Loss Heterozygosity LOH Loss of heterozygosity LOH is

Loss Heterozygosity (LOH) Loss of heterozygosity (LOH) is a common genetic event in cancer development, and is known to be involved in the somatic loss of wild-type alleles in many inherited cancer syndromes. The wider involvement of LOH in cancer is assumed to relate to unmasking a somatically mutated tumour suppressor gene through loss of the wild type allele. Cancer cells undergo multiple genetic and epigenetic hits in the development of tumorigenic phenotypes, including somatic point mutations, increases in copy number, gene deletions, gene rearrangements, translocations and promoter hypermethylation. These random events are selected for due to their effect on oncogenes, where the aberration activates the gene to promote tumorigenesis (e. g. KRAS, MYC), and on tumour suppressor genes (TSG), where the genetic or epigenetic aberrations is inactivating (e. g. TP 53, PTEN), since the normal function of these genes is to restrict tumorigenic potential.

Loss of heterozygosity (LOH) is a common genetic event in many cancer types, so-called because of the early observations of a change in polymorphic markers from a heterozygous state in the germline to an apparently homozygous state in the tumour DNA [2]. LOH is a general term that encompasses both LOH with copy number losses (CNL-LOH) and copy number neutral LOH (CNNLOH). In CNL-LOH all or part of a chromosome is deleted. CNN-LOH originates either through a homologous recombination event (“gene conversion”), or because the retained chromosome was duplicated either before or after the LOH event. LOH is strongly associated with loss of the wild-type allele in individuals with an inherited cancer predisposition syndrome and carry a germline mutation in genes such as RB 1 in retinoblastoma or BRCA 1 in breast and ovarian cancer.

There are several ways a cell can suffer loss of heterozygosity. An entire chromosome containing a normal allele may be lost due to failure of the chromosomes to segregate properly at mitosis (nondisjunction). Alternatively, an unbalanced exchange of genetic material can occur in a process called translocation, resulting in loss of a chromosomal region containing the normal gene. Sometimes when a normal gene is lost, a reduplication of the remaining chromosome with an abnormal gene occurs, leaving the cell with two abnormal gene copies. Normal genes may also be lost during normal mitotic recombination events or as a consequence of a point mutation in the second allele, leading to inactivation of the normal counterpart.

In hereditary cancer syndromes, individuals are called heterozygous (having one or more dissimilar gene pairs) because they start life with a germline mutation in one of the alleles linked to cancer susceptibility, but it is balanced by a normal counterpart. These individuals are predisposed to cancer because all their cells have already sustained the first hit to cancer-linked genes. If the critically needed normal suppressor gene that balances this germline mutation is lost at some time during an individual's life, a condition called loss of heterozygosity (LOH) occurs.

In 1971, Dr. Alfred Knudson proposed the two-hit hypothesis to explain the early onset at multiple sites in the body of an inherited form of cancer called hereditary retinoblastoma. Inheriting one germline copy of a damaged gene present in every cell in the body was not sufficient to enable this cancer to develop. A second hit (or loss) to the good copy in the gene pair could occur somatically, though, producing cancer. This hypothesis predicted that the chances for a germline mutation carrier to get a second somatic mutation at any of multiple sites in his/her body cells was much greater than the chances for a noncarrier to get two hits in the same cell. Tumor suppressors act recessive at the phenotypic level (both alleles must be mutated/lost for cancer to develop), but the "first hit" germline mutation at the genotypic level is actually inherited in an autosomal dominant fashion.

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