Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Melanoma, Cutaneous Malignant

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Hereditary Melanoma

Neuroendocrine Tumor

Neuroepithelioma

In collaboration with members of The International Melanoma Consortium, we propose to study melanoma in families lacking mutations in the cyclin-dependent kinase inhibitor 2 (CDKN2 or p16) gene, or the cyclin-dependant kinase 4 (CDK4). CDKN2 and CDK4 are both genes that encode presumed tumor suppressor genes, mutant forms of which are known to cause increased susceptibility to melanoma. The purpose of the present study then is to confirm the existence of and to identify additional gene(s) involved in heritable melanoma (cutaneous and ocular) and their precursor lesions (atypical nevi) by linkage analysis and gene mapping strategies. It is clear that the risk to develop atypical nevi and/or melanoma is strongly influenced by genetic and environmental factors (e.g. sun exposure). Characterization of such genes could provide important insights into the inheritance, pathogenesis, and treatment of this increasingly important disease.

In collaboration with members of The International Melanoma Genetics Consortium, we propose to study melanoma in families lacking mutations in the cyclin-dependent kinase inhibitor 2 (CDKN2A), or the cyclin-dependant kinase 4 (CDK4) genes. CDKN2 and CDK4 are both genes that encode presumed tumor suppressor genes, mutant forms of which are known to cause increased susceptibility to melanoma. The purpose of the present study then is to confirm the existence of and to identify additional gene(s) involved in heritable melanoma (cutaneous and ocular) and their precursor lesions (atypical nevi) by linkage analysis and gene mapping strategies. It is clear that the risk to develop atypical nevi and/or melanoma is strongly influenced by genetic and environmental factors (e.g. sun exposure). Characterization of such genes could provide important insights into the inheritance, pathogenesis, and treatment of this increasingly important disease.

Genetic Analysis of Familial Melanoma

National Human Genome Research Institute (NHGRI)

Alejandro A Schaffer, Ph.D.

The researchers have developed and distributed several software packages for pedigree analysis (FAST, CASPAR, PedHunter, IIC) and cancer genetics (oncotree, METREX). Users who need assistance with the software or who want to see new features added often send the researchers data files that include human data. The information is normally coded, and the researchers do not have access to the identification of the people whose information is in the files. Sometimes the content of the files gives rise to collaborations between the software developers and the providers of the files. Because concerns over the confidentiality of medical information have increased significantly over the past few years, the researchers must apply for exemptions from detailed ethics committee oversight for every data set they receive. This process is cumbersome and makes it difficult to assist software users. The amount of information required to apply for an exemption also poses a barrier to collaborations.

A full protocol will subject all data sets to ethics committee oversight without the need for individual exemption requests, enabling the researchers to assist users with software problems and to collaborate with other researchers.

From January 1, 2000, through December 15, 2001, the researchers received 71 requests for assistance, 19 of which included data files. None of the data files had any names or patient identifiers. Of these 19, in 8 cases the researchers sent back modified output files. In two of these eight cases, the researchers could see results of research interest; one of them concerned human data. In 2 of the 19 cases, the researchers sent back modified input files; in one such case, they established a collaboration with the originator of the files. In sum, most requests come under the heading of customer service, with no research contents. A few, however, do lead to research results or collaborations, for which ethics committee oversight is required.

Over the three-year time frame of this protocol, the researchers anticipate receiving data on a maximum of 10,000 individuals. They have modified their software documentation to explicitly instruct users to make sure the data files they send have no names. Should they receive files with names, they will delete the files and ask the originator to resubmit them with names encoded. Users submit data through unencrypted e-mail. The data are stored in password-protected computers at the National Institutes of Health.

We have developed software packages for pedigree analysis (FAST, CASPAR, PedHunter, IIC) and cancer genetics (oncotrees, METREX). The purpose of this protocol is to allow us to work on software problems reports that may contain human subjects data in them. The data should be coded, by which we mean that if there are any links between identifiers and names, we do not possess the links to decode the names. Occasionally our assistance leads to a more formal research collaboration. This protocol seeks to clarify the guidelines under which we can provide assistance to users of our human genetics software and to establish a formal procedure under which we can seek IRB approval for the serendipitous collaborations that arise from providing that assistance. We cannot predict the sizes of samples or the diseases studied in the data sets sent to us, so most of the medical aspects of this protocol are necessarily general. We rely on the data being coded and the collectors of the data having their own institutional approvals to protect against most risks. The scientific aspects of investigating problem reports cannot be hypothesis driven because we cannot guess what problems will arise. On the engineering side, the basic hypotheses are that: 1) our software is likely to contain some bugs or other weaknesses, which cannot be easily found except by having others use the software and 2) a good way to improve the functionality of the software is to encourage users to submit problem reports and other suggestions.

This protocol has been in effect since early 2002. The only amendments during that time were to set up three collaborations, as described in Sections 4.6 and 4.7 and 4.8. The protocol has been quite useful and no changes are proposed in procedures.

Exploratory Data Analysis for Disease Pedigrees and Cancer Genetics

Nutritional and Metabolic Diseases

Gland and Hormone Related Diseases

Diseases and Abnormalities at or Before Birth

Symptoms and General Pathology

Metabolic Diseases

Hyperparathyroidism

Endocrine Gland Neoplasms

Multiple Endocrine Neoplasia

Hypercalcemia

Endocrine System Diseases

Neoplasms, Multiple Primary

Syndrome

Neoplastic Syndromes, Hereditary

Genetic Diseases, Inborn

Familial Hypocalciuric Hypercalcemia

Members of families that have had relatives diagnosed with a disease of mineral metabolism. Participants will be asked to give blood samples for DNA extraction.

Smita Jha, M.D.

Diseases of mineral metabolism such as familial multiple endocrine neoplasia type 1 (FMEN1), familial hypocaliuric hypercalcemia (FHH), familial hyperparathyroidism (FH), and pseudohypoparathyroidism (PHP) are known as hereditary abnormalities. Meaning these conditions are passed from parents to their children through genes. These specific conditions result in abnormal levels of calcium in the blood.

This study was designed to help researchers understand more about the genes that are responsible for these disorders. By learning more about the genetic process involved in hereditary abnormalities, new tests and treatments can be developed.

Subjects for this study will be members of families that have had relatives diagnosed with a disease of mineral metabolism. Participants will be asked to give blood samples for DNA extraction. DNA is the part of cells that carries genetic information.

The DNA will be analyzed and the results given to the subjects. Genetic counseling will be provided to subjects to aid in interpreting their results....

Familial multiple endocrine neoplasia type 1 (MEN1), familial hypocalciuric (or familial benign) hypercalcemia (FHH), hyperparathyroidism - jaw tumor syndrome (HPT-JT), other causes of familial isolated hyperparathyroidism (FIHP), and pseudohypoparathyroidism (PHP) are disorders of metabolism that are generally inherited in an autosomal dominant fashion. MEN1 is characterized by overgrowth and hyperfunction of the parathyroids, anterior pituitary and gastrointestinal endocrine tissue. MEN1, p15, p18, p21, and p27 are identified genes for MEN1- like states. FHH is characterized by a usually benign syndrome sometimes mistaken for typical primary hyperparathyroidism, which may result in unnecessary and unsuccessful parathyroid surgery. The CASR gene for the calcium-sensing receptor of the parathyroid cell is mutated in most FHH kindreds; a minority of kindreds with FHH have mutation of the GNA11 or AP2S1 gene. HPT-JT is a distinctive subtype of familial isolated hyperparathyroidism that has combinations of parathyroid adenoma, parathyroid cancer, jaw tumor, uterus tumor, kidney tumor and kidney cysts. It is caused by mutation of the CDC73/HRPT2 gene. PHP is characterized by parathyroid hormone resistance, and one form is associated with mutations in the gene encoding the alpha subunit of the stimulatory G protein. We are continuing to collect blood and tissue samples from affected and unaffected members of kindreds with known or suspected MEN1, FHH, HPT-JT, FIHP, PHP, and related disorders for the purpose of geneticanalysis and gene identification. In most cases, the procurement of specimens under this protocol will be at an off-site location. Samples will be processed for extraction of DNA and RNA.

Studies of Inherited Diseases of Metabolism

Family Studies in Metabolic Diseases and Mineral Metabolism

Studies will be focused around forms of hereditary hypercalcemia, MEN1, FHH, HPT-JT, and FIHP as well as other disorders of mineral metabolism like PHP. In doing so, we will test the hypothesis that MEN1 and MEN1-like states develop as a result of a germ line mutation in MEN1 or a CDKI gene, define the mutations present in the affected members of MEN1 kindreds, and assess the frequency of such mutations in patients with apparently sporadic disease.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study title	NCT ID	Conditions	Eligibility	Organization
Genetic Analysis of Familial Melanoma	NCT00339404	Melanoma	-	National Institutes of Health Clinical Center (CC)
Exploratory Data Analysis for Disease Pedigrees and Cancer Genetics	NCT00339508	Data Analysis Cancer Genetics	-	National Institutes of Health Clinical Center (CC)
Exploratory Data Analysis for Disease Pedigrees and Cancer Genetics	NCT00339508	Data Analysis Cancer Genetics	-	National Institutes of Health Clinical Center (CC)
Genetic Analysis of Familial Melanoma	NCT00339404	Melanoma	-	National Institutes of Health Clinical Center (CC)
Studies of Inherited Diseases of Metabolism	NCT00001345	Multiple Endocr...	4 Years -	National Institutes of Health Clinical Center (CC)
Genetic Analysis of Familial Melanoma	NCT00339404	Melanoma	-	National Institutes of Health Clinical Center (CC)
Genetic Analysis of Familial Melanoma	NCT00339404	Melanoma	-	National Institutes of Health Clinical Center (CC)

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