Subject(s)
Genetic Diseases, Inborn/diagnosis , Medical History Taking , Melanoma/genetics , Skin Neoplasms/genetics , Data Collection , Female , Humans , MaleABSTRACT
Approximately 5% to 10% of patients with pancreatic cancer have one or more first-degree relatives with this disease. A subset of these individuals have a hereditary form of pancreatic cancer designated by association with such hereditary disorders as familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, hereditary pancreatitis, or familial atypical multiple mole melanoma (FAMMM) syndrome. A subset of those FAMMM kindred with the CDKN2A (p16) germline mutation that expresses both pancreatic cancer and malignant melanoma may constitute a new hereditary pancreatic cancer-prone syndrome.
Subject(s)
Adenocarcinoma/genetics , Genetic Predisposition to Disease/genetics , Pancreatic Neoplasms/genetics , Adenocarcinoma/epidemiology , Adenocarcinoma/therapy , Dysplastic Nevus Syndrome/epidemiology , Dysplastic Nevus Syndrome/genetics , Dysplastic Nevus Syndrome/therapy , Family Health , Genetic Predisposition to Disease/epidemiology , Genetic Predisposition to Disease/etiology , Humans , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/therapy , United States/epidemiologyABSTRACT
The mortality from pancreatic cancer coincides closely with its incidence, indicating a dismal outlook. Hereditary factors probably account for approximately 5%-10% of the pancreatic cancer burden. The molecular genetic etiology of pancreatic cancer is only beginning to be identified. We describe our genetic counseling experience with 2 large families prone to pancreatic cancer-malignant melanoma in which p16 (CDKN2) germline mutations had been identified. Members of each family underwent intensive counseling before and at the time of disclosure of p16 germline mutation findings. Two non-cancer-affected siblings from each of the 2 families had p16 mutations identified in DNA from their peripheral blood lymphocytes. In each case, a parent affected with pancreatic cancer also harbored the p16 mutation identified in DNA from their respective tumor blocks. The sibling pairs stated that they would seriously consider prophylactic pancreatectomy if biomarkers or imaging findings suggested a precancerous state. Our experience highlights limited options for managing these families and emphasizes the need for better tools to diagnose pancreatic cancer at a curable stage.
Subject(s)
Genes, p16/genetics , Genetic Counseling , Genetic Testing , Germ-Line Mutation , Melanoma/genetics , Pancreatic Neoplasms/genetics , Adult , DNA, Neoplasm/genetics , Female , Humans , Male , PedigreeABSTRACT
Research into the epidemiology of the melanoma-prone FAMMM syndrome, molecular genetics of the occurrences of melanoma, the photobiology of DNA damage/repair, diagnostic epiluminescence, microscopic/imaging techniques, and a new concept of photoprotection have altered melanoma strategies in surveillance and prevention. Molecular genetic research has implicated the importance of hereditary aspects of melanoma and associated malignancies. High-risk pedigrees can be identified through an informatic analysis of the occurrence patterns of melanoma and systemic cancers in kindreds. All ultraviolet radiation results in cutaneous DNA damage and in high-risk individuals may cause melanoma. We may reverse the epidemic trend in melanoma occurrences in these high-risk pedigrees if we are willing to change our cultural approach to sunlight exposure with restrictive sunlight behavior, wearing of ultraviolet protective clothes, the use of broad-spectrum ultraviolet protection from nightly topical dihydroxyacetone coupled with daytime UVB sunscreens, and periodic surveillance.
Subject(s)
Melanoma/etiology , Dihydroxyacetone/pharmacology , Humans , Melanoma/genetics , Melanoma/prevention & control , Radiation Protection , Sunscreening Agents/pharmacology , Ultraviolet Rays/adverse effectsSubject(s)
Health Maintenance Organizations/statistics & numerical data , Health Services Needs and Demand/statistics & numerical data , Insurance, Health, Reimbursement/statistics & numerical data , Medical Records/standards , Quality Assurance, Health Care , Deception , Health Maintenance Organizations/economics , Health Services Needs and Demand/economics , Health Services Needs and Demand/legislation & jurisprudence , Humans , Insurance, Health, Reimbursement/economics , Insurance, Health, Reimbursement/legislation & jurisprudence , Medical Records/economics , Medical Records/legislation & jurisprudenceABSTRACT
OBJECTIVES: The Muir-Torre syndrome (MTS) is characterized by an autosomal dominant predilection to sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas, in concert with the cancer phenotype of hereditary nonpolyposis colorectal cancer (HNPCC). Proof that patients showing a familial aggregation of MTS's cutaneous signs in combination with a specific pattern of visceral cancers which are consonant with an HNPCC diagnosis has been buttressed by the discovery of hMSH2 and hMLH1 germ-line mutations in such families. Our purpose in this investigation was to determine the germ-line mutation in a Gypsy family with MTS in concert with HNPCC cancer features, and to provide genetic counseling. An added objective for this paper is to review the literature on MTS. METHODS: We describe a Gypsy family with MTS in concert with HNPCC cancer features, as well as the molecular genetic and genetic counseling procedures used in the interest of improved compliance with cancer control recommendations. We review the clinical phenotype, natural history, and molecular genetics involved in the MTS variant HNPCC. RESULTS: An hMSH2 germ-line mutation was identified as the culprit germ-line mutation in this family. CONCLUSIONS: The presence of the hMSH2 germ-line mutation in this family provides powerful predictability of colorectal and other HNPCC integral cancers. The gastroenterologist must assume an important role in the diagnosis and management of MTS.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Neoplastic Syndromes, Hereditary/genetics , Roma , Skin Neoplasms/genetics , Adult , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/ethnology , Female , Germ-Line Mutation , Humans , Male , Middle Aged , Neoplastic Syndromes, Hereditary/diagnosis , Neoplastic Syndromes, Hereditary/ethnology , Pedigree , Skin Neoplasms/diagnosis , Skin Neoplasms/ethnologySubject(s)
Asian People , Dermatitis, Photoallergic/ethnology , Dermatitis, Photoallergic/diagnosis , Dermatitis, Photoallergic/genetics , Humans , Indians, North American , Photosensitivity Disorders/diagnosis , Photosensitivity Disorders/ethnology , Photosensitivity Disorders/genetics , Terminology as Topic , United States/epidemiologyABSTRACT
In most hereditary cancer syndromes, finding a correspondence between various genetic mutations within a gene (genotype) and a patient's clinical cancer history (phenotype) is challenging; to date there are few clinically meaningful correlations between specific DNA intragenic mutations and corresponding cancer types. To define possible genotype and phenotype correlations, we evaluated the application of data mining methodology whereby the clinical cancer histories of gene-mutation-positive patients were used to define valid or "true" patterns for a specific DNA intragenic mutation. The clinical histories of patients with their corresponding detailed attributes without the same oncologic intragenic mutation were labeled incorrect or "false" patterns. The results of data mining technology yielded characterizing rules for the true cases that constituted clinical features which predicted the intragenic mutation. Some of the initial results derived correlations already independently known in the literature, adding to the confidence of using this methodological approach.
Subject(s)
Breast Neoplasms/genetics , Mathematical Computing , Mutation , Ovarian Neoplasms/genetics , Age of Onset , Algorithms , BRCA2 Protein , Breast Neoplasms/epidemiology , Family , Female , Genes, BRCA1 , Humans , Neoplasm Proteins/genetics , Ovarian Neoplasms/epidemiology , Software , Transcription Factors/geneticsABSTRACT
Computer-based data mining methodology applied to family history clinical data can algorithmically create highly accurate, clinically oriented hereditary disease pattern recognizers. For the example of hereditary colon cancer, the data mining's selection of relevant factors to assess for hereditary colon cancer was statistically significant (P < 0.05). All final recognizer-formulated patterns of hereditary colon cancer were independently confirmed by a clinical expert. Applied to previously analyzed family histories, the recognizer identified the definitive hereditary histories, correctly responded negatively to the putative hereditary histories, and correctly responded negatively to empirically elevated colon cancer risk situations. This capability facilitates patient selection for DNA studies in search of gene mutations. When genetic mutations are included as parameters in a patient database for a genetic disease, the process yields an expert system which characterizes variations in clinical disease presentations in terms of genetic mutations. Such information can greatly improve the efficiency of gene testing.
Subject(s)
Expert Systems , Genetic Diseases, Inborn/genetics , Pattern Recognition, Automated , Adult , Algorithms , Colorectal Neoplasms/genetics , Disease Susceptibility , Humans , Medical History Taking , Middle Aged , PedigreeABSTRACT
The role of primary genetic factors in the etiology of cancer has become of intense interest to the research and clinical community. This interest has been heightened by recent discoveries that germ-line mutations such as BRCA1 and BRCA2 in hereditary breast cancer are responsible for an increasing percentage of common solid tumors. A potpourri of proto-oncogenes and tumor-suppressor genes has been identified in hereditary as well as certain common sporadic and rare cancer types, and new cancer genes will likely be discovered every month to account for the 5 to 10% of the cases of cancer that can be attributed to primary genetic factors. Molecular mechanisms in the pathogenesis of hereditary cancer can result in more-targeted cancer-control measures. At least four mutator genes (MHS2, MLH1, PMS1 and PMS2) appear to account for 70-80% of hereditary nonpolypoid colorectal cancer (HNPCC). When one of these germ-line mutations is present in an HNPCC family, the physician is then able to determine the patient's lifetime cancer destiny with an accuracy of about 90% (limited only by the penetrance of the gene). This will enable highly targeted surveillance to be initiated early, such as colonoscopy beginning at ages 20 to 25 or prophylactic subtotal colectomy. Also, in multiple endocrine neoplasia syndromes (MEN 2A and 2B), the identification of the culprit RET proto-oncogene now enables a secure diagnosis and permits testing of children who might benefit from prophylactic total thyroidectomy. Central to translation of these momentous molecular genetic discoveries into patient care is the necessity of determining who requires DNA testing. The cancer family history is the linchpin in making this decision.