1,721,857 research outputs found
Stepwise functional assessment of unclassified DNA variants
No full textVerification of the three-step model in assessing the pathogenicity of mismatch repair gene variants
Genetic counseling in hereditary non-polyposis colorectal cancer
No full textGenetic counseling is a medical process aimed at providing information about disease risks for hereditary conditions, For adult-onset diseases, such as cancer, the main purpose consists in formulating probability estimates of disease appearance, along with details on preventive or follow-up measures, The process of genetic counseling has been substantially modified by the availability of molecular tests to identify mutant gene carriers, So far, 16 autosomal dominant genes associated with cancer susceptibility have been cloned, Four of these, which encode for components of the DNA mismatch repair machinery, have been implicated in hereditary non-polyposis colorectal cancer, one of the most common hereditary cancer syndromes, Genetic counseling and testing in hereditary non-polyposis colorectal cancer is associated with several problems that are common to other hereditary conditions (psychologic consequences, confidentiality, genetic ''discrimination'', testing of miners, prenatal diagnosis) and peculiar Po the specific condition (incomplete penetrance, genotypic and phenotypic heterogeneity, limits of currently available tests), Pbi such reasons, genetic testing should be performed in qualified research laboratories and restricted to highly selected families. In this way, pilot studies? involving both clinicians and researchers, can be undertaken with the aim of providing comprehensive results, potentially applicable to other cancer-predisposing conditions
CDKN2A germline splicing mutation affecting both P16(ink4) and P14(arf) RNA processing in a melanoma/neurofibroma kindred
No full textThe CDKN2A locus encodes two tumor suppressor proteins, p16(lnk4) and p14(arf), through use of alternative first exons. CDKN2A mutations detected in melanoma families are usually missense or nonsense changes which mainly impair p16(lnk4) function. Large genomic deletions spanning the entire locus have been observed in Mo pedigrees with melanomas and nervous tumors. We have detected a novel splice site mutation in a family with melanomas, neurofibromas, and multiple dysplastic nevi. Both alternative mRNAs produced by the mutant allele lacked shared sequences from exon 2, which encodes a substantial portion (> 50%) of both p16(lnk4) and p14(arf) proteins. The development of neurofibromas can be explained by cooperative effects of combined inactivation of p16(ink4) and p14(arf) or, alternatively, of p14(arf) alone. (C) 2001 Wiley-Liss, Inc
Simple and complex genetics of colorectal cancer susceptibility
No full textThere are several hereditary conditions associated with an increased risk of colorectal cancer (CRC). These include well-characterized autosomal dominant syndromes, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). A novel autosomal recessive form of FAP, caused by mutations in the base excision repair gene MYH, has recently been recognized. This discovery has provided further evidence for the importance of DNA repair mechanisms in CRC development, already documented by the involvement of the mismatch repair in HNPCC. Additional CRC-predisposing conditions, such as hyperplastic polyposis and hereditary mixed polyposis syndrome, are being outlined. Heterogeneity of genetic mechanisms has important consequences for counseling and surveillance in hereditary CRC. Nevertheless, classical mendelian conditions represent only a minor share of the total CRC population burden. Alleles of the same genes that are involved in hereditary syndromes might also act as low penetrance variants, as shown for APC 1307K in the Ashkenazi. However, the level of complexity of multifactorial CRC is such that current tools appear inadequate to pinpoint all the involved components. A combination of different strategies, including careful clinical observation, analysis of homogeneous patient populations, and critical evaluation of data derived from experimental models, along with methodological improvements in nucleic acid analysis, will probably be necessary to unravel the basis of nonmendelian CRC. Once this is achieved, it will be possible to realize the ultimate goal of targeted CRC prevention, with the adoption of measures tailored according to individual risk levels. (C) 2004 Wiley-Liss, Inc
Gastrointestinal manifestations in PTEN hamartoma tumor syndrome
No full textThe PTEN hamartoma tumor syndrome (PHTS) is a heterogeneous set of multisystem disorders caused by germline pathogenic variants in the PTEN tumor suppressor gene. Manifestations include developmental anomalies and proliferative lesions. Evidence of involvement of the GI tract has accrued over time, leading to the incorporation of GI manifestations (multiple hamartomas, glycogenic acanthosis and colorectal cancer) into the diagnostic criteria. Polyps of the upper and lower GI tract are found in most adult patients and in a significant fraction of children. Polyps tend to be of mixed histology, with a predominance of hamartomas and ganglioneuromas. PHTS patients are also at increased risk of colorectal cancer, and surveillance by colonoscopy is advised starting at the age of 35–40 years. A number of additional manifestations, including eosinophilic gastrointestinal disorders, have been observed in few or single cases, and their association with PHTS has yet to be determined
Molecular genetics of hereditary non-polyposis colorectal cancer (HNPCC)
No full textThe story of the molecular genetics of HNPCC is one of astonishingly rapid achievements. in just 16 months, from May 1993 to September 1994, four different genes, namely hMSH2, hMLH1, hPMS1 and hPMS2 have been identified and demonstrated to be associated with the disease, Their cloning was facilitated by the finding that tumor cells in HNPCC patients display a hypermutability of DNA short tandem repeats (microsatellite instability). In fact, HNPCC associated genes are the human counterparts of genetic elements known to control the fidelity of DNA replication in lower organisms, So far, more than 50 germline mutations of hMSH2 and hMLH1 genes have been reported in HNPCC kindreds. In addition, somatic mutations have been documented in hereditary as well as sporadic cancers, Unfortunately, the molecular diagnosis of HNPCC is hampered by the lack of mutational ''hot spots'' and of clearly defined genotype-phenotype correlations and different: screening methods are to be employed for the analysis of affected and at-risk individuals
"Limb-Pelvis Hypoplasia/Aplasia: A discrete entity in the fibuloulnar developmental field complex"
No full textThe limb-pelvis hypoplasia/aplasia (LPHA) syndrome is a rare condition of skeletal malformations affecting the ulnae, pelvic bones, fibulae and femora, sometimes associated with extraskeletal defects. Most reported patients are hom the Middle East, and auto-somal recessive inheritance was clearly demonstrated on the basis of multiple occurrences of affected sibs born to consanguineous matings. Here we report on a baby girl presenting with the phenotypic characterics of LPHA. This is second observation of LPHA from Italy, and the fourth outside the Middle East. A paternal first cousin once removed had unilateral fibular hypoplasia and absence of the the 4th and 5th digital rays. The possible Link between these cases is discussed in the Light of the developmental held theory. (C) Wiley-Liss, Inc
Hereditary nonpolyposis colorectal cancer: Review of clinical, molecular genetics, and counseling aspects
No full textLynch syndrome, or hereditary nonpolyposis colon cancer (HNPCC), is an autosomal-dominant disease accounting for approximately 1-5% of all colorectal cancer cases, Due to the lack of pathognomonic morphological or biomolecular markers, HNPCC has traditionally posed unique problems to clinicians and geneticists alike, both in terms of diagnosis and clinical management, Recently, novel insight into the pathogenesis of this syndrome has been provided by the identification of its molecular basis, In HNPCC families, germline mutations in any of four genes encoding proteins of a specialized DNA repair system, the mismatch repair, predispose to cancer development, Mutations in mismatch repair genes lead to an overall increase of the mutation rate and are associated with a phenotype of length instability of microsatellite loci, The present report summarizes the clinicopathological aspects of HNPCC and reviews the most recent molecular and biochemical findings. (C) 1996 Wiley-Liss, Inc
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