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Loss of heterozygosity: Wikis


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Loss of heterozygosity (LOH) in a cell represents the loss of normal function of one allele of a gene in which the other allele was already inactivated. This term is mostly used in the context of oncogenesis; after an inactivating mutation in one allele of a tumor suppressor gene occurs in the parent's germline cell, it is passed on to the zygote resulting in an offspring that is heterozygous for that allele. In oncology, loss of heterozygosity occurs when the remaining functional allele in a somatic cell of the offspring becomes inactivated by mutation. This results in no normal tumor suppressor being produced and this could result in tumorigenesis.


In cancer

It is a common occurrence in cancer, where it indicates the absence of a functional tumor suppressor gene in the lost region. However, many people remain healthy with such a loss, because there still is one functional gene left on the other chromosome of the chromosome pair. However, the remaining copy of the tumor suppressor gene can be inactivated by a point mutation, leaving no tumor suppressor gene to protect the body. Loss of heterozygosity does not imply a reversal to the homozygous state.


Knudson Two Hit Hypothesis of Tumorigenesis

  • First Hit: The first hit is classically thought of as a point mutation that inactivates one copy of a tumor suppressor gene (TSG), such as Rb1. In hereditary cancer syndromes, individuals are born with the first hit. The individual does not develop cancer at this point because the remaining TSG on the other allele is still functioning normally.
  • Second Hit: The second hit is classically thought of as a large deletion that results in loss of functioning TSG allele. This leaves only a non-functioning copy of the TSG, and the individual goes on to develop cancer.

Copy Neutral LOH

Copy neutral LOH can be biologically equivalent to the second hit in the Knudson hypothesis.[1] Other names for copy neutral LOH in tumor cells are acquired uniparental disomy or gene conversion. Acquired UPD is quite common in both hematologic and solid tumors, and is reported to constitute 20 to 80% of the LOH seen in human tumors.[2][3][4][5] Virtual karyotypes using SNP-based arrays can provide genome-wide copy number and LOH status, including detection of copy neutral LOH. Copy neutral LOH cannot be detected by arrayCGH, FISH, or conventional cytogenetics. SNP-based arrays are preferred for virtual karyotyping of tumors and can be performed on fresh or paraffin-embedded tissues.

Copy neutral LOH/uniparental disomy
SNP array Virtual karyotype of a colorectal carcinoma (whole genome view) demonstrating deletions, gains, amplifications, and acquired UPD (copy neutral LOH).


The classical example of such a loss of protecting genes is hereditary retinoblastoma, in which one parent's contribution of the tumor suppressor Rb1 is flawed. Although most cells will have a functional second copy, chance loss of heterozygosity events in individual cells almost invariably lead to the development of this retinal cancer in the young child.


Loss of heterozygosity can be identified in cancers by noting the presence of heterozygosity at a genetic locus in an organism's germline DNA, and the absence of heterozygosity at that locus in the cancer cells. This is often done using polymorphic markers, such as microsatellites or single nucleotide polymorphisms, for which the two parents contributed different alleles. Genome-wide LOH status can be assessed in fresh or paraffin embedded tissue samples using SNP array virtual karyotyping.

See also


  1. ^ Mao X, Young BD, Lu YJ. The application of single nucleotide polymorphism microarrays in cancer research. Curr Genomics. 2007 Jun;8(4):219-28.
  2. ^ Gondek LP, Tiu R, O'Keefe CL, Sekeres MA, Theil KS, Maciejewski JP. Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML. Blood. 2008 Feb 1;111(3):1534-42.
  3. ^ Beroukhim R, Lin M, Park Y, Hao K, Zhao X, Garraway LA, et al. Inferring loss-of-heterozygosity from unpaired tumors using high-density oligonucleotide SNP arrays. PLoS Comput Biol. 2006 May;2(5):e41.
  4. ^ Ishikawa S, Komura D, Tsuji S, Nishimura K, Yamamoto S, Panda B, et al. Allelic dosage analysis with genotyping microarrays. Biochem Biophys Res Commun. 2005 Aug 12;333(4):1309-14.
  5. ^ Lo KC, Bailey D, Burkhardt T, Gardina P, Turpaz Y, Cowell JK. Comprehensive analysis of loss of heterozygosity events in glioblastoma using the 100K SNP mapping arrays and comparison with copy number abnormalities defined by BAC array comparative genomic hybridization. Genes Chromosomes Cancer. 2008 Mar;47(3):221-37.


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