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 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, remarkable progress in molecular biology has enabled isolation of genes responsible for hereditary tumors such as retinoblastoma (RB), Wilms' tumor (WT), von Recklinghausen neurofibromatosis (NF 1), and familial adenomatous polyposis (FAP). Since patients with FAP develop multiple adenomatous polyps in the colon, some of which progress to colon cancer, isolation of the FAP gene allows us a rare opportunity to study genetic events underlying the well defined morphological changes during progression of colorectal tumors. In this report, we presented an approach called "positional cloning" which has become a powerful tool for identifying genes responsible for hereditary tumors, as well as characteristics of some of such genes.
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PMID:[Positional cloning of genes responsible for hereditary tumors]. 134 83

The study goal was to determine the genetic (heritable) contribution to childhood brain tumors (CBT) which cause nearly one quarter of all childhood cancer deaths. Their etiology remains unknown, but previous studies have suggested a proportion of CBT may be heritable. In this study we collected family histories of 243 confirmed CBT patients referred to The University of Texas M. D. Anderson Cancer Center between the years 1944 and 1983, diagnosed before age 15, and residents of the United States or Canada. Family histories were obtained for all the probands' first degree relatives (parents, siblings, and offspring) and extended to include selected second degree relatives (aunts, uncles, grandparents) using sequential sampling. To determine if these CBT families exhibited excess cancer, we compared their cancer experience to age-, race-, sex-, and calendar-year specific rates from the Connecticut Tumor Registry. No cancer excess was observed among 1,099 first and second degree relatives [39 cancers observed (O) and 44 expected (E) for a standardized incidence ratio (SIR) of 0.88]. For colon cancer, although small numbers, five cases were observed among the probands' first degree relatives with 1.6 expected, for a significant SIR of 3.10. Segregation analysis demonstrated that chance alone could not account for the observed cancer distribution with a multifactorial model providing the best overall explanation of the data. Overall, heredity played a role in the etiology of CBT in 4% of the study families: four (1.7%) due to known hereditary syndromes (nevoid basal cell carcinoma syndrome and von Recklinghausens neurofibromatosis--NF-1), four (1.7%) with multifactorial inheritance, and two additional families with cancers aggregating similar to the clinical criteria described for the Li-Fraumeni cancer family syndrome.
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PMID:Genetic epidemiology of childhood brain tumors. 175 48

Cancer is genetic, in the sense that it is caused by DNA alterations at the cellular level. On the other hand, the most important risk factors for the common cancers are environmental: cigarette smoking, environmental pollution, occupational exposures, poor diet, and so on. These two observations are not in conflict: the DNA alterations that lead to cancer are very likely to be caused by environmental mutagens. It would be valuable to know exactly what genes are altered to cause a specific cancer, because the effects of these alterations might then be reversible before cancer has a chance to develop. A key to identifying these cancer genes may lie with rare families at extremely high risk of a specific cancer. Unlike most cancer patients, members of these families may inherit an alteration that confers increased susceptibility to cancer. In these rare instances, cancer is a genetic disease at the level of the family, as well as at the level of the cell. Therefore, in these families, genes predisposing to cancer can be mapped in the same way as genes for purely genetic diseases like sickle cell anaemia, cystic fibrosis, and Huntington's disease. The hypothesis that underlies the mapping of cancer genes in families is that the genes inherited in altered form in these rare families are the same genes that are altered in somatic cells of individuals without a remarkable family history of cancer. This hypothesis has proved correct for retinoblastoma. Genes responsible for other rare cancers have been mapped in families as well: neurofibromatosis, multiple endocrine neoplasia, Wilms' tumour, and colon cancer following familial adenomatous polyps, among others. Genes responsible for common cancers are also being defined by genetic analysis, most notably breast cancer and colon cancer. This review summarizes why, how, and what genetic analysis of families can reveal about human cancers.
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PMID:Genetic analysis of cancer in families. 210 20

Colon cancers commonly have allelic losses of chromosome 22q, which suggests the presence of a tumor suppressor gene on 22q. The candidate tumor suppressor gene on 22q is the neurofibromatosis 2 (NF2) gene. Using single strand conformation polymorphism (SSCP) analysis, we screened 24 pairs of colorectal cancer and adjacent normal mucosa, as well as 10 colon cancer cell lines from non-NF2 patients, for mutations in the coding sequence of the NF2 gene. Two SSCP variants, one in exon 14 and another one in exon 16, were detected in two of the sporadic colorectal cancers, but not in adjacent normal mucosa samples. Sequencing of these variants in one tumor detected an A-to-G transition in bp 1459 of the NF2 cDNA, resulting in the change of Ile to Val at codon 487 of merlin, the NF2 protein product. The other tumor showed a 2-bp (CT) deletion in the intronic sequence of the alternatively spliced exon 16. These results suggest that the NF2 gene is probably involved in some colorectal tumors, but is not the critical chromosome 22q tumor suppressor gene involved in colon tumorigenesis.
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PMID:Neurofibromatosis 2 gene in human colorectal cancer. 749 38

Thirty-two cases of neurofibromatosis Type I (NF1) were identified among 6,678 pediatric cancer patients treated at St. Jude Children's Research Hospital over a 29-year period. A total of 35 malignant neoplasms have been diagnosed in these patients. Two of three patients with second malignant neoplasms had colon cancer at the primary or second tumor. Of particular interest are two cases in which both NF1 and malignant peripheral nerve sheath tumors were present in multiple successive generations: a patient with colon cancer and non-Hodgkin lymphoma who has a constitutional abnormality of the p53 gene, and a patient with acute lymphoblastic leukemia with the Philadelphia chromosome and other cytogenetic abnormalities, including the t(8;14). Outcome of patients in the largest subgroup, that of malignant peripheral nerve sheath tumors, was favorable only for those patients having resectable extremity lesions. In contrast, all patients with central nervous system tumors are surviving. These cases reflect the molecular and cytogenetic abnormalities that can be present in NF1 and the variety of tumors that may result in these patients.
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PMID:Neurofibromatosis type I and malignancy: review of 32 pediatric cases treated at a single institution. 825 5

Since fiscal year 1991, the U.S. Human Genome Project has spent $170.6 million in federal funds to help isolate genes associated with Huntington's disease, amyotrophic lateral sclerosis, neurofibromatosis types 1 and 2, myotonic dystrophy, and fragile X syndrome and to localize genes that predispose people to breast cancer, colon cancer, hypertension, diabetes, and Alzheimer's disease. Now comes the hard part. Biology's 21st century megaproject starts to look relatively manageable compared to another challenge facing the enterprise: sorting out ethical, legal, and social issues associated with using this information. "The Human Genome Project," wrote Senior Editor Barbara Jasny in the October 1 Science editorial, stretches "the limits of the technology and the limits of our ability to ethically and rationally apply genetic information to our lives."
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PMID:Ethical, legal, and social issues of the Human Genome Project: what to do with what we know. 971 68

A rare case of breast cancer associated with von Recklinghausen s neurofibromatosis is reported. This case and review of the literature illustrate the problems of clinical diagnosis. A 66-year-old woman who had undergone sigmoidectomy for sigmoid colon cancer two years previously, was admitted to the hospital because of a left breast skinretraction in October, 1998. The patient had von Recklinghausen fs disease (neurofibromatosis type 1). The TNM clinical staging was T1cN0M0. Modified radical mastectomy was performed. The histopathological diagnosis of the breast tumor was invasive ductal carcinoma and the skin tumor was neurofibroma. The pTNM pathological staging was pT1cN1aM0. Among patients similar to our case, almost all were staged higher than T2. This may be because multiple neurofibromas obscure breast mass at palpation, leading to delayed detection of the cancer. Systemic and careful exploration is essential for patients with von Recklinghausen's neurofibromatosis to detect breast cancer at an early stage.
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PMID:T1 Breast Cancer Associated with Von Recklinghausen's Neurofibromatosis. 1109 21

Rare inherited syndromes that to some extent explain familial glioma include Turcot's syndrome, Li-Fraumeni syndrome and neurofibromatosis types I and II. The majority of families with glioma do not meet the clinical criteria for any of these syndromes. In order to study the genetic origin of familial glioma, tumour DNA (n = 35) or blood samples (n = 8) were collected from 25 families. The glioma tumours were tested for microsatellite instability (MSI) with two markers, BAT25 and BAT26, since glioma is associated with hereditary non-polyposis colon cancer (HNPCC) in Turcot's syndrome. Furthermore, p53 was screened from blood DNA (exons 2-11) with temporal temperature gradient electrophoresis (TTGE) since germline mutations in p53 are seen in Li-Fraumeni syndrome. In gliomas, there is a wide variety of somatic mutations, such as, for instance, in p53, the epidermal growth factor receptor (EGFR) and p16. The tumour suppressor gene PTEN is also often somatically mutated in glioma, therefore it is attractive as a candidate gene for germline mutations in familial glioma. Blood DNA was directly sequenced for mutations in PTEN exons 1-9. The analysis showed that no mutations were found in either of the studied tumour suppressor genes, and no MSI-positive tumours were found. A common polymorphism in p53 at codon 72 (arginine/proline) was found in 6/8 of the patients. Apparently, mutation in the tested tumour suppressor genes or DNA mismatch repair genes does not explain the familial glioma observed in these families.
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PMID:Microsatellite instability, PTEN and p53 germline mutations in glioma families. 1166 37

Germ-line mutations (present in all cells) in genes that are crucial for the cell cycle cause cancer only in specific cell lines (e.g. mismatch repair genes in the colon; BRCA1-2 in breast and ovary; other cancers in Bloom syndrome, neurofibromatosis and xeroderma pigmentosum). The mutation rate of genes other than mismatch repair or p53 is the same in colon cancer and in normal cells, indicating that a 'mutator phenotype', increasing the rate of mutations in many genes, is not an essential feature of sporadic cancers; conversely, fusion genes, TEL-AML1/AML1-ETO, typical of leukemia, are 100 times more frequent at birth than in overt leukemia in children, indicating that further selective events are needed to cause malignancy. The devastating impairment of immunity, as in AIDS patients, does not cause cancer other than Kaposi's sarcoma and non-Hodgkin's lymphoma, although immunological control is considered to be an essential mechanism in preventing the spread of cancer cells. These observations suggest that cell-specific additional events are needed to explain carcinogenesis. Carcinogenesis has been traditionally interpreted as the sequence of initiation (mutation) and promotion (clone expansion), with an interesting similarity with the neo-Darwinian theory of evolution, based on a first stage of genetic change (including recombination) and a second stage of selection. I propose that carcinogenesis consists in two general phases (not necessarily stages), i.e. genetic change followed by clone expansion (selective advantage). As in neo-Darwinian theory selection is chiefly represented by the elimination of the less fit, the selection of mutated cells would mainly consist in resistance to apoptosis or other types of 'bottlenecks' that hamper a cell's survival; an example of such a bottleneck is the autoimmunity that induces paroxysmal nocturnal hemoglobinuria in individuals with PIG-A mutations. Cancer rates show great variation in different countries around the world, a variation only marginally explained by genetic differences. More interestingly, migrants change their risk of cancer by adapting to that of the population into which they move: as these changes are not likely to be entirely due to mutagens in the environment, we have to invoke selective pressure over mutated cells to explain them. My theory is that mutated cells adapt to environmental 'niches' better than normal cells, in a 'gene-environment interaction' that involves the history of the genetic changes the cell has undergone and the kind of environment in which it happens to live.
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PMID:Cancer as an evolutionary process at the cell level: an epidemiological perspective. 1253 42

Inherited forms of gastrointestinal cancer have been a major focus of study and advancement over the past decade. Familial adenomatous polyposis and hereditary nonpolyposis colon cancer are the two most common heritable colon cancer syndromes. Inherited polyposis syndromes are characterized by the dominant type of polyp (whether adenomatous or hamartomatous) present and by the polyp's location within the gastrointestinal tract. The hamartomatous polyposis syndromes are characterized by an overgrowth of cells native to the area in which they normally occur. They represent a small but appreciable number of the gastrointestinal inherited cancer predisposition syndromes; it is now known that many of these syndromes carry a substantial risk for developing colon cancer as well as other gastrointestinal and pancreatic cancers. Patients afflicted with these syndromes are also at significant risk for extraintestinal malignancies. Seven inherited hamartomatous polyposis syndromes have been described: familial juvenile polyposis syndrome, Cowden's syndrome, Bannayan-Ruvalcaba-Riley syndrome, Peutz-Jeghers syndrome, basal cell nevus syndrome, neurofibromatosis 1, and multiple endocrine neoplasia syndrome 2B. Hereditary mixed polyposis syndrome is a variant of juvenile polyposis characterized by both hamartomatous and adenomatous polyps. The hamartomatous syndromes occur at approximately 1/10th the frequency of the adenomatous syndromes and account for <1% of colorectal cancer in Northern America. While the diagnosis of these inherited syndromes is primarily clinical, genetic testing is now available for all six syndromes. However, there are a significant number of spontaneous mutations seen in each of the syndromes. The management of these patients necessitates a coordinated multidisciplinary approach. The purpose of this review is to characterize the clinical and pathological features of these syndromes and to review the targets of cancer surveillance. The molecular alterations responsible for the inherited hamartomatous polyposis syndromes will also be discussed.
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PMID:The hamartomatous polyposis syndromes: a clinical and molecular review. 1566 10


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