precursors to the cone cells in the retina of the eye, and they no longer divide after the cells differentiate in childhood. Dr. Knudson noted that some children would develop only one tumor of the eye, whereas other children who inherited a retinoblastoma gene (assumed to have one mutation, or "hit") would develop multiple of tumors of the eye. This prompted Dr. Knudson to suggest that a second mutation, or "hit" occurred after conception and was necessary for tumor formation. Children who have the sporadic, non-inherited, form of retinoblastoma require the same two "hits," but they both occur after conception, thus making it much less likely to develop several tumors in the eye. The retinoblastoma gene, RB1, is now known to be a tumor suppressor gene that normally functions to regulate cell division. Two "hits" in the RB1 gene in a cell result in a loss of function as a tumor suppressor, resulting in the tumor formation characteristic of Retinoblastoma. Although the theory for tumor suppressor genes was originally developed as a model for retinoblastoma, it is now apparent that the two-hit hypothesis explains the etiology of many forms of cancer.

Surveillance

Individual affected unilaterally who also have a positive family history or a known mutation in the family should be followed closedly due to the potential development of contralateral retinoblastoma tumors. Recommendations include an eye examination every 2-4 months for at least 28 months. Post treatment, patients should be followed closely until the age of seven.