Mosaicism part 2

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In the majority of human cancers, there is no clear-cut mode of inheritance. This and other evidence suggest that cancer is a multigenic (oncogenes, tumor suppressor genes, MHC genes), multifactorial (radiation, chemicals, hormones, viruses, ultraviolet, diet, etc) and multistep (transformation, promotion, overt cancer) process.

2. Non-Mendelian Inheritance.

a. Mosaicism

i. Condition in which there are two or more cell lines, derived from a single zygote but differing genetically because of post-zygotic mutation, non-disjunction, or lyonization. Example cited in lecture were "Lines of Blaschko" which look like zebra striping and are the result of the migration of different epidermal cell lines during development.

ii. Creates sub-populations of cells with different genetic constitutions. Example given: Can have a female that is 46xx in one population of cell which are non-dysfunctional and 45xx in another population that show genetic effect. Visual example: Segmental neurofibromatosis may only see Café Ole Spots only in one quadrant of the body.

iii. Somatic cell mosaicism

1. As long as defect is in somatic cells and not germ cells, won’t create an inherited event

2. Usually less severely affected.

iv. Genomic mosaicism:

1. Seen when child is born with an autosomal dominant disorder but has phenotypically normal parents. Often this is a result of a new mutation in the egg or the sperm from which they were derived; as such, their siblings are neither affected nor at increased risk. Parents are counseled as such and then a second child is born with the same condition, which clearly violates the laws of Mendelian inheritance.

2. Explanation is that one of the parents experienced a post zygotic mutation during development that only affected some or all of the germ line cells. Thus, this person is a mosaic of normal somatic cells and abnormal germ cells. These persons are phenotypically normal but at a much greater risk of passing on the mutation to their offspring.

3. Classic example is Osteogenesis Imperfecta.

Loss of heterogeneity in cancers. Some childhood cancers occur when a cell accumulates two mutations or deletions in the same recessive tumor suppression gene. The imprinting theory may explain that the event, which inactivates the first copy of the tumor suppressor gene, is the genomic imprinting of the maternal/paternal allele. Loss of the other gene leads to loss of tumor suppression.

neurofibromatosis type 2, however, children of affected females show earlier and more severe symptoms than children of affected males.

Mosaicism refers to the presence of the normal (wild type) genotype as well as the abnormal (mutant) genotype in the germ-line of an individual. In this case, the parent will not have the phenotype but the offspring will.

http://home.att.net/~dorak/genetics/notes06.html

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http://www.fondazioneagarini.org/a_laterra2.htm

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