Vol. 17: Summer, 1999
Genetic Cancer Syndromes
Inherited risk for
cancers/tumors
other than
breast
and colon cancer
Melanoma, papillary renal cell carcinoma, retinoblastoma, leukemia/lymphoma associated with immunodeficiency disorders and chromosome instability syndromes, multiple endocrine neoplasias (MEN1, MEN2), von Hippel-Lindau disease are disorders for which causative genes are known.
Melanoma
Melanoma occurrence is on the rise in the United States, with a lifetime risk for the Caucasian population of 1%. Approximately one in ten individuals with melanoma has an inherited predisposition to this cancer. One in four or five melanoma patients with an inherited predisposition has been found to harbor heritable alterations in tumor suppressor gene p16, or in the proto-oncogene CDK3,4. Because hereditary melanoma manifests as an autosomal dominant pattern of transmission, it is often seen in multiple generations.
Offspring of individuals with a constitutional (germ line) alteration in a predisposing melanoma gene have a 50% chance of inheriting the alteration. Families with two or more cases of melanoma on the same side of the family; or a combination of relatives in several generations with dysplastic nevus syndrome (an individual with greater than 50 atypical moles) and/or melanoma; or families with a clustering of melanoma and pancreatic cancer on the same side of the family suggest the presence of an inherited predisposition5,6,7. Patients with an increased risk for melanoma should avoid sun exposure, use sun screen liberally, and undergo careful skin examination beginning in early childhood8.
Papillary renal cell carcinoma
Approximately 4% of all renal cell carcinoma is heritable. The papillary variant of renal cell carcinoma accounts for 14% of all renal cancer cases and is the most frequent inherited renal cell histology. Clustering of papillary renal cell carcinoma in a family often occurs in an autosomal dominant pattern of inheritance and is associated with an alteration in a gene called MET (a proto-oncogene). Offspring of individuals with a MET alteration have a 50% probability of inheriting that alteration and thus having an increased risk of papillary renal cell carcinoma9. Inherited predisposition to non-papillary renal cell carcinoma can be associated with von Hippel-Lindau disease or a translocation involving chromosome 3p14, a heritable chromosomal abnormality10.
Retinoblastoma
The childhood eye tumor, retinoblastoma, has an inherited etiology in 40% of cases. The gene responsible for retinoblastoma is the tumor suppressor gene, RB. Virtually 100% of bilateral cases of retinoblastoma (average age of onset is eight months) are of genetic etiology, as are 10-15% of sporadic unilateral cases (average age of onset is two years of age). Only 90% of those with an alteration in the RB gene develop retinoblastoma. Due to this reduced penetrance and to the occurrence of new RB gene mutations, there may not be a positive family history in an individual with a genetic form of retinoblastoma. Genetic testing can be performed postnatally as well as prenatally. In view of the complexity of the genetics of retinoblastoma, genetic counseling is recommended for all individuals. At risk individuals should begin surveillance at birth.
Leukemia/lymphoma
Individuals with inherited immunodeficiency disorders11,12 and chromosome instability syndromes are at increased risk for leukemia and lymphomas. The known chromosome instability disorders (e.g. ataxia telangiectasia, Bloom syndrome, and Fanconi anemia) are autosomal recessive, hence a family history is often negative, although siblings of the proband may be affected.
Multiple endocrine neoplasias
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disorder. The gene responsible for MEN1 is known as menin. Tumors associated with MEN1 include pituitary (30%), parathyroid (95%), and pancreatic islet cell (41%). Most of the tumors are adenomas. Malignant potential of the tumors, especially those of the pancreatic islet cell is of concern. Other adenomas, lipomas, and carcinoids are occasionally seen in families. It is important to identify individuals who have MEN113,14, as appropriate medical management includes annual biochemical screening, careful radiological assessment, and prompt surgical intervention when tumors are detected15,16,17.
Multiple endocrine neoplasia type 2 (MEN2) is associated with a genetic abnormality in the RET proto-oncogene. 100% of MEN2a patients have medullary thyroid carcinoma/C-cell hyperplasia, 50% have pheochromocytoma, and 10%-25% have hyperparathyroidism. MEN2b patients have medullary thyroid carcinoma, pheochromocytoma, oral mucosal neuromas, ganglioneuromas, and in some cases a marfanoid habitus. Medullary thyroid carcinoma and pheochromocytoma are often bilateral in individuals with RET alterations19. Familial medullary thyroid carcinoma (FMTC) includes families with a RET gene mutation and medullary thyroid carcinoma/C-cell hyperplasia, but without any other tumor manifestations.
Approximately 25% of sporadic cases of medullary thyroid carcinoma (MTC) are due to RET gene mutations, hence genetic testing for sporadic MTC may be appropriate if accompanied by genetic counseling. The sensitivity of RET testing is less than 100%, hence a negative result cannot eliminate the possibility of mutation in a sporadic case18. If a sporadic case is determined to have an abnormality in the RET gene, others in the family can then be tested. At risk individuals should undergo annual biochemical screening and thyroidectomy as appropriate20. Genetic testing of high risk children is recommended because thyroid cancer can occur in very young children. Some clinicians recommend prophylactic thyroidectomy in children with a diagnosis of MEN2 /FMTC21.
Von Hippel-Lindau disease
The diagnosis of von Hippel-Lindau disease (VHL) should be considered in patients with a family history of pheochromocytoma, clear cell renal carcinoma, or cerebellar/spinal/ocular hemangioblastomas, or a personal history of an endolymphatic sac papillary tumor. Endolymphatic sac tumors often manifest as hearing loss. A clustering of several of these tumors in the same individual or in two or more individuals on the same side of the family is also significant. In addition to the above tumors, patients with VHL often have cysts in the pancreas, epidydimis, and kidney. Onset of retinal tumors can be congenital, and other tumors may manifest in early childhood. Prenatal and postnatal genetic testing is available22,23,24.
The gene responsible for VHL is the VHL gene on chromosome 3. It is inherited in an autosomal dominant pattern25. Surveillance of at-risk individuals begins at birth. Biochemical analysis, MRI's ,CT's, ultrasound, opthalmological and audiology examinations are all recommended, commencing at different times26.
Cancers for which genes are unknown, or the approximate chromosomal location is known
Prostate cancer
Approximately 10-20% of men will develop clinically apparent prostate cancer in their lifetime. Nine percent of all prostate cancer and 40% of all early onset prostate cancer (under age 55) is estimated to have an autosomal dominant pattern of inheritance. Early surveillance for prostate cancer is recommended for this high risk group27, but general population screening is still controversial. Indicators of an inherited predisposition to prostate cancer include:
· the patient or one family member diagnosed with prostate cancer before age 55
· two or more relatives, same side of family (maternal or paternal), diagnosed with prostate cancer
A gene has yet to be discovered for inherited prostate cancer, but a candidate gene, hereditary prostate cancer 1 (HPC1), is localized to chromosome 1q24-q2528. There is a suggestion that prostate cancer families linked to the chromosome 1 gene abnormality may also be at risk for other types of cancer29. Because susceptibility to prostate cancer may be inherited in an autosomal dominant pattern, it is important to document the history on both the maternal and paternal sides. A woman can inherit an alteration in a gene that predisposes men to prostate cancer, and, while she obviously will not develop prostate cancer, she can pass that allele to either sons or daughters. Sons and grandsons who inherit the abnormality are at increased risk for prostate cancer. Therefore it is as important to document cases of prostate cancer in maternal uncles, maternal grandfathers and maternal cousins as it is in fathers and their male relatives.
Leukemia
Familial clustering of leukemia is rare. In a few families, an autosomal dominant pattern of inheritance has been demonstrated. Researchers suspect that there are heritable predisposing genes for acute myelogenous leukemia and myelodysplasia on chromosomes 9, 16, and 230. Leukemia and lymphoma are associated with the autosomal dominant Li-Fraumeni syndrome2.
Cancers for which familial occurrence is suggested, but causative genes are unknown
Lung cancer
One in 8 smokers and 1 in 2000 non-smokers will develop lung cancer in their lifetime. The risk for lung cancer is higher among both non-smokers and smokers who have a family history of the disease. Statistical analysis of lung cancer families suggest an autosomal dominant pattern of inheritance31. Researchers at the University of Colorado Health Sciences Center, in collaboration with other institutions, are attempting to locate a predisposing gene. At risk families have the following characteristics:
· two or more relatives on the same side of the family with lung cancer
· early onset lung cancer (before age 55)
· non-smokers with lung cancer
· individuals with Li-Fraumeni syndrome
(The University of Colorado [303 329-3066 or 800 473-2288] is interested in study participants, either affected or unaffected, from families with two or more cases of lung cancer.)
Testicular cancer
Testicular cancer has been observed in some sibships, suggesting an autosomal recessive pattern of inheritance32. However, only a small proportion of individuals with testicular cancer have an inherited risk and a gene has not been identified for heritable testicular cancer. Indicators of an inherited predisposition of testicular cancer that may warrant additional medical management include:
- bilateral tumors
- two or more siblings with testicular cancer
Summary
A genetic etiology has been discovered or postulated for many types of tumors, including breast, colon, prostate, lung, ovarian, renal, pancreatic, testicular, thyroid, and uterine cancers, retinoblastoma, sarcoma, leukemia, lymphoma, brain tumors, and endocrine. The list continues to grow as researchers learn more about genetic risk factors for cancer, identification of which should lead to improved detection and cancer prevention in high risk individuals.
Careful analysis of an accurate family medical history facilitates identification of patients at increased risk for cancer. Genetic counseling and perhaps genetic testing may be appropriate when a physician encounters a family with the following characteristics: multiple members having the same type of tumor; multiple members having specific patterns of tumors; early onset cancer; or rare tumors suggestive of an inherited predisposition. Patients at increased risk for neoplasia require specialized surveillance and medical management.
Contributed by Lisa Mullineaux, MS (CO) and Catherine Klein, MD (CO)
References
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The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131
Genetic Cancer Syndromes
Table of Contents
Introduction
Identifying Patients at Risk
Breast/Ovarian Cancer
Colorectal Cancer
Other Familial Cancers
Web Links
Cancer Genetic Services
Current Research Studies
Glossary
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