Genetic Alterations In

Familial adenomatous polyposis is caused by inheritance of germline mutation in the APC gene (chromosomal locus 5q21-q22). Familial adenomatous polyposis is an autosomal dominant disease with extremely high penetrance, as 95% of individuals with FAP have polyps by age 35. Approximately 20-25% of individuals with FAP have the altered gene as a result of a de novo gene muta-tion[8] and therefore will not have an affected parent. The APC gene is a ''gatekeeper'' tumor suppressor gene encoding a large protein which is involved in chromosome segregation, cell adhesion, cell migration, signal trans-duction, and apoptosis.[9,10] Most FAP-associated mutations in the APC gene cause premature truncation of the APC protein. Individuals with FAP only have one functional copy of the APC gene in each colonic epithelial cell, therefore accelerated tumorigenesis from normal mucosa to polyps and carcinoma occur. The APC gene contains 15 exons and 2843 codons. The colonic (including the density of colonic polyposis) and extra-colonic phenotypical manifestations of FAP, as well as development of desmoid tumors (10-15% of cases), are related to the location and type (frameshifts and point mutations) of the APC gene mutation.[11] A great deal of research has been devoted to the apparent genotype-phenotype correlations for the disease, although due to the variation that occurs among individuals and families with identical mutations in the APC gene,[12] these associations are not routinely used as a basis for clinical management strategies.1-13-1 The most common mutation in APC is located at codon 1309, and patients with this mutation develop a high number of adenomas at an early age, with an average age at presentation of 20 years. Individuals with mutations in codons 1250-1464 often exhibit profuse polyposis (an average of 5000 polyps).[14] In terms of age at onset of colonic symptoms, individuals with mutations between codon 168 and 1580 present at an average age of 30 years, and individuals with mutations proximal to codon 168 and distal to codon 1580 present at an average age of 52 years.[13] Attenuated familial adenomatous polyposis is most commonly associated with APC mutations proximal to codon 168, although germline mutations in exons 6 and 9 as well as in the distal 3' region of the gene have also been identified in AFAP families.[15] The extracolonic manifestations of FAP also show genotype-phenotype correlations. Desmoid tumors are often associated with mutations at codons 1444 and 1578.[16] Congenital hypertrophy of the retinal pigment epithelium is associated with mutations in codons 463-1387,[17] whereas mutations distal to codon 1444 or before exon 9 are associated with the absence of CHRPE.[16] Mutations downstream from codon 1051 are associated with increased risk of malignant transformation of periampullary adenomas. A retrospective study of 190 patients with FAP showed that the ''Gardner'' phenotype, which includes desmoid tumors, osteomas, and epidermoid cysts, is most often associated with mutations in codons 1395-1493, and that hepatoblastoma and brain cancer were seen only in patients with mutations in codons 457-1309.[18] With recent advances in molecular genetics, these genotype-phenotype correlations may eventually influence the accuracy and effectiveness of genetic testing, screening recommendations, and treatment.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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